CLINICAL THERAPEUTICS®/VOL. 26, No. 10, 2004
`
`Ulcer Recurrence in High-Risk Patients Receiving Nonsteroidal
`Anti-Inflammatory Drugs Plus Low-Dose Aspirin: Results of a
`Post Hoc Subanalysis
`
`Jay L. Goldstein, MD, 1 Bidan Huang, PhD, 2 Fouad Amer, MD, MPH, 3 and
`Nikos G. Christopoulos, MD 1
`
`1 University of Illinois at Chicago, Chicago, 2Abbott Laboratories, Abbott Parh, and 3TAP Pharmaceutical Products Inc.,
`Lahe ForesL, Illinois
`
`ABSTRACT
`
`Background: Concomitant aspirin use is a risk factor for nonsteroidal anti-inflammatory drug (NSAID)(cid:173)
`associated upper gastrointestinal toxicity In high-risk individuals, such as those with a history of NSAID-related
`gaslric ulcer bleeding, gaslroproleclive Lherapy wilh a prolon pump inhibilor has been reporled Lo reduce Lhe risk
`of recurrent aspirin-associated gastroduodenal ulcer bleeding.
`Objective: This analysis compared the efficacy of misoprostol, lansoprazole, and placebo in reducing the risk
`of gastric or duodenal ulcer recurrence in patients taking NSAIDs and low-dose aspirin.
`Methods: This post hoc subanalysis was based on a previous multicenter, prospective, randomized, double(cid:173)
`blind, placebo-controlled, 12-week study in patients who had a history of gastric ulcer, were Helicobacter pylmi
`negaLive, required chronic NSAID Lherapy, and were free of gaslric or duodenal ulcer on baseline endoscopy. The
`study treatments were misoprostol200 pg QID or lansoprazole 15 or 30 mg OD. The subanalysis included data
`from patients in the intent-to-treat cohort who took aspirin at an amount ::::;325 mgld. The end point was the
`cumulative rate of gastric ulcers, as assessed by serial endoscopy at 4, 8, and 12 weeks.
`Results: Of 535 intent-to-treat patients from the primary study, 70 (40 men, 30 women; mean [SD] age, 64.7
`[10.0] years; age range, 40-83 years) met the criteria for inclusion in the subanalysis. The proportions of patients
`who were free of gaslric ulcers aLLhe end of 12 weeks were 96% in Lhe misoproslol group, 93% in Lhe lansopra(cid:173)
`zole 15-mg group, 100% in the lansoprazole 30-mg group, and 35% in the placebo group (P ::::; 0.008, each
`active treatment vs placebo). Adverse events considered possibly or probably related to treatment occurred in
`5 (20.0%) misoprostol recipients (4 episodes of diarrhea, 1 episode of abdominal pain), 1 (14.3%) recipient of
`lansoprazole 30 mg (l episode of pharyngitis), and 3 (13.6%) placebo recipients (l episode each of abdominal
`pain, palpitations, and dyspepsia).
`Conclusions: In Lhis subgroup analysis in palienls al high risk for recurrence of gaslric ulcer, use of colher(cid:173)
`apy with misoprostol200 pg QID or lansoprazole 15 or 30 mg OD significantly lowered the risk for gastric ulcer
`recurrence. (Clin Ther. 2004;26:1637-1643) Copyright© 2004 Excerpta Medica, Inc.
`Key words: lansoprazole, misoprostol, NSAIDs, gastroprotection, proton pump inhibitors.
`
`llcccpLcd for publica Lion llugusl 13. 2004.
`Printed in the LS;\. Reproduction in whole or part is not permitted.
`
`Copynght © 2004 Excet·pta Medtca. Inc
`
`dml 0.1 0 I 6/j.clinthera.2004.1 0.002
`0 149-29 I 8/04/$19.00
`
`1637
`
`

`
`CLINICAL THERAPEUTICS®
`
`INTRODUCTION
`Approximately 70% of Americans aged >65 years use
`nonsteroidal anti-inflammatory drugs (NSAIDs) at least
`once weekly, and an estimated 34% take these drugs on
`a daily basis. 1 Use of NSAIDs increases the risk of seri(cid:173)
`ous ulcer complications by -2.5- Lo 5-fold compared
`with nonuse, 2- 4 resulting in significant morbidity and
`mortality and increased use of health care resources. 4- 10
`Use of cardioprotective low-dose aspirin is also com(cid:173)
`mon in the general population, 11 with recent studies
`suggesting that 25% of individuals aged >50 years 12
`and "?.72% of those who have had an acute myocardial
`infarction 13
`14 take aspirin at amounts ::::;325 mgld. Use
`·
`of aspirin alone, even at low cardioprotective doses,
`increases the risk for gastrointestinal ( GI) events by
`-1.5- to 4-fold compared with placebo 1 'Y-18
`Low-dose aspirin taken in combination with
`NSAIDs has been associated with an increased risk
`for complications of upper GI ulcer compared with
`NSAIDs alone; thus, concomitant aspirin use is a
`risk factor for NSAID-associated upper GI toxicity 19
`The association of combined NSAIDs and low-dose
`aspirin with increased upper GI risk was supported
`by the results of a cohort study from Denmark, in
`which patients taking low-dose aspirin (<150 mg/d)
`had a 2.6% incidence of GI bleeding, compared with
`a 5.6% incidence in those taking low-dose aspirin
`plus an NSAID 18
`In high-risk individuals, such as those with a his(cid:173)
`Lory of NSAID-related gastric ulcer bleeding, gaslro(cid:173)
`protective therapy with a proton pump inhibitor has
`been reported to significantly reduce the risk of
`recurrent aspirin-associated gastroduodenal ulcer
`bleeding (P::::; 0.008) 20 ·21 Furthermore, in 2 prospec(cid:173)
`tive, endoscopist-blinded trials, 22 ·23 proton pump in(cid:173)
`hibitors were found Lo be superior Lo hislamine-2-
`receptor antagonists (P::::; 0.04) and of similar efficacy
`to misoprostol for the prevention of recurrent ulcers
`at the time of scheduled endoscopies. In the
`more recent prospective, double-blind study by
`Graham et al, 24 treatment with misoprostol 200 11g
`QID or lansoprazole 15 or 30 mg OD significantly
`reduced the risk of recurrent gastric ulcers in
`Helicobacter pylori-negative patients receiving NSAID
`therapy for 12 weeks (P < 0.001). However, these
`authors did not report results separately for the
`13.1% (70/535) of patients who were taking aspirin
`al amounts ::::;325 mg/d in addition Lo NSAID therapy.
`
`1638
`
`To further understand the efficacy of misoprostol
`and lansoprazole in reducing the risk for gastric or
`duodenal ulcer recurrence in this population at high
`risk for recurrence due to the combined use of aspirin
`and NSAIDs, the present subanalysis used data from
`the study by Graham el al 24 Lo assess the rate of ulcer
`recurrence in patients taking NSAIDs plus aspirin.
`
`PATIENTS AND METHODS
`Primary Study
`The primary study was a multicenter, prospective,
`double-blind, 12-week study in patients aged "?.18
`years who had a history of endoscopically confirmed
`gastric ulcer with or without bleeding and required
`therapeutic doses of NSAIDs for the 12 weeks follow(cid:173)
`ing enrollment 24 Those who required therapy with
`nabumetone or aspirin ("?.1300 mgld) were excluded.
`All patients were H pylori negative (documented by
`urea breath test or histologic analysis) and, on pre(cid:173)
`randomization endoscopy, were negative for gastric
`or duodenal ulcer (defined as a lesion "?.5 mm in
`diameter with appreciable depth), severe erosive
`gastritis (defined as >25 erosions), or erosive
`esophagitis. Patients were excluded if they had used
`a proton pump inhibitor, a histamine-2-receptor
`antagonist, or misoprostol within 24 hours of starting
`the study
`Participants were randomized in blocks of 4 to
`receive l2 weeks of misoprostol 200 11g QID, lanso(cid:173)
`prazole 15 or 30 mg OD, or placebo. Antacids were pro(cid:173)
`vided for symptom relief as needed. Patients recorded
`episodes of daytime and nighttime abdominal pain in
`daily diaries. Endoscopy was performed after 4, 8, and
`l2 weeks of treatment to determine the presence of
`gastric and/or duodenal ulcers "?.5 mm in diameter.
`Endoscopisls were blinded Lo treatment assignment.
`After the exclusion of 2 patients who did not take
`any study medication (l each in the lansoprazole
`30 mg group and the placebo group), the intent-to(cid:173)
`treat population consisted of 535 patients. Two hun(cid:173)
`dred four (38.1 %) of these patients entered the study
`after having documented healing of NSAID-associated
`gastric ulcer with lansoprazole or ranitidine in a sepa(cid:173)
`rate study of ulcer healing25 ·26 ; these patients were
`allowed to enter the primary study within 7 days of
`the completion of previous study treatment.
`Approval for the study was obtained from the insti(cid:173)
`tutional review board of each of the 63 participating
`
`

`
`J. L. Goldstein et al.
`
`North American centers, and written informed consent
`was obtained from each patient before enrollment.
`
`Subanalysis
`The subanalysis involved 70 patients from the
`intenl-lo-treat population (those who received ;:::1
`dose of study medication) in the primary study who
`were receiving aspirin at amounts ~325 mg/d in addi(cid:173)
`tion to NSAID therapy These patients were consid(cid:173)
`ered at high risk for gastric or duodenal ulcers. The
`end point of interest was the cumulative rate of gas(cid:173)
`tric ulcers on endoscopy at 4, 8, and l2 weeks.
`Pairwise comparisons were made between treat(cid:173)
`ment groups for all efficacy and safety end points.
`The comparability of demographic characteristics
`between subanalysis groups at baseline was assessed
`using the chi-square test (F test for age), and medical
`and social characteristics were com pared using the
`Fisher exact test. Life-table methods were used to
`estimate ulcer incidence rates. The life-table analysis
`of time to ulcer occurrence was performed using the
`Cochran-Mantel-Haenszel method to test for treat(cid:173)
`ment differences between subgroups. The Fisher
`exact test was used to compare the between-subgroup
`incidence of adverse events possibly or probably
`related to treatment.
`
`RESULTS
`Of the 70 patients receiving concomitant aspirin and
`NSAIDs in the primary study ( 40 men, 30 women;
`mean [SD] age, 64.7 [ 10.0] years; age range, 40-83
`years), 25 (35.7%) were randomized to receive miso(cid:173)
`prostol, 16 (22.9%) lansoprazole 15 mg, 7 (10.0%)
`lansoprazole 30 mg, and 22 (31.4%) placebo. The
`treatment groups within the subanalysis population
`were predominantly white and were well matched at
`baseline in terms of demographic characteristics
`(Table
`I). The most frequently used nonaspirin
`NSAIDs were ibuprofen, naproxen, and diclofenac
`(Table II).
`Of the 70 patients in the subanalysis population,
`8 (ll. 4%) discontinued the study prematurely (3 miso(cid:173)
`prostol, 1 lansoprazole 15 mg, 1 lansoprazole 30 mg,
`3 placebo). The reasons for discontinuation included
`adverse events (2 misoprostol [chest pain/dyspepsia,
`diarrhea], 1 lansoprazole 15 mg [atrial fibrillation],
`3 placebo [palpitation, tendon disorder, chest pain]),
`personal reasons (l lansoprazole 30 mg), and other
`(2 misoprostol).
`Significantly greater proportions of patients taking
`NSAIDs plus aspirin remained free of gastric ulcers
`by 12 weeks in the misoprostol and lansoprazole 15-
`and 30-mg groups compared with the placebo group
`
`Table I. Baseline demographic and clinical characteristics of intent-to-treat patients included in the subgroup analysis.
`
`Charactenstic
`
`Age, y
`Mean (SD)
`Range
`
`Sex, no.(%)
`Male
`Female
`
`Race, no. (%)
`Wh1te
`Black
`Other
`
`Caffe1ne use, no. (%)
`
`Smok1ng, no. (%)
`
`Alcohol use, no. (%)
`
`M isoprostol
`200 IJg QID
`(n = 25)
`
`Lansoprazole
`15 mg OD
`(n = 16)
`
`Lansoprazole
`30 mg OD
`(n = 7)
`
`Placebo
`(n = 22)
`
`Total
`(N = 70)
`
`63.2 (9.9)
`40-77
`
`14 (56.0)
`II (44.0)
`
`24 (96.0)
`0 (0.0)
`I (4.0)
`
`23 (92.0)
`
`10 (40.0)
`
`7 (28.0)
`
`66.3 (I I .0)
`48-80
`
`I 0.0 (62.5)
`6 (37.5)
`
`16 (100.0)
`0 (0.0)
`0 (0.0)
`
`13 (81.3)
`
`3 ( 18.8)
`
`8 (50.0)
`
`67.6 (I 0.0)
`52-83
`
`64.4 (9.7)
`44-81
`
`64.7 (I 0.0)
`40-83
`
`5 (71.4)
`2 (28.6)
`
`6 (85.7)
`I ( 14.3)
`0 (0.0)
`
`6 (85.7)
`
`I ( 14.3)
`
`3 (42.9)
`
`II (50.0)
`II (50.0)
`
`21 (95.5)
`0 (0.0)
`I (4.5)
`
`18 (81.8)
`
`7 (31.8)
`
`7 (31.8)
`
`40 (57.1)
`30 (42.9)
`
`67 (95.7)
`I (I .4)
`2 (2.9)
`
`60 (85.7)
`
`21 (30.0)
`
`25 (35.7)
`
`1639
`
`

`
`CLINICAL THERAPEUTICS®
`
`Table II. Concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) taken within I month of beginning study treatment
`and during the study (no. [%]).*
`
`NSAID
`
`Asp1rin and asp1rin comb1nat1ons
`Naproxen
`Ibuprofen
`Diclofenac
`Pmx1cam
`Other I
`
`M 1soprostol
`200 ~g QID
`(n = 25)
`
`25 (I 00.0)
`9 (36.0)
`12 (48.0)
`8 (320)
`5 (20.0)
`6 (24.0)
`
`Lansoprazole
`15 mg OD
`(n = 16)
`
`16 (I 00.0)
`6 (37.5)
`3 ( 18.8)
`6 (37.5)
`I (63)
`5 (3 I .3)
`
`Lansop1~azole
`30 mg OD
`(n = 7)
`
`7 (100.0)
`2 (28.6)
`I ( 14.3)
`2 (28.6)
`3 (42.9)
`3 (42.9)
`
`Placebo
`(n = 22)
`
`22 (100.0)
`9 (40.9)
`8 (364)
`7 (31.8)
`2 (9.1)
`9 (40.9)
`
`·'Patients may have taken > I NSAI D.
`~Including fiurbiprofen, sulindac, difiunisal, indomethacin, etodolac, ketoprofen, tolmetin, salicylates, and phenylbutazone.
`
`(all comparisons, P ~ 0.008). Of the 25 patients in the
`misoprostol group, only l had a recurrent gastric ulcer
`(detected at week 4); thus, the proportion of miso(cid:173)
`prostol recipients who remained free of gastric ulcers
`at the end of 12 weeks was 96%. Of the 16 patients
`receiving lansoprazole 15 mg, l had a recurrent gas(cid:173)
`tric ulcer (detected at 12 weeks), with the result that
`the proportion or patients who received lansoprazole
`15 mg and remained free of gastric ulcers over the
`duration of the study was 93%. There were no gastric
`ulcer recurrences in the lansoprazole 30-mg group. Of
`the 22 patients who received placebo, 56% remained
`free of gastric ulcers at week 4, 49% at week 8, and
`35% al week 12 (Figure).
`Adverse events judged possibly or probably related
`to treatment were reported by 20.0% (5/25) of miso(cid:173)
`prostol recipients, 14.3% (117) oflansoprazole 30-mg
`recipients, and 13.6% (3/22) of placebo recipients. In
`the misoprostol group, 4 (16.0%) patients reported
`Lrealmenl-related diarrhea and
`l ( 4.0%) reported
`abdominal pain. One episode of pharyngitis was
`reported by l (14.3%) patient who received lansopra(cid:173)
`zole 30 mg. No treatment-related adverse events were
`reported with lansoprazole 15 mg. One episode each
`of abdominal pain, palpitation, and dyspepsia were
`reported by 3 patients who received placebo.
`
`DISCUSSION
`This post hoc subanalysis of a prospective, double(cid:173)
`blind, controlled clinical trial that enrolled 535 pre(cid:173)
`dominantly white patients (484/535 [90.5%]) 24 was
`conducted Lo examine whether the efficacy of gaslro-
`
`1640
`
`protective therapy against ulcer recurrence extends to
`patients Laking concomitant nonspecific NSAIDs and
`low-dose aspirin. In this subanalysis, placebo recipi(cid:173)
`ents had a gastric ulcer recurrence rate of 65% in the
`course of the 12-week trial; the rate of recurrence was
`significantly reduced in patients receiving gastro(cid:173)
`protective therapy compared with those receiving
`placebo (P < 0.008). Consistent with the results of the
`primary study, this subanalysis found a high rate of gas(cid:173)
`tric ulcer recurrence in patients who received placebo.
`Those randomized to receive placebo in the primary
`study were receiving only an NSAID plus aspirin, with(cid:173)
`out gastroprotective therapy The clinical implication is
`that patients with a history of ulcer who are Laking dual
`therapy with aspirin and an NSAID are at increased risk
`for ulcer recurrence and upper GI ulcer bleeding, indi(cid:173)
`cating a need for strategies that reduce this risk.
`The use oflow "cardioprotective" doses of aspirin is
`common in the general population, as well as in popu(cid:173)
`lations with heightened cardiovascular risk. For
`example, in the relatively healthy population of the
`Nurses' Health Studies,U -25% of women aged >51
`years reported using aspirin 26 days/wk and 42%
`reported using NSAIDs 21 day/wk. In other studies,
`as would be expected, aspirin use was greater in
`patients who had been recently hospitalized for a
`myocardial infarction compared with the general
`population, with 2 72% taking low-dose aspirin at the
`time of hospital discharge. 13·14 Use of traditional
`NSAIDs is also common, particularly in the elderly 1
`In patients requiring low-dose aspirin along
`with anli-innammatory
`therapy, selection or a
`
`

`
`J. L. Goldstein et al.
`
`-D- Misoprostol 200 11g QID
`-6- Lansoprazole IS mg OD
`-0- Lansoprazole 30 mg OD
`*
`Placebo
`
`4Weeks
`
`8 Weeks
`
`12 Weeks
`
`Duration of Tnerapy
`
`'-
`41
`u
`5
`v
`·;::
`....
`"' "'
`c.:>
`0
`
`41
`41
`'-u..
`t>O
`c:
`·c:
`·;;;
`E
`Ql
`a::
`~
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`Baseline
`
`Figure. Proport ion of the intent-to-treat population remaining free of gastric ulcer disease dur ing 12 weeks of therapy.
`calculated by life-table methods. All active treatments were significant versus placebo at each treatment visit
`(P $ 0.008).
`
`cyclooxygenase-2 {COX-2)- selecrive inhibitor rather
`than a nonselective NSAID may be a useful therapeu(cid:173)
`tic approach. Although it has been suggested that the
`COX-2-sd ective inhibito rs ha ve
`less GI toxicity
`than nonselective NSAIDs ,19.27 the safety of low (cid:173)
`dose aspirin coadministered with COX-2- selecrive
`inhibitors has not been well studied. As reported by
`Silverstein et a l, 19
`the unde rpowered analysis in
`patients taking aspirin in the Celecoxib Long-Tenn
`Anhritis Safety Study suggested no benefit for COX-2-
`selective inhibitors compared with ibuprofen o r
`didofenac However, this conclus ion has not been
`su pported by the results of endoscopic trials. In 2 ad
`hoc analyses invol ving patients taking aspiri n who
`were given either a COX-2-selective inhibitor, a non (cid:173)
`selective NSAID, or placebo, 28 •29 the rate of endoscop(cid:173)
`ically documented ulcers in those taking aspirin plus
`a COX-2- selecrive inh ibitor was -50% lower than
`that in patients taking aspirin and a nonselect ive
`NSAID. ln the first of these studies,2R the proportion
`of patients who developed an ulcer while receiving
`celecoxib plus aspirin was 10.4% {l l / 106), co mpared
`with 22.2% (24/ 108) of those who received a non (cid:173)
`se.lective NSAID plus aspirin Similar results were
`observed in the second analysis29 gastroduodenal
`ulcers (de fin ed as lesions >3 mm in depth) were
`
`documented in 11.7% (27/2 31) of those who received
`valdecoxib and aspirin and 21.4% (331154) of those
`who received a nonselective NSAID and aspi1in (rela(cid:173)
`tive risk, 1.8). In a prospective trial, Goldstein et aP0
`found that concomitant use of celecoxib and aspirin
`was associated with a 3 7% risk reduction in 7 -day
`rates of endoscopically documented gastroduodenal
`ulcers compa red with use of naproxen and aspirin .
`However, whether there is an additive effect to aspitin
`plus a COX-2-selective inhibitOr remains unclear. as
`these investigators also found that celecoxib added to
`aspirin was associated with an increased incidence of
`gastrodu odenal ulcers compared with aspirin alone.
`
`CONCLUSIONS
`In this post hoc analysis, patients 'vVith a histOry of gas(cid:173)
`tric ulcer who used aspilin and continued NSAID ther(cid:173)
`apy were at high risk for ulcer recurrence. Cotherapy
`with misoprostol or lansoprazole lowered the risk of
`ulcer recurrence in these high-risk individ ua ls.
`
`ACKNOWLEDGMENTS
`Dr. Goldstein has served as a consultant to TAP Phar(cid:173)
`maceutical Products Inc. , Lake Forest, Illinois. The
`authors thank Susan Rutlalo, PharmD, of MedW rite,
`Inc. , Newport Coast, Califo rnia, for edito rial assistance.
`
`164 1
`
`

`
`CLINICAL THERAPEUTICS®
`
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`specific NSAID: Results from a randomized, double(cid:173)
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`(Suppl):LB14. Abstract.
`
`Address correspondence to: jay L. Goldstein, MD, Professor of Medicine, Vice Head for Clinical Affairs,
`Department of Medicine, University of Illinois at Chicago, 840 South Wood Street (m/c 787), Room 1020, lOth
`Floor, Chicago, IL 60612. E-mail: jlgoldst@uic.edu
`
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