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Ulcer Prevention in Long-term Users of Nonsteroidal Anti-inflammatory Drugs
Results of a Double-blind, Randomized, Multicenter, Active- and Placebo-Controlled Study of Misoprostol vs Lansoprazole
David Y. Graham, MD;
Naurang M. Agrawal, MD;
Donald R. Campbell, MD;
Marian M. Haber, MD;
Cyndy Collis, BS;
Nancy L. Lukasik, BSN;
Bidan Huang, PhD
Arch Intern Med. 2002;162:169-175.
ABSTRACT
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Background Studies that report prevention of ulcer recurrence among long-term users
of nonsteroidal anti-inflammatory drugs (NSAIDs) that do not stratify for Helicobacter pylori status may not be generalizable to
the large population of individuals without H pylori.
Methods This was a prospective, double-blind, multicenter, active- and placebo-controlled
study among 537 patients without H pylori who were
long-term users of NSAIDs and who had a history of endoscopically documented
gastric ulcer. Patients were randomized to receive placebo, 200 µg of
misoprostol 4 times a day, or 15 or 30 mg of lansoprazole once daily for 12
weeks. Ulcer status was determined by endoscopy at 4, 8, and 12 weeks.
Results Patients receiving lansoprazole (15 or 30 mg) remained free from gastric
ulcer longer than those who received placebo (P<.001)
but for a shorter time than those who received misoprostol. By week 12, the
percentages of gastric ulcer–free patients were as follows: placebo,
51% (95% confidence interval [CI], 41.1%-61.3%); misoprostol, 93% (95% CI,
87.2%-97.9%); 15-mg lansoprazole, 80% (95% CI, 72.5%-87.3%); and 30-mg lansoprazole,
82% (95% CI, 75.0%-89.6%). A significantly higher proportion of patients in
the misoprostol group reported treatment-related adverse events and early
withdrawal from the study. When the impact of withdrawals on ulcer development
was considered (as failures), therapy was successful for 69% for each of the
active treatment groups and 35% for the placebo group.
Conclusions Proton pump inhibitors such as lansoprazole are superior to placebo
for the prevention of NSAID-induced gastric ulcers but not superior to misoprostol,
800 µg/d. When the poor compliance and potential adverse effects associated
with misoprostol are considered, proton pump inhibitors and full-dose misoprostol
are clinically equivalent.
INTRODUCTION
NONSTEROIDAL anti-inflammatory drugs (NSAIDs) are widely used for the
relief of pain and inflammation associated with arthritis and other musculoskeletal
disorders. The benefit in terms of relief from pain and stiffness is accompanied
by the risk of developing a peptic ulcer and a serious, life-threatening ulcer
complication.1 Several studies2-3
have been performed in search of cotherapies that might prevent NSAID-induced
ulcers and ulcer complications. The use of the synthetic prostaglandin, misoprostol
(Cytotec; Pharmacia, Bridgewater, NJ), as a form of replacement therapy repeatedly
has been shown to prevent NSAID-induced gastroduodenal ulcers and reduce the
incidence of life-threatening ulcer complications.4-14
In contrast, neither the topical agent sucralfate nor usual doses of histamine2 (H2)-receptor antagonists have been shown to be effective.6, 11, 15-18
Increased doses of H2-receptor antagonists were more effective
than lower doses, but overall, the success rate was modest.17, 19-23
Recently, more profound acid suppression with proton pump inhibitors
has been reported as being associated with acceleration of ulcer healing and
prevention of ulcer relapse among long-term users of NSAIDs.10, 18
Neither of the 2 large multicenter studies comparing the proton pump inhibitor
omeprazole with misoprostol (Omeprazole versus Misoprostol for NSAID-Induced
Ulcer Management [OMNIUM])10 or ranitidine
(Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment [ASTRONAUT])18 for the prevention of ulcer recurrence among long-term
users of NSAIDs presented analyses regarding the association between Helicobacter pylori status and prevention of ulcer relapse.
Subsequent analyses showed that H pylori status had
a marked effect on outcome and the development of endoscopic ulcers, with H pylori infection being associated with an overrepresentation
of duodenal ulcers.24 Separation of the prevention
of ulcers that are unequivocally related to NSAID use and not to H pylori infection is important to the clinician because there are
now considerable data to suggest the gastroduodenal outcome in long-term users
of NSAIDs differs among those with and without H pylori infection.24-25 In addition,
the presence of an ulcer in an H pylori–infected
NSAID user is an indication for eradication of the infection because it is
impossible to ascertain which was the actual cause of the ulcer. There is
also increasing evidence that the use of antisecretory therapy with H2-receptor antagonists or proton pump inhibitors is associated with
acceleration of corpus gastritis in those with H pylori infection,26-31
which may make it prudent to eradicate H pylori in
those for whom long-term NSAID and antisecretory cotherapy is contemplated.
This study attempted to overcome some of the shortcomings of the OMNIUM
and ASTRONAUT studies.10, 18 Although
the OMNIUM study evaluated 2 doses of the proton pump inhibitor for ulcer
healing, this comparison was not extended to the ulcer prevention portion
of the study, in which only the lower dose, 20 mg, was used.10
Those studies also used a dose of misoprostol essentially devoid of antisecretory
activity and a dose of ranitidine that had been proven to be subtherapeutic
for this indication (ie, 400 µg/d and 300 mg/d, respectively).11-12,15-16 In
addition, they did not separate unequivocal NSAID ulcers from those complicated
by H pylori infection. We report the results of a
large, double-blind, multicenter, randomized, active- and placebo-controlled
study designed to identify the optimal therapy for preventing unequivocal
NSAID-induced gastric or duodenal ulcers. This study compared 2 doses of lansoprazole
(Prevacid; TAP Pharmaceutical Products Inc, Lake Forest, Ill) (15 and 30 mg)
with the full therapeutic dose of misoprostol (800 µg/d) and placebo
for preventing ulcer relapse among patients who continued NSAID use and were
known to be free of H pylori.
PATIENTS AND METHODS
Entry criteria included being 18 years or older, history of endoscopically
documented gastric ulcer with or without coexisting duodenal ulcer or gastrointestinal
bleeding, and treatment with stable, full therapeutic doses of an NSAID (with
the exception of nabumetone or aspirin [ 1300 mg/d; low-dose aspirin for
cardiovascular protection was permitted]) for at least the previous month.
Two thirds of patients enrolled in this study had previously completed participation
in a healing trial for NSAID-associated gastric ulcer. Pretreatment H pylori status was determined by a rapid urease test (CLOtest;
Tri-Med Specialties Inc, Draper, Utah) or histologic analysis, which was graded
according to the updated Sydney System.32 Those
patients positive for H pylori were excluded, as
were those with gastric or duodenal ulcer crater (5 mm in diameter) or
severe erosions (defined as >25 erosions) or erosive reflux esophagitis. Use
of a proton pump inhibitor, H2-receptor antagonist, or misoprostol
within 24 hours before study entry was not permitted. Approval for the study
was obtained from the institutional review board of each of the 63 participating
centers in North America, and written informed consent was obtained before
patient enrollment.
STUDY DESIGN
Patients were randomly assigned in blocks of 4 to receive 12 weeks of
placebo, 200 µg of misoprostol 4 times daily with or after meals and
a bedtime snack, or 15 or 30 mg of lansoprazole once daily before breakfast.
Both patients and investigators remained masked to treatment group (with the
exception of those receiving misoprostol). Patients received antacid tablets
(Gelusil; Parke-Davis, Morris Plains, NJ) for use as needed for symptom relief.
Patients were instructed to avoid antiulcer medication other than study medication,
ulcerogenic medication (except NSAIDs or aspirin as noted herein), and agents
that alter hemostasis.
Compliance and adverse events were assessed by returned pill count and
direct questioning at each treatment visit. Symptoms were assessed on a daily
basis by patient diary, where patients recorded episodes of daytime and nighttime
abdominal pain (defined as none, mild, moderate, or severe), study drug and
NSAID dosing information, and frequency of antacid consumption. Endoscopy
with biopsy was performed each month for 3 consecutive months to determine
the presence of a gastric ulcer(s). Esophageal and duodenal mucosa were also
evaluated.
STATISTICAL ANALYSIS
Statistical analyses were conducted using statistical software (SAS
version 6.12; SAS Institute Inc, Cary, NC). Given a gastric ulcer prevention
rate of 92% for one of the active treatment groups at the week 12 evaluation
and a lower limit of 10%, a sample size of 120 subjects per treatment group
would have 81% power to show noninferiority between active treatment groups.
Per-protocol and intent-to-treat analyses were conducted for ulcer occurrence,
abdominal pain, and antacid use, the latter 2 based on patient daily diary
data. For all efficacy and safety end points, pairwise comparisons were made
between treatment groups.
The comparability of the treatment groups at baseline was assessed with
respect to demographic variables using the  2 test (F test
for age) and medical and social histories by the Fisher exact test. Baseline
severity of symptoms, based on an investigator interview, was compared among
the treatment groups using the Cochran-Mantel-Haenszel method for ordered
response variables.
Life table methods were used to estimate the ulcer incidence rates.
The life table analysis of time to ulcer occurrence was performed using the
Cochran-Mantel-Haenszel method to test treatment differences between groups.
Factors including age; sex; race; treatment for an acute NSAID-associated
gastric ulcer immediately before study enrollment; hiatal hernia; investigator;
alcohol, tobacco, or caffeine use; and acute baseline gastric ulcer size (measured
during a screening endoscopy conducted when the subject participated in a
previous healing study) were controlled for in the analysis. The treatment
groups were compared with respect to percentage of days with and average severity
of daytime and nighttime abdominal pain and amount of antacid use based on
diary data using the Wilcoxon 2-sample test. The Fisher exact test was used
to compare the incidence of treatment-related adverse events (defined as possibly
or probably related) between the treatment groups.
RESULTS
A total of 537 patients were randomized to receive placebo (n = 134),
200 µg of misoprostol 4 times a day (n = 134), 15 mg of lansoprazole
once daily (n = 136), or 30 mg of lansoprazole once daily (n = 133) for 12
weeks. Two patients (1 each in the placebo and 30-mg lansoprazole groups)
who did not take study medication were not included in the intent-to-treat
analysis of ulcer occurrence or adverse events (Table 1). Eighty-two (15%) of the 537 enrolled patients were excluded
from the per-protocol analyses because of noncompliance (eg, fewer than 14
days and/or less than 67% of prescribed study medication taken during the
treatment period; n = 33), no evaluable endoscopy after the initiation of
treatment (n = 21), positive for H pylori at baseline
(n = 15), inappropriate ulcer history (n = 6), and other reasons (n = 10).
(Three patients were excluded in 2 categories but were counted once in the
total of 82 excluded patients.) The reasons for exclusion from the per-protocol
analyses were generally balanced across the treatment groups with the exception
that more patients in the misoprostol group did not take the minimum amount
and/or complete the minimum duration necessary for evaluability (7, 19, 1,
and 6 patients in the placebo, misoprostol, 15-mg lansoprazole, and 30-mg
lansoprazole groups, respectively).
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Table 1. Patient Disposition by Treatment Group
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The treatment groups were well matched at baseline, including demographic
characteristics, social history, previous history of gastrointestinal disorders,
recent treatment for an NSAID-associated gastric ulcer, and severity of symptoms
(Table 2). Most patients reported
no daytime or nighttime abdominal pain at baseline. Forty percent of the patients
used ibuprofen, 35% used naproxen, 32% used diclofenac, 22% used aspirin or
aspirin combinations, 17% used piroxicam, and 34% used other NSAIDs. The distribution
across treatment groups was similar. Patients could have taken more than 1
NSAID.
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Table 2. Pretreatment Characteristics of Intent-to-Treat Patients*
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ULCER PREVENTION
Evaluable patients taking an NSAID in the 15- and 30-mg lansoprazole
groups remained free from gastric ulcer significantly longer than those who
received placebo (P<.001). There was no difference
between lansoprazole dosage groups (P = .62). Evaluable
patients in the misoprostol group remained free of gastric ulcer significantly
longer than those who received placebo (P<.001),
15-mg lansoprazole (P = .01), or 30-mg lansoprazole
(P = .04). These observations were unaffected after
adjustment for potentially influential factors, including age, sex, race,
treatment for an acute NSAID-associated gastric ulcer before study enrollment,
hiatal hernia, investigator, and alcohol, tobacco, or caffeine use. There
were no statistically significant differences between any of the active treatment
groups after adjusting for acute baseline gastric ulcer size. Similar trends
were observed in the results of the intent-to-treat analysis of gastric ulcer
prevention data throughout the 12-week treatment period.
Absence of a gastric ulcer after 8 or 12 weeks of treatment was different
among those receiving placebo, misoprostol, or lansoprazole. By week 12, the
percentages of evaluable patients who were free of gastric ulcer were 51%
(95% confidence interval [CI], 41.1%-61.3%), 93% (95% CI, 87.2%-97.9%), 80%
(95% CI, 72.5%-87.3%), and 82% (95% CI, 75.0%-89.6%) for the respective treatment
groups (Figure 1).
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Figure 1. Percentage of evaluable patients
remaining free from gastric ulcer disease during therapy as calculated by
life table methods. Patients in the misoprostol group remained free of gastric
ulcer significantly longer than those who received placebo (P<.001), 15 mg of lansoprazole (P = .01),
or 30 mg of lansoprazole (P = .04). The proportions
of intent-to-treat patients remaining ulcer free at the final evaluation were
51%, 92%, 83%, and 79% for the placebo, misoprostol, 30-mg lansoprazole, and
15-mg lansoprazole groups, respectively.
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When prevention rates were analyzed based on the development of gastric
or duodenal ulcers (gastroduodenal ulcers), those in the misoprostol, 15-mg
lansoprazole, or 30-mg lansoprazole groups remained free of ulcer for a significantly
longer period compared with those who received placebo (P<.001). There was no statistical difference between any 2 of the
active treatments for time to occurrence of gastroduodenal ulcers (Figure 2).
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Figure 2. Percentage of evaluable patients
remaining free from gastric and duodenal ulcer disease during therapy as calculated
by life table methods. Those in the misoprostol, 15-mg lansoprazole, and 30-mg
lansoprazole groups remained ulcer free for a significantly longer period
compared with those who received placebo (P<.001).
The difference between any 2 of the active treatments for time to occurrence
of gastroduodenal ulcer was not statistically significant. The proportions
of intent-to-treat patients remaining ulcer free at the final evaluation were
47%, 88%, 83%, and 79% for the placebo, misoprostol, 30-mg lansoprazole, and
15-mg lansoprazole groups, respectively.
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To evaluate the impact of the early patient withdrawals from the misoprostol
group, the worst-case scenario, where patients who withdrew from the study
prematurely (eg, because of an adverse event) were classified as a treatment
failure (eg, equivalent to having a gastric ulcer), was evaluated. In this
scenario, the proportion of patients who were treatment successes were identical
for the misoprostol and lansoprazole groups and 2-fold higher than that for
the placebo group (69% for each treatment group vs 35% for placebo). When
those patients withdrawing prematurely were classified as the worse case (ie,
having had a gastric or duodenal ulcer), the percentages of patients remaining
free from gastroduodenal ulcer disease throughout the study period were 34%,
67%, 69%, and 68% for the placebo, misoprostol, 15-mg lansoprazole, and 30-mg
lansoprazole groups, respectively.
PATIENT DIARY RESULTS
Lansoprazole-treated patients experienced significantly less severe
and significantly fewer days with daytime abdominal pain than evaluable misoprostol-treated
patients based on analyses of patient diaries (Table 3). Patients in the 15-mg lansoprazole group also had significantly
less severe (P = .01) and significantly fewer days
(P = .001) with nighttime abdominal pain than those
in the misoprostol group. Antacid use was significantly less (P<.001 for each pairwise comparison) among patients in the lansoprazole
groups compared with patients in the misoprostol and placebo groups based
on fewer antacid tablets taken per day and a smaller percentage of days of
antacid use. Similar trends were observed in the results of the intent-to-treat
analysis of diary data throughout the 12-week treatment period.
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Table 3. Mean Diary Results During the 12-Week Treatment Period
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COMPLIANCE AND ADVERSE EFFECTS
More than 90% of patients in the placebo and 15- and 30-mg lansoprazole
groups were compliant with study medication, compared with 73% of patients
in the misoprostol group (P<.001). Thirty-eight
(7%) of the 535 patients discontinued use of the study medication prematurely
primarily because of an adverse event (9, 14, 4, and 10 patients in the placebo,
misoprostol, 15-mg lansoprazole, and 30-mg lansoprazole groups, respectively).
A significantly higher percentage of patients in the misoprostol group
(31%, 41/134) reported a treatment-related adverse event compared with each
of the other treatment groups: 13 (10%) of 133 patients in the placebo group,
10 (7%) of 136 patients in the 15-mg lansoprazole group, and 21 (16%) of 132
patients in the 30-mg lansoprazole group (P<.001
for misoprostol vs placebo and vs 15-mg lansoprazole; P = .006 for misoprostol vs 30-mg lansoprazole; P = .04 for 15-mg lansoprazole vs 30-mg lansoprazole). The most commonly
reported treatment-related event was diarrhea, which was more common in the
misoprostol group (22%, 29/134) compared with the placebo (3%, 4/133), 15-mg
lansoprazole (3%, 4/136), and 30-mg lansoprazole (7%, 9/132) groups (P  .001 for each comparison vs misoprostol). Patients
in the misoprostol group also had a significantly greater incidence of treatment-related
abdominal pain (6%, 8/134) and nausea (4%, 6/134) compared with patients in
the 15-mg lansoprazole group (0/136 for both symptoms) (P = .003 and P = .01, respectively). One patient
(in the 15-mg lansoprazole group) experienced an upper gastrointestinal tract
hemorrhage during the study.
COMMENT
Studies designed to evaluate ulcer prevention among long-term users
of NSAIDs have varied regarding study design, data analysis, and results presented.
Several trials with antisecretory drugs showed the outcome differed with gastric
ulcers compared with duodenal ulcers and H pylori–infected
ulcers compared with ulcers not infected with H pylori.11, 15-17 None
were randomized with regard to H pylori status. That
is unfortunate since randomization would have ensured that if there were a
difference in outcome in relation to H pylori status,
the overall results of the study would not hinge on the proportion of patients
with (or without) the infection. A study conducted in Hong Kong of patients
with bleeding ulcers who were long-term users of NSAIDs shows the importance
of this stratification. Even though the background rate of H pylori infection is high in Hong Kong (>80%), the proportion of study
patients with complicated ulcer and H pylori infection
was only 45.5%.33 Similarly, reanalysis of
the outcomes of the OMNIUM10 and ASTRONAUT18 trials showed that H pylori
infection has an important impact on outcome.24
The lowest effective dose of misoprostol (400 µg/d) was superior to
omeprazole (8.2% vs 16.6%, respectively, developed gastric ulcers) (P = .04) and low-dose ranitidine (150 mg twice daily) was
equivalent to omeprazole (14.6% vs 11.6%, respectively) (P = .56) for the prevention of gastric ulcers in patients with unequivocal
NSAID ulcers who were long-term users of NSAIDs. Among those with H pylori infection, misoprostol was similar to omeprazole (5.7% vs
9.2%, respectively) (P = .48), and omeprazole was
superior to low-dose ranitidine (1.9% vs 17%, respectively) (P = .001).24
The present study was designed to avoid those shortcomings by comparing
2 doses of a proton pump inhibitor (lansoprazole) with the full therapeutic
dose of misoprostol and placebo in patients with unequivocal NSAID-associated
ulcers. As with omeprazole, lansoprazole was superior to placebo, with no
evidence of a major dose response effect. We confirmed that gastric ulcers
recurred during the 12-week follow-up in a greater percentage of patients
receiving placebo compared with those receiving lansoprazole or misoprostol.
The results with gastroduodenal ulcer retained the same rank order.
These conclusions appear to be in sharp contrast to the reported poor
overall results of misoprostol vs omeprazole in the OMNIUM study.10 One difference was that the OMNIUM study used a dose
of misoprostol with minimal antisecretory activity that ensured any benefit
from antisecretory activity would be absent. To claim superiority, the OMNIUM
study also included end points other than ulcer prevention (eg, the presence
of heartburn) to obtain "superiority."10, 34
In contrast, we compared full-dose misoprostol, 800 µg/d, with 2 doses
of lansoprazole.
Endoscopic ulcer prevention does not necessarily equate with prevention
of ulcer complications. In the large MUCOSA (Misoprostol Ulcer Complication
Outcome Safety Assessment) trial,14 misoprostol
was shown to reduce serious NSAID-induced upper gastrointestinal tract complications
by 40% compared with placebo. The median dose of misoprostol in that study
was 800 µg/d (mean dose, 683 µg/d). In that study, a history of
peptic ulcer or ulcer-related bleeding was an important prognostic factor
for identifying those who would develop ulcer complications and currently
would prompt a test-and-treat strategy with regard to H
pylori infection. Whether this would have influenced outcome is not
known. Given that the risk of recurrent hemorrhage after bleeding from an H pylori ulcer is approximately 1% per month compared with
approximately 1% to 2% per year in those with ulcer disease who have not experienced
a complication, it seems likely that it might. Thus, failure to identify and
treat H pylori infection in the MUCOSA study may
have biased the outcome. Studies are needed to test whether a proton pump
inhibitor can prevent life-threatening ulcer complications among long-term
users of NSAIDs. Because misoprostol and antisecretory drugs act by different
mechanisms and low-dose misoprostol is better tolerated than full-dose therapy
(but has a lower rate of protection),12 the
combination of low-dose misoprostol and a proton pump inhibitor might provide
optimum results. Thus, the ideal comparison might be a proton pump inhibitor
with or without low-dose misoprostol (eg, 400 µg/d) vs placebo. However,
such studies are unlikely to be conducted if the COX-2 inhibitors prove to
eliminate life-threatening NSAID ulcer complications.
This study also showed that lansoprazole has several theoretical and
practical advantages over misoprostol, including once-a-day dosing and lack
of adverse effects. Compliance is a significant problem with misoprostol because
full dosage requires 4-times-daily dosing, and the proportion with gastrointestinal
adverse effects is dose dependent. This observation was demonstrated in this
study: compliance with misoprostol was significantly inferior to that with
lansoprazole. When the effect of noncompliance on ulcer development was considered,
the percentage of patients remaining free from gastroduodenal ulcer disease
was approximately 2-fold higher with active treatment vs placebo. As expected,
noncompliance was less of a problem with misoprostol in the OMNIUM study,
because a lower dose was used.10 Thus, it is
apparent that despite the statistical advantage of misoprostol over proton
pump inhibitors for the prevention of ulcer relapse in long-term users of
NSAIDs, there is little, if any, practical advantage.
AUTHOR INFORMATION
Accepted for publication April 30, 2001.
Dr Graham is engaged in research activities supported by Abbott Laboratories,
Astra USA (Westborough, Mass), Astra-Merck, Enteric Products Inc (Stony Brook,
NY), Glaxo Wellcome Inc (Research Triangle Park, NC), Meretek Diagnostics
(Nashville, Tenn), Merck Sharp & Dohme (Essex, England), Merck (West Point,
Pa), Proctor & Gamble (Cincinnati, Ohio), SmithKline Diagnostics (San
Jose, Calif), and TAP Pharmaceutical Products Inc. Dr Agrawal is engaged in
research activities supported by Pharmacia (Bridgewater, NJ), Pfizer Inc (New
York, NY), and TAP Pharmaceuticals. Dr Campbell is engaged in research activities
supported by AstraZenica (Wilmington, Del), Merck, TAP Pharmaceuticals, Wyeth-Ayerst
(Philadelphia, Pa), and Janssen Pharmaceutica (Titusville, NJ).
This study was supported by a grant from TAP Pharmaceutical Products
Inc.
Presented at Digestive Disease Week and the 100th Annual Meeting of
the American Gastroenterological Association, Orlando, Fla, May 16-19, 1999.
Dr Haber performed the histologic and H pylori
analyses for this study. Ms Collis managed study operations and authored the
clinical report. Ms Lukasik oversaw study operations and authored the clinical
report. Dr Huang conducted the statistical analyses of data for this study.
We thank TAP Pharmaceutical Products Inc for their support of this research
project and Sandra Norris, PharmD, for her help with the manuscript.
| Study Group
NSAID-Associated Gastric Ulcer Prevention Study Group
Naurang M. Agrawal, MD, Durham, NC; Robert J. Bailey, MD, Alberta, Canada;
Charles F. Barish, MD, Raleigh, NC; Thomas Bianchi, MD, Tallassee, Ala; Charles
Allen Birbara, MD, Worcester, Mass; Phillip C. Bird, MD, Norman, Okla; Joel
Block, MD, Chicago, Ill; Kevin Block, MD, Madison, Wis; Jeffrey R. Breiter,
MD, Manchester, Conn; Jacques Caldwell, MD, Gainesville, Fla; Donald R. Campbell,
MD, Kansas City, Mo; Stuart Chen, MD, Kansas City; Charles L. Collip, MD,
Portland, Ore; Carleton Davis, MD, Monroe, Wis; Francis Dega, MD, Boise, Idaho;
Jacinto DelMazo, MD, Atlanta, Ga; Michael DeMicco, MD, Anaheim, Calif; James
T. Doyle, MD, Spokane, Wash; Margaret Drehobl, MD, San Diego, Calif; Sudhir
K. Dutta, MD, Baltimore, Md; Raymond Federman, MD, Akron, Ohio; Roy Fleischman,
MD, Dallas, Tex; Fred C. Fowler, MD, Charlotte, NC; Syam P. Gaddam, MD, Garden
Grove, Calif; William Harford, MD, Dallas; W. John Henry, MD, Greer, SC; Samuel
Ho, MD, Minneapolis, Minn; Keith P. Hussey, MD, Naples, Fla; David S. James,
DO, Tulsa, Okla; David Johnson, MD, Norfolk, Va; Lawrence Judy, MD, Evansville,
Ind; David Kalin, MD, Clearwater, Fla; Mukul Khandelwal, MD, Hershey, Pa;
David G. Kogut, MD, Statesville, NC; George Kovalm, MD, Portland; Richard
Krause, MD, Chattanooga, Tenn; Frank Lanza, MD, Houston, Tex; Duncan McCall,
MD, Statesville; Aubrey D. McElroy, MD, Elizabethtown, NJ; Doris Mee-Lee,
MD, Honolulu, Hawaii; Morry Moskovitz, MD, Beaver, Pa; Daniel J. Pambianco,
MD, Charlottesville, Va; Alexander Perrian, MD, Tucson, Ariz; Terry Ponich,
MD, London, Ontario; Ronald E. Pruitt, MD, Nashville, Tenn; Jehangie Rao,
MD, Wayne, Mich; Ralph Rothenberg, MD, Youngstown, Ohio; Seymour Sabesin,
MD, Chicago; Michael A. Safdi, MD, Cincinnati, Ohio; Bruce Sahba, MD, San
Diego; Thomas Schnitzer, MD, Chicago; Howard I. Schwartz, MD, Miami, Fla;
Nayan R. Shah, MD, Hollywood, Md; Paul Siami, MD, Evansville; David R. Silvers,
MD, Metairie, La; Thomas J. Sobieski, MD, Richmond, Va; Stephen Sontag, MD,
Hines, Ill; Lewis Strong, MD, Longmont, Colo; John A. Walker, MD, Medford,
Ore; Peter Winkle, MD, Cypress, Calif; Barry D. Winston, Houston; James Wolosin,
MD, Escondido, Calif; Lawrence D. Wruble, MD, Memphis, Tenn.
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Corresponding author and reprints: David Y. Graham, MD, Veterans
Affairs Medical Center (111D), 2002 Holcombe Blvd, Room 3A-320, Houston, TX
77030-4211 (e-mail: dgraham{at}bcm.tmc.edu).
From the Department of Medicine, Veterans Affairs Medical Center, Houston,
Tex (Dr Graham); Department of Medicine, Duke University Medical Center, Durham,
NC (Dr Agrawal); Department of Medicine, University of Kansas School of Medicine,
University of Missouri, Kansas City, School of Medicine, Department of Veterans
Affairs Medical Center, and Saint Luke's Hospital, Kansas City (Dr Campbell);
MCP Hahnemann University, Philadelphia, Pa (Dr Haber); TAP Pharmaceutical
Products Inc, Lake Forest, Ill (Mss Collis and Lukasik); and Abbott Laboratories,
Abbott Park, Ill (Dr Huang).
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6. Agrawal NM, Roth S, Graham DY, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal
anti-inflammatory drug-induced gastric ulcer: a randomized, controlled trial. Ann Intern Med. 1991;115:195-200.
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8. Graham DY, White RH, Moreland LW, et al for the Misoprostol Study Group. Duodenal and gastric ulcer prevention with misoprostol in arthritis
patients taking NSAIDs. Ann Intern Med. 1993;119:257-262.
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9. Graham DY. Prevention of gastroduodenal injury induced by chronic nonsteroidal
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10. Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal
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11. Raskin JB, White RH, Jaszewski R, Korsten MA, Schubert TT, Fort JG. Misoprostol and ranitidine in the prevention of NSAID-induced ulcers:
a prospective, double-blind, multicenter study. Am J Gastroenterol. 1996;91:223-227.
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12. Raskin JB, White RH, Jackson JE, et al. Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory
drug-induced gastric and duodenal ulcers: a comparison of three regimens. Ann Intern Med. 1995;123:344-350.
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misoprostol—from hypothesis to clinical practice. Dig Dis Sci. 1998;43:447-458.
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14. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients
with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs:
a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123:241-249.
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15. Ehsanullah RS, Page MC, Tildesley G, Wood JR. Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory
drugs: controlled trial of ranitidine. BMJ. 1988;297:1017-1021.
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17. ten Wolde S, Dijkmans BA, Janssen M, Hermans J, Lamers CB. High-dose ranitidine for the prevention of recurrent peptic ulcer disease
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18. Yeomans ND, Tulassay Z, Juhasz L, et al for Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated
Ulcer Treatment (ASTRONAUT) Study Group. A comparison of omeprazole with ranitidine for ulcers associated with
nonsteroidal antiinflammatory drugs. N Engl J Med. 1998;338:719-726.
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21. Hudson N, Taha AS, Russell RI, et al. Famotidine for healing and maintenance in non-steroidal anti-inflammatory
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22. Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused
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23. Simon TJ, Berger ML, Hoover ME, Stauffer LA, Berline RG. A dose ranging study of famotidine in prevention of gastroduodenal
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gastropathy. In: Hunt RH, Tytgat CN, eds. Helicobacter pylori: Basic Mechanisms to Clinical Cure 2000. Dordrecht, the Netherlands:
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27. Klinkenberg-Knol EC, Festen HP, Jansen JB, et al. Long-term treatment with omeprazole for refractory reflux esophagitis:
efficacy and safety. Ann Intern Med. 1994;121:161-167.
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cell growth, and gastritis. Gastroenterology. 1993;104:1356-1370.
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29. Meining A, Kiel G, Stolte M. Changes in Helicobacter pylori-induced gastritis
in the antrum and corpus during and after 12 months of treatment with ranitidine
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30. Meining A, Bosseckert H, Caspary WF, Nauert C, Stolte M. H2-receptor antagonists and antacids have an aggravating effect on Helicobacter pylori gastritis in duodenal ulcer patients. Aliment Pharmacol Ther. 1997;11:729-734.
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31. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori
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32. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis: the updated Sydney System:
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33. Chan FK, Sung JJ, Suen R, et al. Does eradication of Helicobacter pylori impair
healing of nonsteroidal anti-inflammatory drug associated bleeding peptic
ulcers? a prospective randomized study. Aliment Pharmacol Ther. 1998;12:1201-1205.
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