PRACTICAL DRUG SAFETY
`
`Drug Safety 1999 Dec: 21 (6): 503-512
`0114-5916/99/0012-0503/$05.00/0
`
`© Adis International Limited. All rights reserved.
`
`Prevention of the Gastrointestinal
`Adverse Effects of Nonsteroidal
`Anti-Inflammatorv Drugs
`The Role of Proton Pump Inhibitors
`
`Gregor J.E. Brown and Neville D. Yeomans
`The University of Melbourne Department of Medicine, Western Hospital, Melbourne, Victoria, Australia
`
`Contents
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
`Abstract
`. 504
`1. Background.
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . '.'
`. . .
`1. 1 Risks of Damage and Ulceration Induced by Nonsteroidal Anti-inflammatory
`Drugs (NSAIDs)
`. . . 504
`1.2 Rationale for Acid Suppression . . . . . . . . . . . . . . . . . . . . . .
`. . . 504
`2. Non-Proton Pump Inhibitor Strategies for Risk Reduction . . . . . . . . . . . .
`. . . . . . . . 505
`2.1 NSAID Selection . . . . . ..
`. . . . .
`. . . 505
`. . . . . . . . .
`2.2 Cytoprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
`505
`. . . 506
`2.3 Histamine H2 Antagonists . . . . . . . . . . . . . . . . . . . . . . . . .
`. . . . . . 506
`3. Clinical Studies of Proton Pump Inhibitors for Prophylaxis of NSAID Injury .
`.
`506
`3.1 Short Term Studies (Up To 1 Mon·th) .. . . . . . . . . .
`. . . . . ..
`508
`3.2 Longer Term Studies (More Than 1 Month)
`. . . . . . . . . . 508
`3.2. 1 Proton Pump Inhibitors Versus Placebo . . . . . . . . . . . . . .
`3.2.2 Proton Pump Inhibitor Versus H2 Antagonist
`. . . . . . . . . . . . . . . . . . . . . . . 508
`3.2.3 Proton Pump Inhibitor Versus Mlsoprostol ..
`509
`3.3 Future Research Needs .. . .
`. . . . . . . . .
`510
`4. Conclusions
`510
`
`. . . . . ..
`
`.
`
`Abstract
`
`The associations between nonsteroidal anti-inflammatory drugs (NSAIDs)
`and the presence and complications of gastroduodenal erosions and ulcers are
`well established. Evidence that acid aggravates NSAID-induced injury provides
`a rationale for minimising such damage by acid suppression. Other strategies
`discussed include avoidance of NSAIDs or minimising their dosage, selecting
`NSAIDs known to cause less damage, and co-prescription of various agents.
`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 some patients. Histamine
`H2 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 may relate to their relatively modest effect in elevating gastric pH,
`especially in comparison with proton pump inhibitors.
`Several studies now confirm the efficacy of proton pump inhibitors in the short
`and longer term prevention of NSAID-induced upper gastrointestinal injury. Pla-
`
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`

`

`504
`
`Brown & Yeomans
`
`cebo-controlled studies suggest reductions of over 70% in gastric and duodenal
`ulcer rates over 3 to 6 months. The recent ASTRONAUT (Acid Suppression Trial:
`Ranitidine versusOmeprazole 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 omeprazole to be slightly
`more effective overall than misoprostol in preventing the upper gastrointestinal
`adverse effects of NSAIDs, with both substantially more effective than placebo,
`although misoprostol was somewhat less well tolerated.
`Although substantial reductions in NSAID ulceration are now achievable
`when co-therapy with a proton pump inhibitor is given, a few patients will still
`develop ulcers and their complications. Hence the judicious use of NSAIDs in
`the first instance cannot be overemphasised.
`
`The aims of this review are to briefly define the
`problem of ulceration 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(cid:173)
`dresses the evidence for clinical benefit when a
`proton pump inhibitor and some other agents are
`co-prescribed with NSAIDs. The literature was
`searched using Medline supplemented with scan(cid:173)
`ning of abstracts of recent major scientific meet(cid:173)
`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(cid:173)
`trointestinal tract are a frequent cause of morbidity
`and even mortality. [1] Awareness of peptic ulcer as
`a complication of anti-inflammatory dosages of
`NSAIDs is high and, probably because of this,
`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(cid:173)
`stitutive isoenzyme ·COX-l) will cause less gas(cid:173)
`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 myocardial infarction is increasing, and
`this will produce an increasing burden of ulceration
`as an adverse event.
`With the current generation of NSAIDs, the
`great majority of patients develop some erosions in
`the stomach after each dose, [3] and about 15 to 25%
`of patients who have been taking NSAIDs regu(cid:173)
`larly will be found to have a discrete ulcer if they
`are examined with gastroscopy at any point in
`time.l3,4] Most ulcers found in this way are asymp(cid:173)
`tomatic and quite small.[3] They presumably heal
`and reappear a number of times before reaching a
`threshold for diagnosis in normal practice.
`The most important complications of NSAID(cid:173)
`induced ulceration of the stomach or duodenum are
`haemorrhage and perforation. Case-control studies
`have shown that NSAIDs increase the risk of these
`complications by. about 3 to 10 times, [4] and for
`some particular NSAIDs the risk is higher still.
`Even low dosage aspirin increases the chance of
`ulcer haemorrhage or perforation by 2 to 4 times. [5]
`
`1.2 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 of the 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 Intemational Limited. All rights reserved.
`
`Drug Sofety 1999 Dec: 21 (6)
`
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`

`Proton Pump Inhibitors in NSAID-Induced Ulceration
`
`505
`
`high pH is well documented with aspirin. [6,7] Having
`gained entry to the surface cells, aspirin becomes
`trapped at the higher intracellular pH and causes
`local toxicity. There is, however, much less evi(cid:173)
`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
`of the superficial erosions that are very widespread
`soon after administration of an NSAID. Much of
`the superficial injury repairs within an hour or two,
`but here and there the damaged surface seems not
`to repair in time before the acid in the lumen causes
`further deeper destruction of tissue. [9] These focal,
`deeper, areas are the macroscopic erosions seen en(cid:173)
`doscopically in most patients who are taking
`NSAIDs. In rats, vagotomy reduces this deeper
`damage without altering the initial superficial in(cid:173)
`jury by NSAIDs.l10,1l] More recent data from El-
`liott et al.[l2] show that gastric mucosal injury in
`the rat is much reduced when the luminal pH is
`elevated above a threshold of about 4.0 (fig. 1).
`This pH is rarely achieved for long after H2 antag(cid:173)
`onists, but can be readily achieved for at least half
`of each 24-hour period during administration of
`proton pump inhibitors at standard dosages.l13.14]
`
`2. Non-Proton Pump Inhibitor
`Strategies for Risk Reduction
`
`2.1 NSAID Selection
`
`Against this background of ulcer risk, there are
`a number of clinical and pharmacological strate(cid:173)
`gies that can be employed to reduce it. The first and
`most obvious is to avoid NSAIDs when they are
`not necessary. Secondly, when NSAIDs do need to
`be used, there is now good evidence that the risk
`of ulcer complications is dosage dependent,[15] so
`the NSAID should be used at the lowest effective
`dosage. A recent meta-analysis has confirmed that
`some NSAIDs are more damaging than others.[15]
`For example, the short-acting NSAIDs ibuprofen
`and diclofenac (at standard dosage) have usually
`been found to have relative risks of the order of 3
`to 5 for ulcer bleeding, whereas some of the long-
`
`acting drugs recommended for once-daily admin(cid:173)
`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-2 inhibitors, already marketed in some coun(cid:173)
`tries, offer a further choice, particularly in patients
`at high risk of NSAID ulceration.
`
`2.2 Cytoprotection
`
`Coadministering a prostaglandin analogue re(cid:173)
`duces the gastric and duodenal damage caused by
`NSAIDs. This approach was developed knowing
`that prostaglandins are defensive factors in the nor(cid:173)
`mal gastric mucosa and that NSAIDs exert their
`damage, at least in part, by inhibiting the produc(cid:173)
`tion of these mucosal prostaglandins. In short term
`studies, prostaglandins markedly reduce the num(cid:173)
`ber of erosions in the stomach during NSAID ad(cid:173)
`ministration. [16-18] In longer term studies (3 to 12
`months), misoprostol- an analogue of prostaglan(cid:173)
`din E1- has been shown to reduce the incidence of
`gastric and duodenal ulcers by about 60 to
`70%, [3,19] although higher protection rates have
`also been reported. [20] One large study also showed
`an approximate halving in the number of episodes
`of ulcer bleeding over a 6-month period.[21]
`Thus, cytoprotection with a coadministered
`prostaglandin is an effective strategy for reducing
`
`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
`indomethacin in rats. Injury was markedly reduced when the pH
`of the lumen was buffered to higher than 4 (after Elliott et al.,[12}
`with permission).
`
`© Adis Intemational Umited. 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(cid:173)
`tion is dosage dependent, but so are the adverse
`effects of diarrhoea and abdominal cramps, which
`occur in about 10% of patients.
`
`focused on proton pump inhibitors as an effective
`yet tolerable means of protecting the stomach from
`the important adverse effect of NSAIDs - peptic
`ulceration.
`
`2.3 Histamine H2 Antagonists
`
`3.1 Short Term Studies (Up To 1 Month)
`
`Histamine H2 antagonists, at least at standard
`dosages, have only limited efficacy for preventing
`NSAID-induced ulcers in humans. Two well-con(cid:173)
`ducted controlled trials showed that ranitidine
`150mg twice daily gave substantial protection
`against the development of duodenal ulcers during
`NSAID administration. [22,23] 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(cid:173)
`other large survey of patients with arthritis, the use
`of cimetidine produced no reduction in the inci(cid:173)
`dence of ulcer bleeding. [24]
`More marked acid suppression with larger doses
`of H2 antagonists may give better results. A recent
`trial by Taha et al. [25] showed a 60% reduction in
`gastric ulceration, and an 85% reduction in duode(cid:173)
`nal ulcers, during 6 months treatment with famotid(cid:173)
`ine 40mg twice daily.
`Even at these larger dosages, H2 antagonists
`have a fairly modest effect in elevating intragastric
`pH. For instance, in patients taking a standard dos(cid:173)
`age of ranitidine, median pH in the stomach over a
`24-hour period is rarely greater than 3.[14] In con(cid:173)
`trast, median intragastric pH in patients taking
`standard dosages of proton pump inhibitors is usu(cid:173)
`ally at least 1 unit higher, of the order of 4 to 5.[13]
`These are the pH values that we had previously
`shown need to be reached if the acid component of
`NSAID gastric injury is to be reduced. [12] The next
`section reviews the data now available about the
`use of proton pump inhibitors for preventing
`NSAID injury.
`
`3. Clinical Studies of Proton
`Pump Inhibitors for Prophylaxis
`of NSAID Injury
`
`Given the limitations of standard preventive
`measures, it is not surprising that attention has been
`
`Whether or not proton pump inhibitors protect
`against acute NSAID damage in humans has been
`examined in a number of short term trials. In most
`instances, the proton pump inhibitor used has been
`omeprazole.
`Table I summarises the findings from 8 control(cid:173)
`led, randomised, double-blind trials since 1988.
`The study by Bianchi Porro et al.[26] recruited pa(cid:173)
`tients with arthritis, who were treated with om(cid:173)
`eprazole or placebo concurrently with an NSAID
`for 3 weeks. This was the 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
`pump inhibitor or comparator drug was started 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 pump inhibitors,[13] so this de(cid:173)
`sign ensured that acid suppression was well estab(cid:173)
`lished when the NSAID was given.
`All studies demonstrated protection against
`NSAID gastric damage when co-therapy was given
`with either omeprazole or lansoprazole.
`Daneshmend et al.[27] assessed gastric damage
`by using a gastric lavage technique to measure gas(cid:173)
`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
`examine the effect of dosage. However, they found
`a significant negative correlation between the vol(cid:173)
`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.
`
`Drug Sofety 1999 Dec; 21 (6)
`
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`

`Proton Pump Inhibitors in NSAID-Induced Ulceration
`
`507
`
`during such short term studies, and these were
`quantified on an ordinal scale in each report. Table
`I shows the percentage reduction in the proportion
`of patients with numerous erosions in the active
`treatment arms compared with placebo. The cut(cid:173)
`off categories are arbitrary and vary somewhat be(cid:173)
`tween studies, but 'protected' patients generally
`had less than 10 erosions in gastric mucosa. Pro(cid:173)
`tection against erosions, defined in this way, was
`seen in 79 to 100% of patients treated with om(cid:173)
`eprazole 20 to 40 mg/day. A similar protection was
`seen in the study by Bigard[28] using omeprazole
`60 mg/day, and in the small study with lanso(cid:173)
`prazole 30 mg/day.[29] Protection may be some(cid:173)
`what less when lansoprazole 15 mg/day is used. [30]
`Two studies included arms treated with ranitidine
`
`300 mg/day, which did not confer significant pro(cid:173)
`tection. [30,31]
`It is uncommon for ulcers to develop during
`such short term administration of NSAIDs. How(cid:173)
`ever, a few acute ulcers were seen in the studies by
`Scheiman et al.[32] and Bianchi Porro et al.[26] Om-
`eprazole 40 or 20 mg/day reduced this incidence
`by 80 to 100% (table I), although the numbers were
`small and significance was reached only in the
`larger study. [26]
`Duodenal ulcers also appeared in a few patients.
`In the Scheiman et al. [32] study, none occurred in
`the omeprazole group but 15% developed them
`while taking placebo plus aspirin (p < 0.01). Only
`2 duodenal ulcers developed in the Bianchi Porro
`et al. [26] study, 1 in each group.
`
`Table I. Blinded controlled studies of effects of co-treatment with proton pump inhibitors on gastric damage during short term treatment with
`nonsteroidal anti-inflammatory drugs (NSAIDs)
`
`Reference
`
`Scheiman et al.[32]
`
`NSAID (daily
`dosage)
`Aspirin
`(acetylsalicylic
`acid) [2.6g]
`
`Duration of No. of
`NSAID use patients
`14 days
`20
`
`Co-treatment (daily
`dosage)
`Placebo
`
`Reduction in gastric
`damagea
`
`p-Value
`
`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
`Lansoprazole (30mg)
`
`790/0 (erosions)
`80% (ulcers)
`
`85% (erosions)
`
`1000/0 (ulcers)
`
`60%
`100%
`
`79% (blood loss)
`850/0 (blood loss)
`
`770/0 (erosions)
`850/0 (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
`
`Bigard(28]
`
`Aspirin (600mg)
`
`1 dayb
`
`20
`
`Bianchi Porro et al.(26] Several
`
`21 days
`
`114
`
`Oddsson et al.(31]
`
`Naproxen (1g)
`
`5 daysb
`
`15
`
`Daneshmend et al.[27] Aspirin (900mg)
`
`2 daysb
`
`16
`
`Simon et al.[33]
`
`Aspirin (300mg)
`
`14 days
`
`36
`
`Muller et al.[30]
`
`Aspirin (300mg)
`
`14 days
`
`30
`
`Bergmann et al.[29]
`
`Aspirin (1g)
`
`1.dayb
`
`12
`
`<0.005
`700/0 (mean erosion score)
`<0.05
`100% (erosion score >2)
`a Erosions were usually quantified on scales of 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 =not significant.
`
`© Adislntemational Limited. All rights reserved.
`
`Drug Safety 1999 Dec; 21 (6)
`
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`

`508
`
`Brown & Yeomans
`
`Table II. Development of nonsteroidal anti-inflammatory drug (NSAID)-related peptic ulcer during proton pump inhibitor prophylaxis in
`placebo-controlled trials
`
`p-Value
`
`<0.01
`
`<0.05
`
`0.298
`
`Patients developing peptic ulcer (%)
`active
`placebo
`4
`18
`
`17
`
`41
`
`5 2
`
`8
`
`Authors
`
`Cullen et al.[35]
`
`EkstrOm et al.[36]
`
`Bianchi Porro et al.[37]
`
`No. of
`patients
`169
`
`175
`
`104
`
`a The power of this X? test was only 0.2.
`
`Agent
`
`Duration
`
`Omeprazole
`20 mg/day
`Omeprazole
`20 mg/day
`Pantoprazole
`40 mg/day
`
`6 months
`
`3 months
`
`3 months
`
`Another measure ofgastric mucosal injury is the
`fall in transmucosal potential difference which
`reproducibly follows a dose of an NSAID.[34} This
`fall occurs within minutes of giving aspirin, and
`reflects the widespread denudation of the cells lin(cid:173)
`ing the mucosal surface.[34} Bergmann et al. [Z9}
`measured this for 3 hours after administration of
`aspirin before performing endoscopy to quantify
`erosions. It is interesting that lansoprazole did not
`protect against this fall in potential difference, al(cid:173)
`though it did protect against the development of
`endoscopic erosions. This is consistent with the
`idea presented in section 1.2 that acid is more im(cid:173)
`portant for the' second wave' of injury that leads to
`the deeper lesions than for the initial superficial
`injury produced by NSAIDs.
`
`3.2 Longer Term Studies (More
`Than 1 Month)
`
`3.2.1 Proton· Pump Inhibitors Versus Placebo
`To date, 3 placebo-controlled studies that com(cid:173)
`pared proton pump inhibitor therapy with placebo
`for 3 months or longer have been published (see
`table II). All have been well conducted, with pro(cid:173)
`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 of more than 70% in over(cid:173)
`all ulcer rates (gastric plus duodenal) when om(cid:173)
`eprazole 20 mg/day was co-prescribed with the
`NSAID.[35,36] A placebo arm was also included in
`the large misoprostol versus omeprazole trial de(cid:173)
`scribed in section 3.2.3. In the smaller study by
`Bianchi Porro et al. [37] (available only as an abstract
`
`the protection by
`the time of writing),
`at
`pantoprazole was less marked (32%), although the
`results are not readily comparable with other stud(cid:173)
`ies because of the very high ulcer occurrence rates
`in both active treatment and placebo groups.
`Dyspeptic symptoms also benefited from proton
`pump inhibitor treatment in these studies, although
`it is interesting that the correlation between symp(cid:173)
`toms and endoscopic end-points was poor.
`The data on site of ulcer occurrence in these
`papers raise the possibility that proton pump inhib(cid:173)
`itors may protect the duodenum a little better than
`the stomach, although the differences do not ap(cid:173)
`proach statistical significance. However,
`this
`would be consistent with the previous observations
`about the differential efficacy of Hz antagonists in
`this setting.
`
`3.2.2 Proton Pump Inhibitor Versus H2 Antagonilt
`The recently published Acid Suppression Trial:
`Ranitidine versus Omeprazole for NSAID-Associ(cid:173)
`ated Ulcer Treatment (ASTRONAUT) study[38} re(cid:173)
`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 independent of the
`omeprazole dosage, 20 and 40 mg/day being
`equally efficacious.
`In the subsequent maintenance phase, those pa(cid:173)
`tients whose lesions healed were randomised to ei-
`
`© Adis International Limited. All rights reserved.
`
`Drug Sofety 1999 Dec: 21 (6)
`
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`

`

`Proton
`
`Inhibitors in NSAID-Induced Ulceration
`
`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(cid:173)
`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 apparent difference
`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 more ulcers on
`omeprazole in the OMNIUM study as compared
`with the ASTRONAUT study. Presumably this re(cid:173)
`flects differences in the patient populations re-
`
`40
`
`30
`
`20
`
`10
`
`0
`
`a
`
`b
`
`ASTRONAUT
`
`II Duodenal ulcer
`o Gastric ulcer
`
`Omeprazole
`
`Ranitidine
`
`OMNIUM
`
`-
`
`~ Q
`
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`
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`c:
`'5.
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`
`ther omeprazole 20 mg/day or ranitidine 150mg
`twice daily and assessed after 6 months. Om(cid:173)
`eprazole was again more effective, with 94% re(cid:173)
`maining ulcer-free overall compared with 79.5%
`on ranitidine (see fig. 2).
`Again there was a trend to higher protection
`against duodenal ulcer: only 1 duodenal ulcer
`(0.5%) was noted during omeprazole maintenance
`treatment compared with 11 gastric ulcers (5.2%),
`whereas with ranitidine there were 9 duodenal and
`35 gastric ulcers (4.2% and 16.3% respectively).
`As expected, both these acid-suppressant drugs
`were well tolerated.
`
`3.2.3 Proton Pump Inhibitor Versus Mlsoprostol
`The Omeprazole versus Misoprostol for NSAID(cid:173)
`Induced Ulcer Management (OMNIUM) study[39]
`was of similar design to ASTRONAUT,l38] compar(cid:173)
`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 (200Jlg 4 times
`daily) for overall ulcer healing at 8 weeks (86 vs
`74%). However, misoprostol had greater efficacy
`for healing erosive disease alone. As a result, there
`was no significant difference in efficacy between
`the 2 agents for the primary end-point of the study,
`which was a composite requiring healing of ulcers
`and erosions and symptom relief.
`In the maintenance phase, those healed were
`randomised to omeprazole 20 mg/day, misoprostol
`200Jlg twice daily or placebo for 6 months. Overall
`ulcer recurrence rates were 15% in patients receiv(cid:173)
`ing omeprazole, 21 % in patients receiving miso(cid:173)
`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(cid:173)
`prostol have similar efficacy in the stomach (13
`and 10% recurrence respectively), but omeprazole
`appears superior for prophylaxis of duodenal ulcer
`(3% recurrence vs 10% for misoprostol).
`In terms of adverse effects, misoprostol was dis(cid:173)
`continued more often than either omeprazole or
`placebo (16.8 vs 12.1 vs 10.3% respectively, p <
`
`30
`
`20
`
`10
`
`o ....a..-_-L--.....a..-
`Omeprazole
`
`---A-
`
`_
`
`Misoprostol
`
`Placebo
`
`Fig. 2. Proportion of patients developing nonsteroidal anti(cid:173)
`inflammatory drug (NSAID)-associated ulcers during 6 months
`of co-treatment with omeprazole 20 mg/day, ranitidine 150mg
`twice daily, misoprostol 200~g twice daily or placebo. (a) Acid
`Suppression Trial: Ranitidine versus Omeprazole for NSAID(cid:173)
`Associated Ulcer Treatment (ASTRONAUT) study;[38] (b) Om(cid:173)
`eprazole versus Misoprostol for NSAID-Induced Ulcer
`Management (OMNIUM) study.l39]
`
`© Adis Intemotionol Limited. All rights reserved.
`
`Drug Safety 1999 Dec: 21 (6)
`
`Page 7 Dr. Reddy's Exh. 1042
`
`

`

`510
`
`Brown & Yeomans
`
`cruited in the 2 studies (including the spectrum of
`NSAIDs taken).
`
`3.3 Future Research Needs
`
`Both the ASTRONAUT[38] and OMNIUM[39]
`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,[35]
`they included a spectrum of patients similar to the
`NSAID-taking population at large, Le. patients
`who ranged from low risk (young and without prior
`ulceration) to those at the high risk end (older and
`with recent ulceration). However, there are a num(cid:173)
`ber of questions still unanswered about the role of
`proton pump inhibitors in protecting against
`NSAID-associated ulcers. One is whether all pro(cid:173)
`ton pump inhibitors are equally effective at equiv(cid:173)
`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(cid:173)
`eprazole. To settle this question, comparative stud(cid:173)
`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(cid:173)
`NAUTand OMNIUM studies,[38,39] omeprazole 20
`mg/day was as effective as 40 mg/day, but only the
`20 mg/day dosage was examined in the mainte(cid:173)
`nance phases of the studies. Whether a higher dos(cid:173)
`age would give even better protection is therefore
`not known.
`Protection by proton pump inhibitors against
`NSAID ulcer complications has now been demon(cid:173)
`strated in a recent study)40] 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 of ulcers will be reflected in a re(cid:173)
`duction in ulcer complications as well - after all,
`an ulcer that is not present cannot bleed or perfo(cid:173)
`rate.
`
`With these benefits come costs, mostly for the
`prophylactic medication. There are of course sav(cid:173)
`ings as well, measured in reduced medical costs
`and greater workplace productivity.. The relation(cid:173)
`ship between these deserves formal analysis. One
`recent cost-effectiveness study calculated that the
`cost of NSAID complications (in Sweden) is
`around US$450 (1999 values) per patient per an(cid:173)
`num.[41] 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 factor in patients taking NSAIDs.
`If it did, it would be rational to routinely treat H.
`pylori in such patients. However, studies have been
`conflicting. In both the ASTRONAUT[38] and OM(cid:173)
`NIUM[39] studies 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 and less likely to
`have one develop during healing or maintenance
`therapy with omeprazole or ranitidine. However, 1
`study has shown a marked reduction in the inci(cid:173)
`dence of ulcers during· 2 months' treatment with
`naproxen when H pyloriwas successfully treated.[42]
`Another study, over a longer period in patients who
`had been taking NSAIDs prior to the. H pylori
`treatment, found no such benefit.[43] Differences in
`study populations may account in part for these
`opposing findings, but more research is needed to
`guide clinical management of this issue.
`
`4. Conclusions
`
`Proton pump inhibitors have demonstrated effi(cid:173)
`cacy in the prevention of the adverse gastrointesti(cid:173)
`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(cid:173)
`through' ulcers on the dosages of proton pump in(cid:173)
`hibitor tested to date, especially in the stomach.
`Hence, the importance of reviewing the need for
`
`© Adis International Limited. All rights reserved.
`
`Drug Safety 1999 Dec; 21 (6)
`
`Page 8 Dr. Reddy's Exh. 1042
`
`

`

`Proton Pump Inhibitors in NSAID-Induced Ulceration
`
`511
`
`NSAIDs at the outset, as well as selecting the low(cid:173)
`est dosage of the least toxic agent, cannot be over(cid:173)
`stressed.
`The new generation of highly selective COX-2
`inhibitors is beginning to provide a further option
`for reducing ulcer risk in patients who need anti(cid:173)
`inflammatory drugs, although they are likely to be
`expensive and it is a little early to assess their
`longer term adverse effect profile. These drugs will
`not, of course, be a substitute for aspirin used for
`its anti-platelet (COX-I) effect.
`When aspirin or other nonselective COX inhib(cid:173)
`itors are used, the proton pump inhibitors 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 Kalms for administrative
`assistance.
`
`References
`1. Griffin MR. Epidemiology of nonsteroidal anti-inflammatory
`drug-associated gastrointestinal injury. Am J Med 1998; 104
`(3A): 23S-9S
`2. Henry D, Robertson J, Non-steroidal anti-inflammatory drugs
`and peptic ulcer hospitalisation rates in New South Wales.
`Gastroenterology 1993; 104: 1083-91
`3. Elliott SL, Yeomans ND, Buchanan RRC, et al. Efficacy of 12
`months' misoprostol as prophylaxis against NSAID-induced
`gastric ulcers: a placebo controlled trial. Scand J Gastro(cid:173)
`enterol1994; 23: 171-6
`4. Langman MJS, Brooks P, Hawkey CJ, et al. Management of
`non-steroidal anti-inflammatory drug associated ulcer: epide(cid:173)
`miology, causation and treatment. J. Gastroenterol Hepatol
`1991; 6: 442-9
`5. Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin
`and risk of peptic