Ulcer Prevention in Long-term Users
`of Nonsteroidal Anti-inflammatory Drugs
`
`Results of a Double-blind, Randomized, Multicenter, A ctive- 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; Bidnn Huang, PhD
`
`Background: Studies that report prevention of ulcer re(cid:173)
`currence among long-term users of nonsteroidal anti(cid:173)
`inflammatory drugs (NSAIDs) that do not stratify for Heli(cid:173)
`cobacter pylori status may not be generalizable to the large
`population of individuals without H pylori.
`
`Methods: This was a prospective, double-blind, multi(cid:173)
`center, 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 docu(cid:173)
`mented gastric ulcer. Patients were randomized to re(cid:173)
`ceive placebo, 200 pg of misoprostol 4 times a day, or 15
`or 30 mg of lansoprazole once daily for 12 weeks. Ulcer
`status was detennined 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<.OOl ) 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%); misopros(cid:173)
`tol, 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 re(cid:173)
`ported treatment-related adverse events and early with(cid:173)
`drawal 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 lanso(cid:173)
`prazole are superior to placebo for the prevention of
`NSAID-induced gastric ulcers but not superior to rniso(cid:173)
`prostol, 800 pgld. When the poor compliance and po(cid:173)
`tential adverse effects associated with misoprostol are con(cid:173)
`sidered, proton pump inhibitors and full-dose misoprostol
`are clinically equivalent.
`
`Arch Intern Med. 2002;162:169-175
`
`N ONSTEROIDALanti-inflam(cid:173)
`
`matory drugs (NSAIDs)
`are widely used for the
`relief of pain and inflam(cid:173)
`mation associated with
`arthritis and other musculoskeletal dis(cid:173)
`orders. The benefit in tenns of relief from
`pain and stiffness is accompanied by the
`risk of developing a peptic ulcer and a se(cid:173)
`rious, life-threatening ulcer complica(cid:173)
`tion. 1 Several studies2·3 have been per(cid:173)
`fonned in search of co therapies that might
`prevent NSAID-induced ulcers and ulcer
`complications. The use of the synthetic
`prostaglandin, misoprostol ( Cytotec; Phar(cid:173)
`macia, Bridgewater, Nj), as a form of re(cid:173)
`placement therapy repeatedly has been
`shown to prevent NSAID-induced gastro(cid:173)
`duodenal ulcers and reduce the inci(cid:173)
`dence of life-threatening ulcer complica(cid:173)
`tions.4-14 In contrast, neither the topical
`agent sucralfate nor usual doses of hista(cid:173)
`mine2 (H2)-receptor antagonists have been
`
`shown to be effective.6 •11·u-Js Increased
`doses ofH2-receptor antagonists were more
`effective than lower doses, but overall, the
`success rate was modest. 17.19·23
`Recently, more profound acid suppres(cid:173)
`sion with proton pump inhibitors has been
`reported as being associated with accel(cid:173)
`eration of ulcer healing and prevention of
`ulcer relapse among long-term users of
`NSAIDs.10·18Neitherofthe2largemulticenter
`studies comparing the proton pump inhibi(cid:173)
`tor omeprazole with misoprostol ( Omepra(cid:173)
`zole versus Misoprostol for NSAID-Induced
`Ulcer Management [OMNIUM))10 or ran(cid:173)
`itidine (Ranitidine versus Omeprazole for
`NSAID-Associated Ulcer Treatment [AS(cid:173)
`TRONAUT)) 18 for the prevention of ulcer
`recurrence among long-term users ofNSAIDs
`presented analyses regarding the association
`between He! icobacter py Iori status and pre(cid:173)
`vention of ulcer relapse. Subsequent analy(cid:173)
`ses showed that H pylori status had a marked
`effect on outcome and the development of
`
`Author affiliations are listed at
`the end of this article. Members
`of the NSAID-Associated Gastric
`Ulcer Prevention Study Group
`are listed in a box on page 174.
`
`( REPRINTED) ARCH INTERN MED/VOL 162, JAN 28, 2002
`169
`
`WWW.ARCHlNTERNMED.COM
`
`©2002 American Medical Association. All rights reserved.
`
`

`
`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 [2:1300 mgld;
`low-dose aspirin for cardiovascular protection was permit(cid:173)
`ted]) for at least the previous month. Two thirds of pa(cid:173)
`tients enrolled in this study had previously completed par(cid:173)
`ticipation in a healing trial for NSAID-associated gastric
`ulcer. Pretreatment H pylori status was determined by a rapid
`urease test ( CLOtest; T ri-Med Specialties Inc, Draper, Utah)
`or histologic analysis, which was graded according to the
`updated Sydney System.32 Those patients positive for H py(cid:173)
`lori were excluded, as were those with gastric or duodenal
`ulcer crater (2:5 mm in diameter) or severe erosions (de(cid:173)
`fined as >25 erosions) or erosive reflux esophagitis. Use
`of a proton pump inhibitor, H2-receptor antagonist, or mi(cid:173)
`soprostol within 24 hours before study entry was not per(cid:173)
`mitted. Approval for the study was obtained from the in(cid:173)
`stitutional 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 pg 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 re(cid:173)
`ceived antacid tablets (Gelusil; Parke-Davis, Morris Plains,
`NJ) for use as needed for symptom relief. Patients were in(cid:173)
`structed to avoid antiulcer medication other than study
`medication, ulcerogenic medication (except NSAIDs or as(cid:173)
`pirin as noted herein), and agents that alter hemostasis.
`Compliance and adverse events were assessed by re(cid:173)
`turned 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, moder-
`
`ate, or severe), study drug and NSAID dosing informa(cid:173)
`tion, 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). Esopha(cid:173)
`geal and duodenal mucosa were also evaluated.
`
`STATISTICAL ANALYSIS
`
`Statistical analyses were conducted using statistical soft(cid:173)
`ware (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 8 1% power to show noninferiority between ac(cid:173)
`tive treatment groups.
`Per-protocol and intent-to-treat analyses were con(cid:173)
`ducted 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 base(cid:173)
`line was assessed with respect to demographic variables us(cid:173)
`ing the x2 test (F test for age) and medical and social his(cid:173)
`tories by the Fisher exact test. Baseline severity of symptoms,
`based on an investigator interview, was compared among
`the treaunent groups using the Cochran-Mantei-Haenszel
`method for ordered response variables.
`Life table methods were used to estimate the ulcer in(cid:173)
`cidence rates. The life table analysis of time to ulcer occur(cid:173)
`rence was performed using the Cochran-Mantei-Haenszel
`method to test treatment differences between groups.
`Factors including age; sex; race; treatment for an acute
`NSAID-associated gastric ulcer immediately before study en(cid:173)
`rollment; hiatal hernia; investigator; alcohol, tobacco, or caf(cid:173)
`feine use; and acute baseline gastric ulcer size (measured dur(cid:173)
`ing 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 ant(cid:173)
`acid use based on diary data using the Wilcoxon 2-sample
`test. The Fisher exact test was used to compare the inci(cid:173)
`dence of treatment-related adverse events (defined as pos(cid:173)
`sibly or probably related) between the treatment groups.
`
`endoscopic ulcers, with H pylori infection being associ(cid:173)
`ated with an overrepresentation of duodenal ulcers. 24 Sepa(cid:173)
`ration of the prevention of ulcers that are unequivocally
`related to NSAID use and not to H pylori infection is im(cid:173)
`portant to the clinician because there are now consider(cid:173)
`able data to suggest the gastroduodenal outcome in long(cid:173)
`term users ofNSAIDs differs among those with and without
`H pylori infection.24
`' In addition, the presence of an ulcer
`2
`•
`in an H pylori- infected NSAID user is an indication for eradi(cid:173)
`cation of the infection because it is impossible to ascertain
`which was the actual cause of the ulcer. There is also in(cid:173)
`creasing evidence that the use of antisecretory therapy with
`Hrreceptor antagonists or proton pump inhibitors is as(cid:173)
`sociated with acceleration of corpus gastritis in those with
`H pylori infection,2c;.31 which may make it prudent to eradi(cid:173)
`cate H pylori in those for whom long-term NSAID and an(cid:173)
`tisecretory co therapy is contemplated .
`
`This study attempted to overcome some of the short(cid:173)
`comings of the OMNIUM and ASTRONAUT stud(cid:173)
`ies.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 mi(cid:173)
`soprostol essentially devoid of antisecretory activity and
`a dose of ranitidine that had been proven to be subthera(cid:173)
`peutic for this indication (ie, 400 pgld and 300 mgld,
`respectively).U·12·u ·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(cid:173)
`blind, multicenter, randomized , active- and placebo(cid:173)
`controlledstudy designed to identify the optimal therapy
`for preventing unequivocal NSAID-induced gastric or duo(cid:173)
`denal ulcers. This study compared 2 doses of lansopra-
`
`( REPRINTED) ARCH INTERN MED/VOL 162, JAN 28, 2002
`170
`
`WWW.ARCHlNTERNMED.COM
`
`©2002 American Medical Association. All rights reserved.
`
`

`
`Table 1. Patient Disposition by Treatment Group
`
`No. of Patients
`
`Variable
`Enrolled
`Randomized
`Withdrawn
`Did not receive study drug
`Adverse event
`Personal reasons
`Poor compliance
`Therapeutic failure
`Other
`Completed trial
`
`I
`Placebo
`134
`134
`23
`1
`9
`3
`3
`4
`3
`111
`
`Misoprostol, 200 pg 4 Times Daily
`134
`134
`23
`0
`14
`1
`2
`1
`5
`111
`
`Lansoprazole, 15 mg/d
`136
`136
`14
`0
`4
`3
`1
`2
`4
`122
`
`Lansoprazole, 30 mgtJ
`133
`133
`19
`1
`10
`2
`1
`0
`5
`114
`
`zole (Prevacid; TAP Pharmaceutical Products Inc, Lake
`Forest, Ill) (15 and 30 mg) with the full therapeutic dose
`of misoprostol (800 11g/d) and placebo for preventing ul(cid:173)
`cer relapse among patients who continued NSAID use
`and were known to be free of H pylori.
`
`RESllLTS
`
`A total of 537 patients were randomized to receive
`placebo (n = 134), 200 11g of misoprostol 4 times a day
`(n = 134), 15 mg oflansoprazole once daily (n= 136), or
`30 mg oflansoprazole once daily (n= 133) for 12 weeks.
`Two patients (I each in the placebo and 30-mg lanso(cid:173)
`prazole groups) who did not take study medication were
`not included in the intent-to-treat analysis of ulcer oc(cid:173)
`currence or adverse events (Table 1 ). Eighty-two (15%)
`of the 537 enrolled patients were excluded from the per(cid:173)
`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=2l), positive for H pylori at baseline (n= 15), inap(cid:173)
`propriate 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 misopros(cid:173)
`tol group did not take the minimum amount and/or
`complete the minimum duration necessary for evaluabil(cid:173)
`ity (7, 19, l , and 6 patients in the placebo, rnisoprostol,
`15-mg lansoprazole, and 30-mg lansoprazole groups,
`respectively).
`The treatment groups were well matched at base(cid:173)
`line, including demographic characteristics, social his(cid:173)
`tory, previous history of gastrointestinal disorders, re(cid:173)
`cent treatment for an NSAID-associated gastric ulcer, and
`severity of symptoms (Table 2 ). Most patients re(cid:173)
`ported no daytime or nighttime abdominal pain at base(cid:173)
`line. 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
`l NSAID.
`
`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<.OOI). There was no difference between lansopra(cid:173)
`zole dosage groups (P= .62). Evaluable patients in the mi(cid:173)
`soprostol group remained free of gastric ulcer signifi(cid:173)
`cantly longer than those who received placebo (P<.OOI),
`15-mg lansoprazole (P = .Ol), or 30-mg lansoprazole
`(P = .04). These observations were unaffected after ad(cid:173)
`justment for potentially influential factors, including
`age, sex, race, treatment for an acute NSAID-associated
`gastric ulcer before study enrollment, hiatal hernia, in(cid:173)
`vestigator, 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 ul(cid:173)
`cer prevention data throughout the 12-week treatment
`period.
`Absence of a gastric ulcer after 8 or l2 weeks of treat(cid:173)
`ment was different among those receiving placebo, mi(cid:173)
`soprostol, 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 treat(cid:173)
`ment groups (Figure 1).
`When prevention rates were analyzed based on the
`development of gastric or duodenal ulcers (gastroduo(cid:173)
`denal ulcers), those in the misoprostol, 15-mg lansopra(cid:173)
`zole, or 30-mg lansoprazole groups remained free
`of ulcer for a significantly longer period compared with
`those who received placebo (P<.OOI). There was no
`statistical difference between any 2 of the active treat(cid:173)
`ments for time to occurrence of gastroduodenal ulcers
`(Figure 2 ).
`To evaluate the impact of the early patient with(cid:173)
`drawals from the misoprostol group, the worst-casesce(cid:173)
`nario, where patients who withdrew from the study
`prematurely (eg, because of an adverse event) were
`classified as a treatment failure (eg, equivalent to hav(cid:173)
`ing a gastric ulcer), was evaluated. In this scenario, the
`proportion of patients who were treatment successes
`
`( REPRINTED) ARCH INTERN MED/VOL 162, JAN 28, 2002
`171
`
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`
`©2002 American Medical Association. All rights reserved.
`
`

`
`Table 2. Pretreatment Characteristics of Intent-to-Treat Patients*
`
`Characteristic
`Age, mean± SO, y
`Sex
`Female
`Male
`Race
`White
`Black
`Other
`Smokert
`Alcohol uset
`Previous gastrointestinal disease
`Reflux esophagitis
`Duodenal ulcer
`Gastric ulcer
`Previous treatment§
`Daytime abdominal pain
`None
`Mild to moderate
`Severe
`Nighttime abdominal pain
`None
`Mild to moderate
`Severe
`
`Placebo
`(n = 133)
`60.5 ± 11.8
`
`Misoprostol, 200 pg 4 Times Daily
`(n = 134)
`59.4 ± 12.0
`
`lansoprazole, 15 mg/d
`(n = 136)
`61.6± 12.1
`
`l ansoprazole, 30 mg/d
`(n = 132)
`60.2 ± 11.8
`
`87 {65)
`46 {35)
`
`118(89)
`10 (8)
`5 (4)
`38 (29)
`50 (38)
`
`79 {59)
`69 {52)
`131 (98)
`53 (40)
`
`79 (59)
`51 (38)
`3 (2)
`
`92 (69)
`38 (29)
`3 (2)
`
`91 (68)
`43 (32)
`
`125 (93)
`3 (2)
`6 (4)
`26 (19)
`49 (37)
`
`84 (63)
`70 (52)
`131 (98)
`50 (37)
`
`73 (54)
`58 (43)
`3 (2)
`
`96 (72)
`33 (25)
`5 (4)
`
`86 (63)
`50 (37)
`
`124 (91)
`8 (6)
`4 (3)
`24 (18)
`48 {35)
`
`77 (57)
`65 (48)
`135 (99)
`49 (36)
`
`79 (58)
`57 (42)
`0
`
`92 (68)
`42 (31)
`2 (1)
`
`84 (64)
`48(36)
`
`117 (89)
`10 (8)
`5 (4)
`23 (17)
`39 (30)
`
`76 {58)
`63 (48)
`132 (100)
`52 (39)
`
`71 {54)
`58 (44)
`3 (2)
`
`83 (63)
`46 (35)
`3 (2)
`
`*Data are given as number (percentage) of patients unless otherwise indicated.
`tSmoker defined as any tobacco use.
`tAicohol use defined as consumption of any quantity of alcohol on a routine basis.
`§Patient received either lansoprazole or ranitidine during the 8 weeks before study enrollment for healing of a nonsteroidal anti-inflammatory drug- associated
`gastric ulcer.
`
`{!}~-=-----·
`*-
`... ~~=--=""'9:o;:::::::::::::::::::::::::::::::::::::-•
`iw
`~
`~ 60
`~
`~
`-~ 40
`a:
`~ 20
`~
`
`· - - - .
`
`------------------
`
`-
`
`100
`
`• Pla<:ebo
`• Misop ostol
`.. lansoprazole, 15 mg
`l>. lansoprazole, 30 mg
`
`100 ·~ <f'
`·---.
`
`~
`
`.,;
`~ 80
`:;;
`.Y
`:::J w
`.~
`c ·o;
`E "' a:
`~ 20
`.!!1
`1;j
`0.
`
`40
`
`• Pla<:ebo
`• Misop ostol
`.. lansoprazole, 15 mg
`t>. lansoprazole, 30 mg
`
`0
`
`4
`Duration of Therapy, wk
`
`12
`
`0
`
`12
`
`Duration of Therapy, wk
`
`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.
`
`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.
`
`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 prema(cid:173)
`turely 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 sig(cid:173)
`nificantly less severe (P= .01) and significantly fewer days
`(P= .001) with nighttime abdominal pain than those in
`the misoprostol group. Antacid use was significantly
`
`( REPRINTED) ARCH INTERN MED/VOL 162, JAN 28, 2002
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`
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`
`©2002 American Medical Association. All rights reserved.
`
`

`
`Table 3. Mean Diary Results During the 12-Week Treatment Period
`
`Variable
`Daytime al>dominal pain
`Days with pain, %
`Average pain severity per day*
`Nighttime abdominal pain
`Nights with pain, %
`Average pain severity per night*
`Antacid use
`Days used, o/o
`Average number per day
`
`Placebo
`(n = 113)
`
`Misoprostol, 200 pg 4 Times Daily
`(n = 108)
`
`l ansoprazole, 15 mg/d
`(n = 126)
`
`l ansoprazole, 30 mg/d
`(n = 119)
`
`34.5
`0.51
`
`30.4
`0.45
`
`37.1
`1.24
`
`41.0
`0.60
`
`32.7
`0.49
`
`41.6
`1.35
`
`27.5t
`0.39t
`
`22.2t
`0.32§
`
`24.6t ll
`0.72fll
`
`30.8§
`0.46§
`
`27.1
`0.41
`
`24.7tll
`0.72t ll
`
`*Severity was scored as follows: 0, none; 1, mild; 2, moderate; and 3, severe.
`tP<.001 vs misoprostol.
`tP<.01 vs misoprostol.
`§P<.05 vs misoprostol.
`I!P<.01 vs placebo.
`
`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.
`
`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 miso(cid:173)
`prostol group (P<.001). Thirty-eight (7%) of the 535
`patients discontinued use of the study medication pre(cid:173)
`maturely 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 %, 411134) reported a treatment(cid:173)
`related adverse event compared with each of the other
`treatment groups: 13 (lO%) of 133 patients in the pla(cid:173)
`cebo group, 10 (7%) of 136 patients in the 15-mg lan(cid:173)
`soprazole 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 miso(cid:173)
`prostol vs 30-mg lansoprazole; P =.04 for 15-mg lanso(cid:173)
`prazole 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-re(cid:173)
`lated abdominal pain ( 6%, 8/134) and nausea ( 4%,
`6/134) compared with patients in the 15-mg lansopra(cid:173)
`zole group (0/136 for both symptoms) (P= .003 and
`P =.01, respectively). One patient (in the 15-mg lanso(cid:173)
`prazole group) experienced an upper gastrointestinal
`tract hemorrhage during the study.
`
`COMME~T
`
`Studies designed to evaluate ulcer prevention among long(cid:173)
`term users of NSAIDs have varied regarding study de(cid:173)
`sign, 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 in(cid:173)
`fected with H pylori. 11
`1
`17 None were randomized with
`•
`'·
`regard to H pylori status. That is unfortunate since ran(cid:173)
`domization would have ensured that if there were a dif(cid:173)
`ference in outcome in relation to H pylori status, the over(cid:173)
`all results of the study would not hinge on the proportion
`of patients with (or without) the infection. A study con(cid:173)
`ducted 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, reanaly(cid:173)
`sis of the outcomes of the OMNIUM10 and ASTRONAUT18
`trials showed that H pylo·ri infection has an important im(cid:173)
`pact on outcome. 24 The lowest effective dose of miso(cid:173)
`prostol ( 400 J.lg/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 equiva(cid:173)
`lent to omeprazole (14.6% vs 11.6%, respectively) (P= .56)
`for the prevention of gastric ulcers in patients with un(cid:173)
`equivocal NSAID ulcers who were long-term users of
`NSAIDs. Among those with H pylo·ri infection, misopros(cid:173)
`tol was similar to omeprazole (5.7% vs 9.2%, respec(cid:173)
`tively) (P=.48), and omeprazole was superior to low(cid:173)
`dose ranitidine (1.9% vs 17%, respectively) (P=.001). 24
`The present study was designed to avoid those short(cid:173)
`comings by comparing 2 doses of a proton pump inhibi(cid:173)
`tor (lansoprazole) with the full therapeutic dose of miso(cid:173)
`prostol and placebo in patients with unequivocal
`NSAID-associated ulcers. As with omeprazole, lansopra(cid:173)
`zole was superior to placebo, with no evidence of a major
`dose response effect. We confirmed that gastric ulcers re(cid:173)
`curred during the 12-week follow-up in a greater percent-
`
`( REPRINTED) ARCH INTERN MED/VOL 162, JAN 28, 2002
`173
`
`WWW.ARCHlNTERNMED.COM
`
`©2002 American Medical Association. All rights reserved.
`
`

`
`MUCOSA (Misoprostol Ulcer Complication Outcome
`Safety Assessment) trial,14 misoprostol was shown tore(cid:173)
`duce serious NSAID-induced upper gastrointestinal tract
`complications by 40% compared with placebo. The me(cid:173)
`dian dose of misoprostol in that study was 800 pgld (mean
`dose, 683 pgld). In that study, a history of peptic ulcer
`or ulcer-related bleeding was an important prognostic fac(cid:173)
`tor for identifying those who would develop ulcer com(cid:173)
`plications 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 l% per month com(cid:173)
`pared with approximately l % 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 ul(cid:173)
`cer complications among long-term users ofNSAIDs. Be(cid:173)
`cause misoprostol and antisecretory drugs act by differ(cid:173)
`ent mechanisms and low-dose misoprostol is better
`tolerated than full-dose therapy (but has a lower rate of
`protection),12 the combination oflow-dose misoprostol
`and a proton pump inhibitor might provide optimum re(cid:173)
`sults. Thus, the ideal comparison might be a proton pump
`inhibitor with or without low-dose rnisoprostol (eg, 400
`pgld) 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, in(cid:173)
`cluding once-a-day dosing and lack of adverse effects. Com(cid:173)
`pliance is a significant problem with misoprostol because
`full dosage requires 4-times-daily dosing, and the propor(cid:173)
`tion with gastrointestinal adverse effects is dose depen(cid:173)
`dent. This observation was demonstrated in this study: com(cid:173)
`pliance with misoprostol was significantly inferior to that
`with lansoprazole. When the effect of noncompliance on
`ulcer development was considered, the percentage of pa(cid:173)
`tients remaining free from gastroduodenal ulcer disease was
`approximately 2-fold higher with active treatment vs pla(cid:173)
`cebo. 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 sta(cid:173)
`tistical advantage of misoprostol over proton pump inhibi(cid:173)
`tors for the prevention of ulcer relapse in long-term users
`of NSAIDs, there is little, if any, practical advantage.
`
`Accepted for publication April30, 2001.
`From the Department of Medicine, Veterans Affairs
`Medical Center, Houston, Tex (Dr Graham); Department
`of Medicine, Dune University Medical Center, Durham, NC
`(Dr Agrawal); Department of Medicine, University ofKan(cid:173)
`sas School of Medicine, University of Missouri, Kansas City,
`School of Medicine, Department of Veterans Affatrs Medi(cid:173)
`cal Center, andSaintLuk.e's Hospital, Kansas City (Dr Camp(cid:173)
`bell); 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).
`
`Stud) Group
`
`NSAID-Associated Gastric Ulcer Prevention Study Gror1p
`Naurang M. Agrawal, MD, Durham, NC; Robert]. Bai(cid:173)
`ley, MD, Alberta, Canada; Charles F. Barish, MD, Ra(cid:173)
`leigh, 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;JeffreyR. 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, Dal(cid:173)
`las, Tex; Fred C. Fowler, MD, Charlotte, NC; Syam P.
`Gaddam, MD, Garden Grove, Calif; Willian1 Harford, MD,
`Dallas; W.John Henry, MD, Greer, SC; Samuel Ho, MD,
`Minneapolis, Minn; Keith P. Hussey, MD, Naples, Fla;
`DavidS. James, DO, Tulsa, Okla; David Johnson, MD,
`Norfolk, Va; Lawrence judy, MD, Evansville, lnd; David
`Kalin, MD, Clearwater, Fla; Mukul Khandelwal, MD, Her(cid:173)
`shey, Pa; David G. Kogut, MD, Statesville, NC; George
`Kovalm, MD, Portland; Richard Krause, MD, Chatta(cid:173)
`nooga, Tenn; Frank Lanza, MD, Houston, Tex; Duncan
`McCall, MD, Statesville; Aubrey D. McElroy, MD, Eliza(cid:173)
`bethtown, NJ; Doris Mee-Lee, MD, Honolulu, Hawaii;
`Morry Moskovitz, MD, Beaver, Pa; Daniel J. Pam(cid:173)
`bianco, 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 l. Schwartz, MD, Mi(cid:173)
`ami, Fla; Nayan R. Shah, MD, Hollywood, Md; Paul Siami,
`MD, Evansville; David R. Silvers, MD, Metairie, La;
`Thomas J. Sobieski, MD, Richmond, Va; Stephen Son(cid:173)
`tag, MD, Hines, Ill; Lewis Stron