Prevention of Peptic Ulcer and Dyspeptic Symptoms with Omeprazo!e m
`Patients Receiving Continuous Non-Steroidal Anti-Inflammatory Drug
`Therapy
`
`A Nordic Multicentre Study
`
`P. EKSTROM, L. CARUNG, S. WEITERHUS, P. E. WINGREN, 0. ANXER-HANSEN,
`G. LUNDEGARDH, E THORHALLSSON & P. UNGE
`Dc:pt. of Surgery and Dept. of Medicine, Sandvikens Hospital, Sandviken; Dept. of Medicine, Bolinas
`Hospital. Bo!lnas; Dept nf S11rge.ry, Mota!a Hospital, Motala; Dept. of Surgery, Lu!d-Boden Hospiiai,
`Lu!e:i-Boden; and De-pt. of Medicine, V3.xj6 Hospital, VaxjO; Sweden; Dept. of Medicine, Kongsvinger
`Hospital, Kongsvinger, Norway; and Dept. of Medicine, Maim's Hospital, Jakobstad, Finland
`
`Fk'>tr6m P, Carling L, We!terhus S. \1/ingrcn PE, Anker-Hansen 0, Lurideg~rclh G, lnorOaiisson E, Unge
`P. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in palients receiving continuous
`non-steroidal anti-inflammatory dr~g !herapy. A Nordic multkenrre study. Scand I Gastroenterol
`i996;31 :}53-75~.
`
`Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to cause gao:.trodtiOdena!
`lesions and dyspeptic symptoms. Methods: Patients with a hiswry of dyspepsia or unoomplic<Hed pepric
`ulcer disease and with a need for continuous KSAID treatment \\.'ere randomized to receive either 20 mg
`omf:'prazo!e once daily or phcebo. G.o:s::oduoderwl ulcers, erosiuns, and dyspeptic symptoms were
`evaluated after 1 and 3 months. ReS11lts: During a 3-month study period 4.7% (4 of 85) of omeprazole(cid:173)
`treated patients developed peptic ulcer, compared with 16.7% (15 oC90) of patients treated with p!.'lcebo
`Thts prophylactic effect of omeprazole was sustained independently of previous peptic ulcer history or
`Hdicobacter pylori status. Development of dyspeptic symptoms requiring active treatment, either alone
`or in combinatinn with uker(s) or erosions, occurred in 15.3% (15 of 85) uf padems !reated with
`omeprazole and 35.6% of those who received placebo. Conclusions: Omeprazole, 20 mg once daily,
`proYides cffectiYc prophylactic therapy in patients at risk of developing NSAID-associated peptic ulcers
`or dyspeptic symptoms.
`
`Key words: Arthritis; dyspeptic symptoms; erosions; non-steroidal anti-inflammatory drugs; omeprazole;
`peptic uicer; placebo; prophylaxis
`
`Per Eksrr6m, M.D., Depr. of Surge!}', Sandvikcns Hospital, S-8/1 89 Sand~,iken, Swedfn (fax: + 46
`26256092)
`
`Non-steroidal anti-inflammatory drugs (NSAIDs) account for
`21% of all reported adverse drug events in the USA and 25%
`in the UK (1, 2). Most of the side effects of NSAIDs are
`gastrointestinal, predominantly gastroduodenal, ulcers, era·
`sions, or dyspeptic symptoms, and epidemiologic studies
`that 8-16% of patients using NSAIDs have
`suggest
`gastrointestinal ~yniptoms at some time (3, 4). The pre(cid:173)
`valence of gastric ulcers among chronic NSAID users has
`been es!imated to be approximately 13%, and
`that of
`duodenal ulcer <:tpproximately II% (5). Other reviews have
`estimated gastric ulc-er !O occur ir: 9-22% of patients taking
`NSAIOs, with less consistent results for duodenal ulcer (6),
`whereas the prevalence of peptic ulcer in chronic NS."'.!D
`users has been put at 10-30% (7). More serious side effects,
`such as gastrointestinal bleeding or perforations, are not
`unusual in these patients, particularly in those more than
`60-65 years of age (6, 7),
`More recent formulations of NSAIDs have been claimed to
`have less damaging effects on the gastroduodenal mucosa,
`and it has been postulated that a new generation uf NSAIDs,
`
`which primarily inhibit cyclooxygenase-2, may have im·
`proved gastrointestinal tolerability (8). Despite this, there is
`still an unacceptably high frequency of gastrointestinal side
`effects associated with NSAID use. In
`the absence of
`improved medical
`treatment for patients with arthritic
`conditions such as osteoarthritis, lhere is a need to protect
`such patients who are receiving long-term NSAID therapy
`from developing dyspepsia and peptic ulcers.
`Hrreceptor antagonists offer some protection against
`NSAID-associated ulcers, but this is limited to protection
`again~t duodenai uicers, and they are less effective against
`NSAID-associated gastric ulcers (9). Misoprostol, a prosta(cid:173)
`glandin·EI analogue, provides some protection against
`NSAID-associated ulcers in both the duodenum and the
`stomach. However, it h<:~s often been ieported to have an high
`incidence of side effects, notably diarrhoea and abdominal
`cramps (7, 1 0--12). There is thus a need for improved
`prophylactic therapy for patients receiving NSAIDs who are
`at risk of developing gastrointestinal side.effecfso
`The efficacy of the acid pump inhibitor omeprazole in
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 1
`
`

`

`754
`
`P. EkstrOm et a!.
`
`providing symptom resolution and healing in patients with
`peptic ulcer disease is well established (13), and healing of
`botlt gasiric and duodenal uiccrs with omeprazole has been
`shown to be unaffected by concomitant NSAID use (14, 15).
`i\dditionally, studies in hcaithy voiunteers have indicated that
`omeprazole protects against gastroduodenal damage induced
`by aspirin (16, 17) and naproxen (18). However, to date there
`have been no studies of the possible prophylactic efficacy of
`acid pump inhibitors such as cmeprazole in preventing the
`gastrointestinal side effects associated with continuous
`NSAID use in the clinical situa!ion.
`We therefore evaluated the prophylactic use of omeprazole,
`20 mg once daily, in patients at risk of developing NSAID(cid:173)
`associated gastroduodenal lesions and dyspeptic symptoms.
`We studied patients receiving continuous NSAID treatment
`who had a history of previous dyspepsia or uncomplicated
`peptic ulcer disease, which
`is
`typical of the situation
`encountered in routine clinical practice.
`
`SUBJECfS AND METHODS
`
`Pa1ients between 25 and 78 years of age requiring continuous
`NSAID
`treatment
`for at
`least 3 months because of
`osteoilnhriiis. rheumatoid arthritis, spondylarthritis, ankylos(cid:173)
`ing spondylitis, or any other condition requiring continuous
`NSAID
`therap) and wi1h a history of dyspepsia or
`uncomplicated peptic ulcer disease were included in the
`study. Pattems who had taken more than half the recom(cid:173)
`mended minimum dose of NSAIDs during the 4 weeks
`before randomization were exduded, as were patiems with
`complicated ulcer disease (recent ulcer bleeding or previous
`major bleeding or pe-rforation). Pat.ien~s wen: aha exch.J~e~ if
`they had more than mild dyspeptic symptoms at inclusion, a
`history of gastric surgery, or verified g.astro-oesophagcal
`reflux disease, were pregnant or breast-feeding, needed
`systemic medication with prednisolone in doses of more
`than 10 mg daily or equivalent doses of other steroids, were
`contraindicated for study drugs, or had clinically significan!
`abnormalities in the base-line laboratory screen.
`
`Study design
`The study was a randomized, double-blind, placebo(cid:173)
`oontroiied, paraiiel-group study conducted in 18 hospitals in
`Finland, Norwas. and Sweden. The study was approved by
`the local ethic~ commillee at each hospital, and informed
`consent was obtained from all patients.
`Physical examinaiion, ~ympwm assessment, and standard
`laboratory screens were performed at the base-line visit,
`together with an ELISA-based seroiogic test of Helicobactcr
`pylori status. Dyspeptic symptoms were scored as mild
`(awareness of symptoms but easily iolerated), moderate
`(sufficient discomfort to interfere with normal activities), or
`inabi!i!y to perform normal
`severe {incapacitating with
`activities). Patients were
`randomized
`to
`receive either
`omeprazole, 20 mg, or identical placebo, once daily for 3
`
`months. All patients were gh:en open NSAID treatment in
`accordance with hospital routines and received NS/dDs in at
`least the minimurri recommended dose. Combinations of
`NSAJDs were permitted, as were changes in the type or dose
`of NSAID. Antacids (Novaluco[TM, Novum) were available
`for the relief of mild dyspeptic symptoms.
`After 1 month and again after 3 months patients underwent
`endoscopy and physical examination. Compliance with the
`study medication was assessed, together with the severity of
`dyspeptic symptoms and adverse events, which were scored
`a.::. mi!d, moderate, or severe, as previously. If patients
`experienced more than mild dyspeptic symptoms, they made
`an unscheduled visii at which the above assessments were
`made. At the last visit standard laboratory screens Were
`performed, and Jf. pylori siatus was assessed with a rapid
`urease test (CLO-test) on two antral biopsy samples. The
`three defined study end points were ulcer(s) in the stomach or
`than 10 erosions in
`duodenum, more
`the stomach or
`duodenum, or'more !han mild dyspeptic symp!Oms requiring
`active treatment. Ulcers had to be at least 3 mm in diameter
`and with an unequivocal depth of at least 1 mm, and erosions.
`could be red (haemorrhagic) or white (fibrin-coated). Patients
`who reached an end point were withdrawn,
`
`Statistical methods
`A sample size of 170 patients was calculated, assuming
`relapse rates Of 30% and 10% in the placebo and omepr;~zo!e
`groups, respectively, 20% dropouts, a power of 80%, and a 2-
`sided test (log-rank) at the 5% significance leveL The primary
`variable, time in remission (time until one of the end points
`ulcer(s), > 10 erosions, or more than mild dyspeptic symp(cid:173)
`iOms), was assessed with the log-rank test, and prognostic
`factors with Cox's regression models. Between-group com(cid:173)
`parison:-> of the proportion of patients reaching study end
`points were made using Fisher's exact test. Patients who took
`at least one dose of the study drug and about whom
`subsequent study information was available were included
`in !he adverse event analysis. Muitipie episodes of the same
`adverse event were counted only once during the treatment
`period, The data presented for patients who dcveioped peptic
`ulcer include those who also had erosions and dyspeptic
`symptoms at the 'iiame investigaticm.
`
`RESULTS
`
`Study population
`Of the 177 patients recruited
`the study between
`to
`December 1992 and June 1994, 86 were randomized to
`receive omeprazole and 91 to receive placebo. One patient in
`the omeprazole
`treatment group failed
`to
`take NSAID
`therapy, and one patient in the placebo group did not take
`study medication. These two patients were excluded from the
`A.ii Patients Treated analysis. The two treatment groups were
`comparable with regard to gender, age, smoking habits,
`wcigbi, lype of arthritic disease, H. pylori status, and history
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 2
`
`

`

`Ti!ble 1. Demographic details of patients included in the analysis
`
`Tui<~l, no.
`Gender
`Female
`Male
`Age (years),
`mean (range)
`Smokers
`Mean weight (kg)
`Fcm;~!e
`Male
`Type of arthritic disease
`Osteoarthrith;
`Rheumatoid arthritis
`Other
`H. pylori-positive
`Previous-peptic ulcer
`
`Orncprazole
`
`Placebo
`
`S5
`
`54
`31
`
`9()
`
`67
`23
`
`58 (25-80)
`18 (21%)
`
`59 (30-78)
`20 (22%)
`
`71
`83
`
`49 (58%)
`14 (16%)
`22 (26%)
`45 (53%)
`23 (27%)
`
`73
`84
`
`<:A
`lhr\Of_\
`....... , ........ "'I
`8 (9%)
`28 (31%)
`46 (51%)
`21 (23%)
`
`T<!b!e H_ Number and percentage of pa!ients in earh !reatment group
`with peptic ulcers, more than 10 erosions, or more than mild
`dyspeptic symptoms during the 3-month treatment period
`
`Omeprazole
`
`Placebo
`
`n
`(85)
`
`4
`10
`7
`21
`
`%
`
`%
`
`n
`(90)
`
`p
`value
`
`4.7
`11.8
`8.2
`24.7
`
`15
`16.7
`13.3
`12
`18 20.0
`45
`50.0 <0.001
`
`Peptic ulcers
`> 10 erosions•
`>Mild dyspeptic symptomst
`All end points
`
`•ooes not include patients who also had ulcer.
`tDoes not include patients who also had ulcer or erosions.
`
`of peptic ulcer (Table I). H. pylori status was unknown for one
`patient in the placebo group, and chis patient was excluded.
`from analyses reiated to N pyiorr status. 1 ne two most
`commonly prescribed NSAIDs were naproxen and diclo-
`
`Omeprazole for NSAID Dyspepsia
`
`755
`
`fenac, followed by tenoxicam, ibuprofen, ketoprofen, and
`sulindac. Other NSAIDs were prescribed less frequently.
`
`Prophylactic efficacy
`Treatment with omeprazole, 20 mg once daily, kept
`significantly more patients free of peptic ulcers and dyspeptic
`symptoms than treatment with placebo (Table II). Ulcers
`occurred in 4.7% of omeprazole-treated patients (two with
`gastric ulcer, two with duodenal ulcer) and 16.7% of patients
`who received piacebo (six with gastric ulcer, nine with
`duodenal ulcer), whereas 15.3% of patients treated with
`omeprazoie and 35.6% of those who received piacebo
`experienced more than mild dyspeptic symptoms requiring
`aclivt:: itCi:limt:nL In patients other than those who deveioped
`peptic ulcer or more than IO erosions, dyspeptic symptoms
`requiring active
`treatment occurred
`in 8.2% (7 of 85)
`receiving omeprazole, compared with 20.0% (18 of 90) of
`placebo-treated patients. There '.vas no slgnlficant diff~rence
`between the two treatment groups with regard to the number
`of pMients with more. !han 10 erosions in either the stomach or
`the duodenum but without ulcer. There was no clear
`correlation between the incidence of symptoms and erosions
`as a study end point. In total, 24.7% of patients treated with
`omeprazole developed gastric or duodenal ulcers, more than
`10 erosions, or more
`than mild dyspeptic symptoms.
`compared with 50% of patients who received placebo
`(p < 0.001).
`The main efficacy variable was time in remission (that is,
`having not reached a defined study end point or left the study
`for some other reason). Of the 85 patients treated with
`omeprazolc who were included in the analysis, 58 were still in
`remission after 3 months, compared with 40 of the 90
`placebo-treated patients. From the remission curves drawn in
`accordance with the life-cable method, including patients who
`
`1.0
`
`0.9 j
`
`-~---·----
`
`omeprazole
`-
`-+- placebo
`
`c
`0
`
`0
`
`o; ..
`'"
`E v.o ~
`:!!
`0.7
`~·~ i
`"
`" 0 :;::
`~:: ~
`<>. e a. ., 0.3 j
`.. ;;
`.. 0.1
`' '
`:§ v.~~
`w
`
`0.0
`
`0
`
`14
`
`28
`
`56
`42
`Days in study
`
`70
`
`84
`
`Fig. 1. Remission curves constructed in accordance with the life-table method, including both patients
`who reached a study end point (peptic ulcer, more than 10 erosions, or more than mild dyspeptic
`symptoms) and those who left the study for some other reason.
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 3
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 3
`
`

`

`7:"i(o
`
`1'. Ehlrbm el a!.
`
`reached a study end point and those who lefi the study for
`some oiher reason (Fig. l ), ihe proportion of paiients in
`remission after 3 months were 74% in the omeprazole-lreated
`group .and 48% in the p!acebo"treated group. The difference
`was statistically significant (p = 0.0005).
`The time in remission with regard !o peptic ulcers differed
`between omeprazole· and placebo-treated patients. In the
`placebo group 14 of the 15 patients who developed ulcers did
`so within the 1st month, and 11 of these 15 patients also had
`more than mild dyspeptic symptoms. Of the four ulcers in the
`omeprazole-treatcd group, two were found at the scheduled
`visit after 1 month. One of these patients was symptomatic.
`The other two patients were asymptomatic and found at the
`final visit after 3 months.
`
`JnjluellCC of peptic ulcer history and H. pylori status
`A history of peptic ulcer disease and infection with H.
`pylori are both risk factors for the development of ulcer, and
`thi:-. wa~ reflecied in the piacebo group, in which 43% (9 of21)
`of patients with a history of peptic ulcer disease and 26% (12
`of 46) of H. pylori-positive paiients deveiopcd peptic uicer
`during the course of the study (Table III). The risk of ulcer
`u:as reduced :!pprmdmately fou;fold in patients treated v..·ilh
`omeprazole, compared with placebo, irrespective of peptic
`ulcer history or H pylori status. The incidence of erosions
`\\·<Js independent of peptic ulcer history and H. pylori status.
`DcYclopmcnt of dyspeptic symptoms without ulcers or.
`rrosions was also unrelated to H. pylori status but occurred
`J;ngcly in patients with no history of peptic ulcer dist;"<!Se.
`
`Prognostic factors
`Omcprazolt.'-trc<llcd patients had a higher probability of
`those who received placebo
`staying
`in
`remission
`than
`(p = 0.0()1). Additionally, whereas patients with osteoarthri·
`tis had a probability of staying in remission (71 of 103)
`comparable to that of patients with rheumatoid arthritis (16 of
`22), they had a higher probability than patients with other
`arihritic diseases (22 of 50) (p = 0.003).
`Smoking, age, and gender had no significant influence on
`the probabiliij' of remaining in remission. The protective
`effect of omeprazole was not significantly influenced by any
`of these prognostic factors.
`
`Adverse events were generally mild and did not differ
`
`between the treatment groups. None of the reported adverse
`events was an uicer complication. Five patients stopped
`treatment owing to adverse events, four in the omeprazole
`t;;:.atment group and one pariem who received placebo.
`Serious adverse events were reported in two patients, both in
`!he cmeprazole treatment g;oup. 9ne was a patient hospiia(cid:173)
`lized because of aggravation of her rheumatoid arthritis, and
`!ho:;o other was a patient ._,.,ith an <:~ccidenta! fall resulting in a
`vertebral fracture.
`
`DISCUSSION
`
`This is the first study to demonstrate that the acid pump
`inhibitor omeprazole, 20 mg once daily, provides effective.
`prophylaxis against peptic ulcers and dyspeptic symptoms in
`patients receiving continuous NSAID therapy. Additionally,
`the study closely mirrors
`the situation encountered by
`prim~ry care physicians, who are frequently f~ced with
`arthritic patients for whom the only therapeutic option is
`continuous NSAID therapy. They are unlikely to refer these
`patients for endoscopy but may be aware that the patient has
`a history of peptic ulcer disease or dyspeptic symptoms and
`is lherefore at high risk of developing gastrointestinal side(cid:173)
`effects during NSAID therapy and should thus be a candidate
`for effective prophyiaxis. The study also reflects clinical
`practice in that various NSAJDs were used depending on
`local practice and paiient preference. indeed, the number of
`different NSAIDs and the variety of combinations used was
`too large to enable a separate analysis of end poinis in
`relation to the NSAID used.
`Previous peptic ulcers and infection with H. pylori ace
`strong predictors for peptic ulcer development (7, 11),
`although the role of H. pylori in NSA!D-associ:::ted ulcer is
`not fully understood. The risk of developing an ulcer in
`patients who received placebo was increased approximately
`fourfold in H. pylori-positive patients and fivefold in patients
`•;;ith a history of peptic ulcer disease. compared with patients
`who
`received omeprazole
`treatment. Additionally,
`the
`prophylactic effect of omeprazo\e was observed irrespective
`of H. pylori status and peptic ulcer history. Almost 60% of the
`ulcers observed in the study were duodenal, which is a larger
`proportio,n than expected, possibly reflecting the high rate of
`H. pylori infection in patients with ulcer.
`Omeprazole, 20 mg once daily, reduced the incidence of
`peptic ulcer to 4.7%, compared with 16.7% in the placebo
`
`Ta~le fll. The incidence of peptic ulcer in the two treatment groups in relation to peptic ulcer his~nry (PUH) and Helicobac!er pylori status
`durmg the 3·moiiih ireatmcnt period
`
`PUH and H. pylori-positive {n = 33}
`PUH and H. pylori-negative (n = 11)
`No PUH and H. pylori.positive (tr = 58)
`No PUH and !!. py!ori·negativc (n = 72)
`
`Omeprazole
`"
`2/i6
`0/7
`1129
`1i33
`
`%
`
`1L6
`0
`3.4
`3.0
`
`Pla('ebo
`
`n
`
`7/17
`214
`5129
`1139
`
`%
`
`41.2
`50.0
`17.2
`2.6
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 4
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 4
`
`

`

`group, whereas dyspeptic symptoms requiring active treat(cid:173)
`ment occurred, in total, in 15.3% of patients who received
`omeprazole, compared with 35.6% of those treated with
`piacebo. Comparison with other prophylactic agents can only
`be approximate owing
`to differences
`in study design.
`Additionaliy, few other studies have assessed prophylaxis of
`dyspeptic symptoms. Ehsanullah et al. (9) investigated the
`prophylactic effect of the H2-receptor antagonist ranitidine,
`150 mg twice daily, in arthritic patients receiving continuous
`NS.A.ID therapy, although they did not select patients wiih a
`history of dyspepsia or peptic ulcer. The incidence of
`dtiOdenal ulcer after 2 months was 1.5% in patients treated
`with ranitidine and 8% in those receiving placebo, but there
`was no difference in the incide-nce of gli.str!c ulcer between the
`two groups. A similar Jack of protection against gastric ulcers
`with ranitidine has been observed by other workers (19)_
`Whereas the study by Ehsanullah eta!. (9) was not designed to
`evaluate symptoms, the authors comment that gastrointestinal
`symptoms were the same after treatment with ranitidine or
`placebo. In our study omcprazole reduced the incidence of
`botb gastric and duodenal ulcers and dyspeptic symptoms.
`The apparent prophylactic advantage of omeprazole com·
`pared with ranitidine may reflect the greater control of gastric
`acid secretion achieved with omeprazole.
`Prophylactic treatment with the prbstaglandin analogue
`misoprostol in patients receiving continuous NSAJD therapy
`has been reponed to reduce the incidence of peptic ulcer to
`approximately 5% compared with placebo rates of ll% to
`22% {lO, 11) after 3 monihs. it shouid be noted, however, that
`in the study by Verdickt et al. (10), diclofenac was the only
`NS,6..JD used, and in the study _by Grahan1 et ai. (11) uniy
`gastric ulcers were considered. In the latter study dose-
`dependent diarrhoea was reported in up to 40% of patients
`receiving misoprostol. This could potentially interfere with
`patient compliance., p<J.rticularly in disabled arthritic ?atients
`(7).
`Omeprazole was well tolerated in our study_ Adverse
`events in the study were mild and did not differ from those
`with placebO. There were no ulcer corilplications in either
`treatment group, although this may be a consequence of the
`early occurrence of symptoms, which made the patients
`contact the investigator for an early re-examination, since 14
`of the 15 placebo-treated patients who had an ulcer developed
`I month, and most of these patients were
`this within
`symptomatic. The efficacy of omeprazole in preventing
`iong-term uicer complications, such as bleeding and perfora(cid:173)
`tion, associated with NSAID use could not be determined in
`oui study, aod this warrants further investigation.
`Symptoms as a study end point were most commonly seen
`in placebo-treated pa~ients who had no hisiury of pep[ic uicer,
`but
`the pronounced effect of omeprazole
`in
`reducing
`dyspeptic symptoms suggests that these dyspeptic symptoms
`are probably, at least in part, acid-related.
`Erosions as a study end point were unre:!!lted to H. pylori
`status or peplic ulcer history, and omeprazole had no effect on
`
`Omepraznlt' for ~SMD Dyspepsia
`
`757
`
`incidence of erosions compared with placebo. High
`the
`frequencies of erosions have been reported in other studies
`(20, 21), but these largely occurred early in NSAID treatme-nt.
`Given that mucosal adaptation is known to occur (22), the ].
`month control used in our study may have missed erirly
`erosions. The clinical relevance of NSAID-associated muco(cid:173)
`sal erosions is unclear, however, and this is reinforced by our
`to dyspeptic
`observation
`that erosions were unrelated
`symptoms, previous peptic ulcer, and H. pylori status,
`indicating that erosions are unlikely to be precursors of ulcer
`development.
`In conciusion, omeprazoie, 20 mg once daily, is signifi·
`cantly more effective than placebo in the prevention of peptic
`ulcers and dyspeptic symptoms in arthritic patients who
`require continuous NSAID treatment and who have a history
`of peptic ulcer disease or dyspepsia. We anticipat..:: thai
`omcprazole will provide effective, well-tolerated prophylaxis
`in thes~ high-risk patients and
`rnay provide ~Unica.l
`advantages over currently available prophylactic therapies.
`
`ACKNOWLEDGEMENTS
`
`The authors are grateful to Astra, Sweden, for financial
`support of th.e study and ar~. ind~bted to the input from the
`other
`investigators
`involved: Hans Stokke
`(Eiverum,
`NoN~ay): Gunnar· EngstrOm and Pont us GOt ell (Nyk43ping
`Hospital, Sweden); Henrik Forssell, Ebbe Lyrenas, and Bo
`Ohlin (Karlskrona Hospital, Sweden); Hans Glise (Nona
`Alvsborg Hospital, Trollhiittan, Sweden); Nils Hovdcnak.
`Rolf Pedersen, and Arne Skarstein (Diakonhjemmets Hospi(cid:173)
`tal, Bergen, NoN~ay); Christina LindstrOm (SOdcrhamn
`Hospital, Sweden); Kjc\1 Lundberg and Berti! Persson
`(Hudiksvall Hospital, Sweden); Magnus Melsom (Moss
`Hospital, Norway); Jan Helge Solhaug and Njaal Stray
`(Diakonhjemmets Hospital, Oslo, Norway); Jon Arny Sparby
`(Kongsvinger Hospilal, Norway); Arild Stubber6d {V.lrnamo
`Hospital, Sweden); Lars-Erik Svedberg (Bolinas Hospital,
`Sweden); and Egil Tveit (Kungalv Hospilal, Sweden).
`
`REFERENCES
`
`I. Wolfe F, Kleinheksel SM, Spitz PW, Lubeck DP, Fries JF,
`Young DY, et al. A multicentre study of hospitalis<Jt.io~ in
`rheumatoid anhri.tis. Frequency, medical-surgical adm1SSmns
`and charges. Arthritis Rheum 1986;29:614-9.
`2. Hazleman BL. Incidence of gas!ropa!hy i!1 d'.'-S-!rtJc!!ve arthro(cid:173)
`pathies. Scand J Rheumatol 1989; Suppl 78:1-4.
`3. Butt JH. Clinical spectrum of the upper gastrointestinal effects
`of nom!ero!da! anti-inft:::mmatory drugs. N:llt:ral history,
`symptomatology and signifi~nce. Am J Med 1988; 84 Suppl
`2A:5-14.
`4. Larkai EN, Smith JL, Lidsky MD, Set.~ms SL. Graham DY.
`Dyspepsia in NSAID users: the size of the prol;11cm. J Clin
`Gastroenterol 1989; I I :158-62.
`S. McCanhy DM. Non-steroidai anti-infiammatory drug-induced
`ulcers: management by traditional therapies. Gastroenterology
`1989;96:662-74.
`6. Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic
`ulcers. BMJ 1990;300:278-84.
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 5
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 5
`
`

`

`75H
`
`P. EkstrOm et a/.
`
`7. Myerson RM. NSATD-associated gastroduodenal damage. J
`Pharm Mcd 1992;2:277--84.
`8. Bauistini B, Boning R, BaJ.:hle YS. COX-I and COX-2: toward
`the development of more selective NSAIDs. Drugs News Pcrsp
`i994;7:50i-i2.
`IJ. Ehsanullah RSB, Page MC, Tildesley G, Wood JR. Prevention
`of gastroduodenal damage
`induced by non-steroidal anti·
`inflammatory drugs: controlled trial of ranitidine. BMJ 1988;
`297:1017-20.
`10. Verdickt W, Moran C, Hantschel H, Fraga AM, Stead H, Geis.
`GS. A double blind comparison of the gastroduodenal safety and
`efficacy of diclofenac and a fixed dose combination of
`d!dof('.rH•c and misopro~tnl in the treatment of rheumatoid
`arthritis. Scand J Rheumatol 1992;21:85-91.
`11. Graham DY, Agrawal NM. Roth SH. Prevention of NSAID(cid:173)
`induced gastric ulcer with misoprosto!: mu!ticen!re, double(cid:173)
`blind, placebo-controlled trial. lancet 1988;2:1277-80.
`12. McCarthy DM. NSAID-induced gastrointestinal damage. J Clin
`Gastroemeroi i990;i2 Suppl2:Si3-20.
`13. Eriksson S, UngstrOm G. Rikner L, Carlsson R, Naesdal J.
`Omeprazole and H 2-receptor antagonists in the acute treatment
`of duodenal ulcer, gastric ulcer and reflux oesoph<:~gttis: a meta·
`analysis. Eur J Gastroenterol Hcpatol 1995;7:467-75.
`14. Walan A, Bader J-P, Classen M, Lamers CBHW, Piper DW,
`Rutgers son K, et al. Effect of omcprazole and ranitidine- on ulcer
`healing and relapse rates in patients with benign gastric ulcer. N
`Fngl J Mcd 1989;320·69-75
`
`15. Lauritsen K, Rutgers.son K, Bolling E, Brunner G, Eriksson S,
`Frison L. e! a!. Omeprazo!e 20 or 40 mg daily fer healing cf
`duodenal ulcer? A double-blind comparatiye study. Eur J
`GastroenteroJ Hepatol 1992;4:995-1000.
`1u. Daneshmend TK, Stein AG, Bhaskar NK, Hawkey CJ. Abolition
`by omeprazole of aspirin induced gastric mucosal injury in man.
`Gut 1990;31:514-7.
`17. Scheiman JM, Behier EM, Loefller KM, Eita GH. Omeprazoie
`ameliorates aspirin-induced gastroduodenal injury. Dig Dis Sci
`1994;39:97-103.
`18. Oddson E, Gudjonsson H, Thjodleifsson B. Comparison
`between ranitidine and omeprazole for protection against
`gastroduodenal damage caused by naproxen. Scand J Gastro(cid:173)
`enterol1992;27:1045-8.
`19. French PC, Darekar BS, Mills JG, Wood JR. Ranitidine in the
`prevention cf non-steroidal anti-inflammatory dn:g-associated
`in arthritic patients. Eur J
`gastric and duodenal ulceration
`Gastroenterol Hepatol 1994;6:1141-7.
`20. Lanza FL. Graham DY, Davi~ RE, Raci-; MF. Endoscopic
`comparison of cimetidine and sucralfate for prevention of
`naproxen-induced acute gastroduodenal injury. Dig Dis Sci
`1990;35:1494--1).
`21. Jvey K.J, Paone DB, Krause WJ. Acute effect of systemic aspirin
`on gastric mucosa in man. Dig Dis Sci 1980;25:97-9.
`22. Graham DY, Smith JL, Dobbs SM. Gastric adaptation occurs
`with aspirin administration in man. Dig Dis Sci 1983;28:1--6.
`
`Received 19 February 1996
`A(:~..:epied i i March j996
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 6
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 6
`
`