Drug Safety 1999 Dec; 21 (6): 503-512
`PRACTICAL DRUG SAFETY
`0114-5916/90/0012-C503/$05.00/0
`
` ITE
` siRTIESUEBIRENEESSSIERSERESESESELBIULLSBSESDISOOADSHELOOHERASSTRESSDESERTEDNILSD
`© AdisInternationalLimited.All rights reserved.
`
`Prevention of the Gastrointestinal
`Adverse Effects of Nonsteroidal
`Anti-Inflammatory Drugs
`
`The Role of Proton Pump Inhibitors
`
`Gregor J.E. Brown and Neville D. Yeomans
`The University of Melbourne Departmentof Medicine, Western Hospital, Melbourne, Victoria, Australia
`
`Contents
`Abstract ke 503
`]. Background... 504
`1.1. Risks of Damage and Ulceration induced by Nonsteroidal Anti-inflammatory
`Drugs (NSAIDS)0ee 504
`1.2 Rationale for Acid Suppression2. ee 504
`2, Non-Proton PumpInhibitor Strategies for Risk Reduction ©... ee 505
`9.1 NSAIDSelection2. 505
`2.2 Cytoprotection2. 505
`2.3 Histamine He Antagonists20 506
`3. Clinical Studies of Proton PurpInhibitors for Prophylaxis of NSAID Injury... 6 ee 506
`3.1. Short Term Studies (Up To 1] Month)20 506
`3.2 Longer Term Studies (More Than 1] Month) 266 508
`3.2.1 Proton PumpInhibitors Versus Placebo... ee 508
`3.2.2 Proton PumpInhibitor Versus Ho Antagonist ©.6 ee 508
`3.2.3 Proton PumpInhibitor Versus Misoprostol .
`66 509
`3.3 Future Research Needs2... 510
`4. Conclusions .0... 510
`
`
`Abstract
`
`The associations between nonsteroidal anti-inflammatory drugs (NSAIDs)
`and the presence and complications of gastroduodenal erosions andulcers are
`well established. Evidence that acid aggravates NSAID-inducedinjury provides
`a rationale for minimising such damage by acid suppression. Otherstrategies
`discussed include avoidance of NSAIDs or minimising their dosage, selecting
`NSAIDs knownto cause less damage, and co-prescription of variousagents.
`Cytoprotection with misoprostol, a prostaglandin analogue, has been shown
`to be effective in reducing NSAID-related peptic ulcers and their complications.
`Unfortunately, adverse effects may limit compliance in somepatients. Histamine
`H} antagonists have only limited efficacy in the prevention of NSAID-induced
`ulcers in humans, particularly in the stomach, except at higher than standard
`dosages. This mayrelateto their relatively modesteffectin elevating gastric pH,
`especially in comparison with proton pump inhibitors.
`Several studies now confirm theefficacy ofproton pumpinhibitorsin the short
`and longer term prevention ofNSAID-induced uppergastrointestinal injury. Pla-
`
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`Brown & Yeomans
`
`
`cebo-controlled studies suggest reductions of over 70% in gastric and duodenal
`ulcerrates over 3 to 6 months. The recent ASTRONAUT(Acid Suppression Trial:
`Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment) study
`documented the greater prophylactic efficacy of omeprazole over ranitidine at
`standard dosages for 6 months. The OMNIUM (Omeprazole versus Misoprostol
`for NSAID-Induced Ulcer Management) study showed omeprazoleto beslightly
`more effective overall than misoprostol in preventing the upper gastrointestinal
`adverse effects of NSAIDs, with both substantially more effective than placebo,
`although misoprostol was somewhatless well tolerated.
`Although substantial reductions in NSAID ulceration are now achievable
`when co-therapy with a proton pumpinhibitor is given, a few patients willstill
`develop ulcers and their complications. Hence the judicious use of NSAIDsin
`the first instance cannot be overemphasised.
`
`
`The aims of this review are to briefly define the
`problem ofulceration of the upper gut induced by
`nonsteroidal anti-inflammatory drugs (NSAIDs),
`then discuss the rationale for the hypothesis that
`markedly reducing gastric acidity should reduce
`this ulcer risk. The remainder of the review ad-
`dresses the evidence for clinical benefit when a
`proton pump inhibitor and some other agents are
`co-prescribed with NSAIDs. Theliterature was
`searched using Medline supplemented with scan-
`ning of abstracts of recent major scientific meet-
`ings.
`
`1. Background
`
`1.1 Risks of Damage and Ulceration
`induced by Nonsteroidal Anti-inflammatory
`Drugs (NSAIDs)
`
`The toxic effects of NSAIDs on the upper gas-
`trointestinal tract are a frequent cause of morbidity
`and even mortality!) Awareness ofpeptic ulcer as
`a complication of anti-inflammatory dosages of
`NSAIDs is high and, probably because ofthis,
`NSAID usage has diminished recently in some
`Western countries.2] There is also hope that the
`newer NSAIDs that are selective inhibitors of
`cyclo-oxygenase (COX)-2 (rather than of the con-
`stitutive isoenzyme COX-1) will cause less gas-
`troduodenal ulceration in the future. On the other
`hand, prescribing of low dosage (75 to 300 mg/day)
`aspirin (acetylsalicylic acid) for the prevention of
`
`stroke and myocardialinfarction is increasing, and
`this will produce an increasing burden ofulceration
`as an adverse event.
`With the current generation of NSAIDs, the
`great majority of patients develop someerosionsin
`the stomach after each dose,!3) and about 15 to 25%
`of patients who have been taking NSAIDs regu-
`larly will be found to have a discrete ulcerif they
`are examined with gastroscopy at any point in
`time.34] Most ulcers found in this way are asymp-
`tomatic and quite small.!5! They presumably heal
`and reappear a numberof times before reaching a
`threshold for diagnosis in normalpractice.
`The most important complications of NSAID-
`induced ulceration of the stomach or duodenum are
`haemorrhage and perforation. Case-control studies
`have shown that NSAIDs increasetherisk of these
`complications by about 3 to 10 times,"! and for
`some particular NSAIDsthe risk is higher still.
`Even low dosage aspirin increases the chance of
`ulcer haemorrhageorperforation by 2 to 4 times.)
`
`].2 Rationale for Acid Suppression
`
`Luminal acid appears to contribute to NSAID
`injury in the stomach in 2 ways. First, most
`NSAIDs are weak acids with pKa values in the
`range 3.5 to 6. This means that they are mostly
`non-ionised at the usual pH ofthe stomach and the
`duodenal bulb. As a consequence,they are usually
`lipid soluble and can diffuse into the surface cells
`fairly readily. This increase in gastric absorption at
`
`© Adis International Limited.All rights reserved.
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`Drug Safety 1999 Dec; 21 (6)
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`505
`Proton PumpInhibitors in NSAID-Induced Ulceration 7
`
`
`high pH is well documented with aspirin.'7! Having
`gained entry to the surface cells, aspirin becomes
`trapped at the higherintracellular pH and causes
`local toxicity. There is, however, muchless evi-
`dence that this local effect is important with other
`NSAIDs_8]
`Secondly, acid (and possibly pepsin) appears to
`produce a ‘second wave’ of injury, deepening some
`ofthe superficial erosionsthat are very widespread
`soon after administration of an NSAID. Muchof
`the superficial injury repairs within an houror two,
`but here and there the damaged surface seems not
`to repair in time beforethe acid in the lumen causes
`further deeperdestruction oftissue.!! These focal,
`deeper, areas are the macroscopic erosions seen en-
`doscopically in most patients who are taking
`NSAIDs.In rats, vagotomy reduces this deeper
`damage withoutaltering the initial superficial in-
`jury by NSAIDs.!!9!4] More recent data from El-
`liott et al.U2] show that gastric mucosalinjury in
`the rat is much reduced when the luminal pH is
`elevated above a threshold of about 4.0 (fig. 1).
`This pHis rarely achieved for long after H2 antag-
`onists, but can be readily achieved for at least half
`of each 24-hour period during administration of
`proton pumpinhibitors at standard dosages.!!*4)
`
`2. Non-Proton PumpInhibitor
`Strategies for Risk Reduction
`
`2.1 NSAID Selection
`
`Against this backgroundofulcerrisk, there are
`a numberofclinical and pharmacological strate-
`gies that can be employedto reduceit. Thefirst and
`most obvious is to avoid NSAIDs whenthey are
`not necessary. Secondly, when NSAIDsdo needto
`be used,there is now good evidence that the risk
`of ulcer complications is dosage dependent,!'*! so
`the NSAID shouldbe used at the lowest effective
`dosage. A recent meta-analysis has confirmed that
`some NSAIDsare more damagingthan others.!!*]
`For example, the short-acting NSAIDsibuprofen
`and diclofenac (at standard dosage) have usually
`been found to haverelative risks of the order of 3
`to 5 for ulcer bleeding, whereas someofthe long-
`
`acting drugs recommendedfor once-daily admin-
`istration have relative risks of 10 or higher. Thus
`the clinician should consider choosing an agent
`from the less damaging end of the spectrum unless
`there is a particular need for one of the more potent
`agents or formulations. The new highly selective
`COX-2inhibitors, already marketed in some coun-
`tries, offer a further choice, particularly in patients
`at high risk of NSAID ulceration.
`
`2.2 Cytoprotection
`
`Coadministering a prostaglandin analogue re-
`duces the gastric and duodenal damage caused by
`NSAIDs. This approach was developed knowing
`that prostaglandinsare defensivefactorsin the nor-
`mal gastric mucosa and that NSAIDsexert their
`damage,at least in part, by inhibiting the produc-
`tion of these mucosal prostaglandins. In short term
`studies, prostaglandins markedly reduce the num-
`ber of erosions in the stomach during NSAID ad-
`ministration.!!*!81 In longer term studies (3 to 12
`months), misoprostol — an analogueofprostaglan-
`din E, — has been shownto reducethe incidence of
`gastric and duodenal ulcers by about 60 to
`70%,8.!91 although higher protection rates have
`also been reported.!?°) One large study also showed
`an approximate halving in the numberof episodes
`of ulcer bleeding over a 6-month period.!?!!
`Thus, cytoprotection with a coadministered
`prostaglandin is an effective strategy for reducing
`
`
`
`
`
`Gastricdamage(%)
`
`NO
`
`2
`
`5.5
`4
`pH of gastric lumen
`
`7
`
`Fig. 1. Effect of gastric luminal pH on the gastric damage (% of
`mucosa with macroscopic haemorrhagic lesions) produced by
`indomethacinin rats. injury was markedly reduced whenthe pH
`of the lumen wasbuffered to higher than 4 {after Elliott et al."
`with permission).
`
`© Adis International Limited. All rights reserved.
`
`Drug Safety 1999 Dec: 21 (6)
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`506
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`
`Brown & Yeomans
`
`NSAID injury and its complications. The protec-
`tion is dosage dependent, but so are the adverse
`effects of diarrhoea and abdominal cramps, which
`occur in about 10% ofpatients.
`
`focused on proton pumpinhibitors as an effective
`yet tolerable means ofprotecting the stomach from
`the important adverse effect of NSAIDs — peptic
`ulceration.
`
`2.3 Histamine Hz Antagonists
`
`3.1 Short Term Studies (Up To 1 Month)
`
`Histamine H> antagonists, at least at standard
`dosages, have only limited efficacy for preventing
`NSAID-induced ulcers in humans. Two well-con-
`ducted controlled trials showed that ranitidine
`150mg twice daily gave substantial protection
`against the development of duodenalulcers during
`NSAID administration.!22,73] Unfortunately, there
`was no significant protection against gastric ulcers
`in either study, and these are a greater problem than
`duodenal ulcer in NSAID users. Similarly, in an-
`other large surveyofpatients with arthritis, the use
`of cimetidine produced no reduction in the inci-
`denceofulcer bleeding./*4)
`More markedacid suppression with larger doses
`of H, antagonists may give better results. A recent
`trial by Tahaet al.?5] showed a 60% reduction in
`gastric ulceration, and an 85% reduction in duode-
`nal ulcers, during 6 months treatment with famotid-
`ine 40mg twice daily.
`Even at these larger dosages, Hz antagonists
`have a fairly modesteffect in elevating intragastric
`pH. Forinstance,in patients taking a standard dos-
`age of ranitidine, median pH in the stomach over a
`24-hourperiodis rarely greater than 3.!'4] In con-
`trast, median intragastric pH in patients taking
`standard dosages of proton pump inhibitorsis usu-
`ally at least 1 unit higher, of the order of 4 to 5 131
`These are the pH values that we had previously
`shownneedto be reached if the acid componentof
`NSAIDgastric injury is to be reduced.{!"! The next
`section reviews the data now available about the
`use of proton pump inhibitors for preventing
`NSAIDinjury.
`
`3. Clinical Studies of Proton
`PumpInhibitors for Prophylaxis
`of NSAID Injury
`
`Given the limitations of standard preventive
`measures,it is not surprising that attention has been
`
`Whetheror not proton pump inhibitors protect
`against acute NSAID damage in humanshas been
`examined in a numberofshort term trials. In most
`instances, the proton pumpinhibitor used has been
`omeprazole.
`Table I summarisesthe findings from 8 control-
`led, randomised, double-blind trials since 1988.
`The study by Bianchi Porroet al.!?°) recruited pa-
`tients with arthritis, who were treated with om-
`eprazole or placebo concurrently with an NSAID
`for 3 weeks. This wasthe largest of the short term
`studies. All the others used healthy volunteers
`given an NSAID (mostly aspirin) as a single dose
`or for up to 2 weeks. In those studies where the
`NSAID was given for 5 days or less, the proton
`pumpinhibitor or comparator drug wasstarted a
`few days before the NSAID.It takes several days
`from the start of treatment before steady state
`plasma concentrations and acid suppression are
`reached with proton pumpinhibitors,|!*] so this de-
`sign ensured that acid suppression was well estab-
`lished when the NSAID wasgiven.
`All studies demonstrated protection against
`NSAIDgastric damage when co-therapy was given
`with either omeprazole or lansoprazole.
`Daneshmendet al.?7] assessed gastric damage
`by usinga gastric lavage technique to measure gas-
`tric micro-bleeding after aspirin. Blood loss was
`reduced about 80% when omeprazole 20 or 80
`mg/day was given for a week, then aspirin 900mg
`administered daily on the last 2 days. The gain in
`protection by increasing the omeprazole dosage
`was small, although the study was not powered to
`examinethe effect of dosage. However, they found
`a significant negative correlation between the vol-
`ume of micro-bleeding and the intragastric pH
`achieved.
`All the other studies measured gastric damage
`endoscopically. Usually only erosions are found
`
`© Adis International Limited.All rights reserved.
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`Drug Safety 1999 Dec; 21 (6)
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`507
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`
`
`Proton PumpInhibitors in NSAID-Induced UlcerationMOESUESTELLEUBS
`
`during such short term studies, and these were
`quantified on an ordinalscale in each report. Table
`I showsthe percentage reduction in the proportion
`of patients with numerouserosions in the active
`treatment arms compared with placebo. The cut-
`off categories are arbitrary and vary somewhatbe-
`tween studies, but ‘protected’ patients generally
`had less than 10 erosions in gastric mucosa. Pro-
`tection against erosions, defined in this way, was
`seen in 79 to 100% of patients treated with om-
`eprazole 20 to 40 mg/day.A similar protection was
`seen in the study by Bigard!*] using omeprazole
`60 mg/day, and in the small study with lanso-
`prazole 30 mg/day.*! Protection may be some-
`what less when lansoprazole 15 mg/dayis used.0!
`Twostudies included armstreated with ranitidine
`
`300 mg/day, which did not confer significant pro-
`tection.603]
`It is uncommon for ulcers to develop during
`such short term administration of NSAIDs. How-
`ever, a few acute ulcers were seen in the studies by
`Scheimanetal.{32] and Bianchi Porroetal.!?6] Om-
`eprazole 40 or 20 mg/day reducedthis incidence
`by 80 to 100% (tableI), although the numbers were
`small and significance was reached only in the
`larger study.[2°]
`Duodenalulcers also appeared in a few patients.
`In the Scheimanet al.{3?! study, none occurred in
`the omeprazole group but 15% developed them
`while taking placeboplus aspirin (p < 0.01). Only
`2 duodenal ulcers developed in the Bianchi Porro
`et al.!26] study, | in each group.
`
`TableI. Blinded controlled studies of effects of co-treatment with proton pumpinhibitors on gastric damage during short term treatment with
`nonsteroidal anti-inflammatory drugs (NSAIDs)
`Reference
`NSAID (daily
`Duration of No. of
`dosage}
`NSAID use
`patients
`Aspirin
`14 days
`20
`(acetylsalicylic
`acid) {2.6g]
`
`Co-treatment(daily
`dosage}
`Placebo
`
`Reduction in gastric
`damage?
`
`p-Value
`
`Scheiman et al.84i
`
`Bigard!26]
`
`Aspirin (600mg)
`
`1 day?
`
`Bianchi Porro etal.61 Several
`
`21 days
`
`Cddssonetal.21!
`
`Naproxen(1g)
`
`5 days?
`
`20
`
`114
`
`15
`
`Daneshmend et al.2”1 Aspirin (900mg)
`
`2 days?
`
`16
`
`Simonetal.P3
`
`Aspirin (300mg)
`
`14 days
`
`36
`
`Milleret al.8%
`
`Aspirin (300mg)
`
`14 days
`
`30
`
`Bergmannetal.!41
`
`Aspirin (1g)
`
`4 day”
`
`12
`
`Omeprazole (40mg)
`
`Placebo
`
`Omeprazole (60mg)
`Placebo
`
`Omeprazole (20mg)
`Placebo
`
`Ranitidine (300mg}
`Omeprazole (40mg)
`Placebo
`
`Omeprazole (20mg)
`Omeprazole (80mg)
`Placebo
`
`Omeprazole (20mg)
`Omeprazole (40mg)
`Placebo
`
`Ranitidine (300mg)
`Lansoprazole (15mg)
`Placebo
`
`79% (erosions)
`80% {ulcers}
`
`85% (erosions)
`
`100% (ulcers)
`
`60%
`100%
`
`79% {blood loss}
`85% {blood joss)
`
`77% (erosions)
`85% (erosions)
`
`43% (erosions)
`64% (erosions)
`
`<0.01
`NS
`
`<0.001
`
`<0.01
`
`NS
`<0.05
`
`<0.01
`<0.01
`
`<0.001
`<0.001
`
`NS
`<0.05
`
`Lansoprazole (30mg)
`
`<0.005
`70% (mean erosion score)
`<0.05
`100% {erosion score >2)
`SnagevergnaTemnntTn
`a Erosions were usually quantified on scalesof 0 to 4; percentage reductions generally calculated here as reduction in patients with
`grade 3 or 4 damage.
`b Co-treatment started 2 to 6 days prior to NSAID treatment.
`NS = notsignificant.
`
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`Drug Safety 1999 Dec: 21 (6)
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`Brown & Yeomans
`508
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`
`Table II. Developmentof nonsteroidal anti-inflammatory drug (NSAID)-related peptic ulcer during proton pumpinhibitor prophylaxis in
`placebo-controlled trials
`Durationee
`Patients developing peptic ulcer (%)
` p-Value
`Authors
`No. of
`Agent
`active
`placebo
`patients
`4
`18
`469
`
`Cullen etal4
`
`6 months
`
`<0.01
`
`<0.05
`
`0.29?
`
`Omeprazole
`20 mg/day
`Omeprazole
`20 mg/day
`Pantoprazole
`40 mg/day
`
`a_ The powerofthis 2 test was only 0.2.
`
`Ekstrdm etal,56
`
`Bianchi Porroetal.!971
`
`175
`
`104
`
`3 months
`
`3 months
`
`5
`
`28
`
`17
`
`41
`
`the protection by
`the time of writing),
`at
`Another measureofgastric mucosalinjury is the
`pantoprazole was less marked (32%), although the
`fall
`in transmucosal potential difference which
`results are not readily comparable with other stud-
`reproducibly followsa dose of an NSAID.41 This
`ies because of the very high ulcer occurrence rates
`fall occurs within minutes of giving aspirin, and
`in both active treatment and placebo groups.
`reflects the widespread denudationofthe cells lin-
`Dyspeptic symptomsalso benefited from proton
`ing the mucosal surface.'4] Bergmann etal.
`pumpinhibitor treatmentin these studies, although
`measured this for 3 hours after administration of
`it is interesting that the correlation between symp-
`aspirin before performing endoscopy to quantify
`toms and endoscopic end-points was poor.
`erosions. It is interesting that lansoprazole did not
`The data on site of ulcer occurrence in these
`protect againstthis fall in potential difference, al-
`papersraise the possibility that proton pump inhib-
`though it did protect against the developmentof
`itors may protect the duodenumalittle better than
`endoscopic erosions. This is consistent with the
`the stomach, although the differences do not ap-
`idea presented in section 1.2 that acid is more im-
`proach statistical significance. However,
`this
`portant for the ‘second wave’ofinjury that leadsto
`would be consistent with the previous observations
`the deeper lesions than for the initial superficial
`aboutthe differential efficacy of Hz antagonists in
`injury produced by NSAIDs.
`this setting.
`
`3.2 Longer Term Studies (More
`Than 1 Month)
`
`3.2.7 Proton PumpInhibitors Versus Placebo
`To date, 3 placebo-controlled studies that com-
`pared proton pumpinhibitor therapy with placebo
`for 3 months or longer have been published (see
`table If). All have been well conducted, with pro-
`tocols that allow their findings to be generalised to
`the NSAID-taking population at large. Despite
`varying somewhat in design, the 2 larger studies
`both reported reductions ofmore than 70% in over-
`all ulcer rates (gastric plus duodenal) when om-
`eprazole 20 mg/day was co-prescribed with the
`NSAID.135361 A placebo arm wasalso included in
`the large misoprostol versus omeprazole trial de-
`scribed in section 3.2.3. In the smaller study by
`Bianchi Porroet al.87! (available only as an abstract
`
`3.2.2 Proton PumpInhibitor Versus H2 Antagonist
`The recently published Acid Suppression Trial:
`Ranitidine versus Omeprazole for NSAID-Associ-
`ated Ulcer Treatment (ASTRONAUT)study!?8! re-
`cruited patients continuing treatment with NSAIDs
`who had peptic ulcer or more than 10 gastric or
`duodenal erosions. It consisted of 2 phases — an
`initial healing phase and a subsequent maintenance
`phase.
`Healing of peptic ulcers in patients continuing
`treatment with NSAIDs was significantly better
`with omeprazole than with ranitidine over 2
`months (87 vs 70.5%) but was independentof the
`omeprazole dosage, 20 and 40 mg/day being
`equally efficacious.
`In the subsequent maintenance phase, those pa-
`tients whose lesions healed were randomisedto ei-
`
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`Proton PumpInhibitors in NSAID-Induced Ulceration
`
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`509
`
`0.1 by x? analysis), particularly as a result of an
`adverse event (7.7 vs 3.9 vs 1.9%, p < 0.02). Rates
`of individual adverse effects were not dramatically
`different between any of the agents (e.g. miso-
`prostol was associated with diarrhoea in 8.4% of
`patients compared with 7.6% of patients taking
`omeprazole), although this may be a function of
`sample size.
`It is interesting to note the apparentdifference
`in efficacy of omeprazole prophylaxis between the
`2 studies despite the tandem design. It can be seen
`from fig. 2 that there were 3 times moreulcers on
`omeprazole in the OMNIUMstudy as compared
`with the ASTRONAUTstudy. Presumably this re-
`flects differences in the patient populations re-
`a
`
`40
`
`ASTRONAUT
`
`Duodenal ulcer
`O Gastric ulcer
`
`30
`
`20
`
`ther omeprazole 20 mg/day or ranitidine 150mg
`twice daily and assessed after 6 months. Om-
`eprazole was again moreeffective, with 94% re-
`maining ulcer-free overall compared with 79.5%
`onranitidine (see fig. 2).
`Again there wasa trend to higher protection
`against duodenal ulcer: only | duodenal ulcer
`(0.5%) was noted during omeprazole maintenance
`treatment compared with 11 gastric ulcers (5.2%),
`whereas with ranitidine there were 9 duodenaland
`35 gastric ulcers (4.2% and 16.3% respectively).
`As expected, both these acid-suppressant drugs
`were well tolerated.
`
`3.2.3 Proton PumpInhibitor Versus Misoprosfol
`The Omeprazole versus Misoprostol for NSAID-
`Induced Ulcer Management (OMNIUM)study}?!
`wasofsimilar design to ASTRONAUT,?®! compar-
`ing omeprazole with misoprostol in the healing
`phase and adding a placebo arm to the maintenance
`phase.
`Omeprazole (either 20 or 40 mg/day) was slightly
`more effective than misoprostol (200ug 4 times
`daily) for overallulcer healing at 8 weeks (86 vs
`74%). However, misoprostol had greater efficacy
`for healing erosive disease alone. Asa result, there
`was no significant difference in efficacy between
`the 2 agents for the primary end-pointofthe study,
`which was a composite requiring healing of ulcers
`and erosions and symptomrelief.
`In the maintenance phase, those healed were
`randomised to omeprazole 20 mg/day, misoprostol
`200pg twicedaily or placebo for 6 months. Overall
`ulcer recurrencerates were 15% in patients receiv-
`ing omeprazole, 21% in patients receiving miso-
`prostol and 44.5% in patients receiving placebo
`(see fig. 2).
`Again, examination of ulcer-site data as shown
`in figure 2 is of interest. Omeprazole and miso-
`prostol have similar efficacy in the stomach a3
`and 10% recurrence respectively), but omeprazole
`appears superior for prophylaxis of duodenal ulcer
`(3% recurrence vs 10% for misoprostol).
`In termsofadverse effects, misoprostol wasdis-
`continued more often than either omeprazole or
`placebo (16.8 vs 12.1 vs 10.3% respectively, p <
`
`© Adis internationalLimited.All rights reserved.
`
`
`
`Patientsdevelopingulcer(%)
`
`
`
`
`
`Omeprazole
`
`Ranitidine
`
`OMNIUM
`
`40
`
`
`Omeprazole
`
`Misoprostol
`
`Placebo
`
`Fig. 2. Proportion of patients developing nonsteroidal anti-
`inflammatory drug (NSAID)-associatedulcers during 6 months
`of co-treatment with omeprazole 20 mg/day, ranitidine 150mg
`twice daily, misoprostol 200g twice daily or placebo. (a) Acid
`Suppression Trial: Ranitidine versus Omeprazole for NSAID-
`Associated Ulcer Treatment (ASTRONAUT) study:4) (b) Om-
`eprazole versus Misoprostol for NSAID-Induced Ulcer
`Management (OMNIUM) study.!*9
`
`Drug Safety 1999 Dec; 21 (6)
`
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`

`

`Brown«
`510
`
`
`PLAINSONESENOEAEREOADIASETOSSESSNORESAMSESEOIEELLERRONSIREEATONVIESEITE
`
`With these benefits come costs, mostly for the
`prophylactic medication. There are of course sav-
`ings as well, measured in reduced medical costs
`and greater workplace productivity. The relation-
`ship between these deserves formalanalysis. One
`recent cost-effectiveness study calculated that the
`cost of NSAID complications (in Sweden) is
`around US$450 (1999 values) per patient per an-
`num.4!] The cost of prophylactic co-therapy needs
`to be set against this.
`Another question that needs answering is
`whether Helicobacter pylori infection constitutes
`an additional risk factorin patients taking NSAIDs.
`If it did, it would be rational to routinely treat 7.
`pyloriin such patients. However, studies have been
`conflicting. In both the ASTRONAUT®®! and OM-
`NIUM2%1studies described in section 3.2, patients
`who were H.pylori positive were more likely than
`patients who were H. pylori negative to have their
`NSAID-associated ulcer healed andless likely to
`have one develop during healing or maintenance
`therapy with omeprazoleor ranitidine. However,1
`study has shown a marked reduction in the inci-
`dence of ulcers during 2 months’ treatment with
`naproxen whenH. pylori was successfully treated.[42]
`Anotherstudy, over a longerperiod in patients who
`had been taking NSAIDsprior to the H. pylori
`treatment, found no such benefit.!*7! Differences in
`study populations may accountin part for these
`opposing findings, but more research is needed to
`guide clinical managementofthis issue.
`
`4, Conclusions
`
`
`
`cruited in the 2 studies (including the spectrum of
`NSAIDs taken).
`
`3.3 Future Research Needs
`
`Both the ASTRONAUT®! and OMNIUMP?!
`studies were high quality trials with large numbers
`of patients. Taken together with the Omeprazole
`versus Placebo as Prophylaxis ofUlcers and Erosions
`from NSAID Treatment (OPPULENT) study,!5!
`they included a spectrumofpatients similar to the
`NSAID-taking population at large, i.e. patients
`whorangedfrom low risk (young and withoutprior
`ulceration) to those at the high risk end (older and
`with recent ulceration). However,there are a num-
`ber of questionsstill unanswered about the role of
`proton pump inhibitors in protecting against
`NSAID-associated ulcers. One is whetherall pro-
`tonpump inhibitorsare equally effective at equiv-
`alent dosages.It is likely that this will be the case,
`although the studies so far with lansoprazole and
`pantoprazole have been small and have given less
`impressive results than the large studies with om-
`eprazole. Tosettle this question, comparative stud-
`ies with at least several hundred patients in each
`arm would be needed.
`The optimally effective dosage of a proton
`pump inhibitor for preventing ulcers has not been
`examined. In the healing arms of the ASTRO-
`NAUTand OMNIUMstudies,839) omeprazole 20
`mg/day wasaseffective as 40 mg/day, but only the
`20 mg/day dosage was examined in the mainte-
`nance phasesofthe studies. Whether a higher dos-
`age would give even better protection is therefore
`not known.
`.
`Protection by proton pump inhibitors against
`NSAIDulcer complications has now been demon-
`strated in a recent study.!4°] To date this has been
`published only as an abstract. This result may be
`worth confirming, although it is very much to be
`expected that the now well documented reduction
`in the incidence ofulcers will be reflected in a re-
`duction in ulcer complications as well — afterall,
`an ulcer that is not present cannot bleed or perfo-
`rate.
`
`Proton pumpinhibitors have demonstratedeffi-
`cacy in the prevention of the adverse gastrointesti-
`nal effects of NSAIDs.
`They reduce ulcer rates by up to 80% compared
`with no treatment, and have clear benefits over H2
`antagonists (particularly in the stomach) and to a
`lesser extent over misoprostol(particularly in the
`duodenum,and in patient tolerability).
`Nevertheless there are still some ‘break-
`through’ ulcers on the dosages of proton pump in-
`hibitor tested to date, especially in the stomach.
`Hence, the importance of reviewing the need for
`
`rc
`
`© Adis International Limited.All rights reserved.
`
`Drug Safety 1999 Dec: 21 (6)
`
`MYLAN PHARMS.INC. EXHIBIT 1063 PAGE 8
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`MYLAN PHARMS. INC. EXHIBIT 1063 PAGE 8
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`

`

`Proton PumpInhibitors in NSAID-Induced Ulceration
`
`511
`
`
`NSAIDsatthe outset, as well as selecting the low-
`est dosageofthe least toxic agent, cannotbe over-
`stressed.
`The new generation of highly selective COX-2
`inhibitors is beginning to provide a further option
`for reducing ulcerrisk in patients who need anti-
`inflammatory drugs, althoughtheyare likely to be
`expensive and it is a little early to assess their
`longer term adverseeffect profile. These drugs will
`not, of course, be a substitute for aspirin used for
`its anti-platelet (COX-1) effect.
`Whenaspirin or other nonselective COX inhib-
`itors are used, the proton pumpinhibitors appear
`to provide a significant advance in improving the
`tolerability of NSAID therapy.
`
`Acknowledgements
`
`This work was supported in part by the National Health
`and Medical Research Council of Australia. The authors
`thank Ms Julie Holland and Ms Lyn Kalmsfor administrative
`assistance.
`
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