Medical Progress
`
`The New England Journal of Medicine
`
`Review Article
`
`G
`
` T
`OXICITY
`ASTROINTESTINAL
` N
`
`OF
`ONSTEROIDAL
` D
`NTIINFLAMMATORY
`RUGS
`
`A
`
`M. M
`ICHAEL
`
` R. L
`, M.D., D
` W
`ICHTENSTEIN
`AVID
`OLFE
` G
` S
`, M.D.
`URKIRPAL
`AND
`INGH
`
`, M.D.,
`
`O
`
`NE hundred years have passed since Felix
`Hoffman, working at Bayer Industries, re-
`ported the successful synthesis of acetylsali-
`cylic acid as the first nonsteroidal antiinflammatory
` At the suggestion of Hermann
`drug (NSAID).
`1,2
`Dreser, Bayer’s chief pharmacologist at the time,
` the
`3
`compound was called “aspirin” and was purported
`to represent a convenient mechanism for the delivery
`of salicylic acid in the treatment of rheumatic diseas-
` Approximately 40 years
`es, menstrual pain, and fever.
`2
`elapsed before Douthwaite and Lintott
` provided
`4
`endoscopic evidence that aspirin could cause gastric
`mucosal damage. Numerous reports have corrobo-
` and the introduction of more
`rated this observation,
`5-8
`potent agents with an even greater propensity for
`toxic effects has increased the awareness of NSAID-
`induced gastroduodenal ulcer and provided impetus
`for the development of effective NSAIDs with a more
`favorable safety profile.
`Starting in the early 1970s, numerous new NSAIDs
`were developed that were initially believed to be de-
`void of gastrointestinal toxicity, but few, if any, are
`entirely harmless. These agents constitute one of the
`most widely used classes of drugs, with more than
`70 million prescriptions and more than 30 billion
`over-the-counter tablets sold annually in the United
`States.
` Although NSAIDs are generally well tolerat-
`9
`ed, adverse gastrointestinal events occur in a small
`but important percentage of patients, resulting in
`substantial morbidity and mortality.
`
`From the Section of Gastroenterology, Boston University School of
`Medicine and Boston Medical Center, Boston (M.M.W., D.R.L.); and the
`Division of Immunology and Rheumatology, Stanford University School
`of Medicine, Palo Alto, Calif. (G.S.). Address reprint requests to Dr. Wolfe
`at the Boston Medical Center, Section of Gastroenterology, 88 E. Newton
`St., Boston, MA 02118-2393, or at michael.wolfe@bmc.org.
`©1999, Massachusetts Medical Society.
`
`1888
`
`·
`
`June 17, 1999
`
`EPIDEMIOLOGY OF GASTROINTESTINAL
`COMPLICATIONS
`Because of the broad and nonspecific definitions
`of gastrointestinal disorders caused by the use of
`NSAIDs, as well as differences in patient populations,
`drugs, dosages, and periods of use, estimates of the
`prevalence of adverse effects vary greatly. In general,
`at least 10 to 20 percent of patients have dyspepsia
`while taking an NSAID, although the prevalence
` Within a six-
`may range from 5 to 50 percent.
`10,11
`month period of treatment, 5 to 15 percent of pa-
`tients with rheumatoid arthritis can be expected to
`discontinue NSAID therapy because of dyspepsia.
`11
`According to prospective data from the Arthritis,
`Rheumatism, and Aging Medical Information Sys-
`tem (ARAMIS), 13 of every 1000 patients with
`rheumatoid arthritis who take NSAIDs for one year
`have a serious gastrointestinal complication. The risk
`in patients with osteoarthritis is somewhat lower
`(7.3 per 1000 patients per year).
`12
`The rate of NSAID-related serious gastrointestinal
`complications requiring hospitalization has decreased
`in recent years. The decrease may be due, at least in
`part, to extensive medical-education campaigns that
`have persuaded physicians to use newer, less toxic
`NSAIDs and non-NSAID analgesics in populations
`at high risk.
`12
`The mortality rate among patients who are hospi-
`talized for NSAID-induced upper gastrointestinal
`bleeding is about 5 to 10 percent.
` An analysis of
`13
`data from ARAMIS has shown that the mortality
`rate attributed to NSAID-related gastrointestinal tox-
`ic effects is 0.22 percent per year, with an annual
`relative risk of 4.21 as compared with the risk for
`persons not using NSAIDs.
` Although the annual
`12
`mortality rate is low, it must be emphasized that be-
`cause a large number of patients are exposed to
`NSAIDs, often for extended periods of time, the risk
`over a lifetime is substantial. In the United States,
`for instance, it is estimated that NSAIDs are used
`regularly by at least 13 million people with various
`arthritides. On the basis of these conservative figures
`and ARAMIS data, the annual number of hospital-
`izations in the United States for serious gastrointes-
`tinal complications is estimated to be at least 103,000.
`At an estimated cost of $15,000 to $20,000 per hos-
`pitalization, the annual direct costs of such compli-
`cations exceed $2 billion.
`14
`It has been estimated conservatively that 16,500
`NSAID-related deaths occur among patients with
`rheumatoid arthritis or osteoarthritis every year in
`the United States. This figure is similar to the num-
`ber of deaths from the acquired immunodeficiency
`
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`For personal or educational use only. No other uses without permission. All rights reserved.
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`Page 1 of 12
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`Patent Owner Ex. 2008
`Lupin v. Pozen
`IPR2015-01773
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`MEDICAL PROGRESS
`
`10,503
`
`5338
`
`4441
`
`1437
`
`20,197
`
`16,685 16,500
`
`25,000
`
`20,000
`
`15,000
`
`10,000
`
`5,000
`
`No. of Deaths
`
`0
`
`Leuke mia
`
`AID S
`
`M ultiple m yelo m a
`N S AID toxicity
`
`Hodgkin’s disease
`Asth m a
`Cervical cancer
`
`Cause of Death
`
`Figure 1.
` U.S. Mortality Data for Seven Selected Disorders in 1997.
`A total of 16,500 patients with rheumatoid arthritis or osteo-
`arthritis died from the gastrointestinal toxic effects of NSAIDs.
`Data are from the National Center for Health Statistics and the
`Arthritis, Rheumatism, and Aging Medical Information System.
`12
`
`D
`
` 1.
`T
`
`
` F
` R
`ABLE
`THE
`FOR
`ACTORS
`ISK
`
` NSAID-A
`SSOCIATED
`EVELOPMENT
`OF
`G
` U
`.*
`ASTRODUODENAL
`LCERS
`
`
`
`Established risk factors
`Advanced age (linear increase in risk)
`History of ulcer
`Concomitant use of corticosteroids
`Higher doses of NSAIDs, including the use of more
`than one NSAID
`Concomitant administration of anticoagulants
`Serious systemic disorder
`Possible risk factors
`Concomitant infection with
`Cigarette smoking
`Consumption of alcohol
`
`Helicobacter pylori
`
`*Information on risk factors is from Singh and
`Triadafilopoulus,
` Bjorkman,
` Longstreth,
` Greene
`12
`16
`17
` Gabriel et al.,
` Griffin et al.,
` Lang-
`and Winickoff,
`18
`19
`20
`man et al.,
` Garcia Rodriguez and Jick,
`Hallas
`21
`22
`et al.,
` Silverstein et al.,
` Hochain et al.,
` Piper
`23
`24
`et al.,
` Shorr et al.,
` and Barkin.
`26
`27
`28
`
`25
`
`on univariate analysis and do not consider the inter-
`actions among multiple factors and coexisting con-
`ditions.
`Helicobacter pylori infection
`
`The identification of
`as a factor in the development of peptic ulcer has
`raised the question of a possible synergistic relation
`between the presence of
`infection and
`H. pylori
` have found
`NSAID use. Although several studies
`29-32
`these two factors to be independent, two prospec-
`tive studies have suggested a synergistic relation. Bi-
`anchi Porro et al.
` used the combination of amox-
`33
`icillin and omeprazole to treat NSAID users infected
`
`syndrome and considerably greater than the number
`of deaths from multiple myeloma, asthma, cervical
` If deaths
`cancer, or Hodgkin’s disease (Fig. 1).
`12,15
`from gastrointestinal toxic effects of NSAIDs were
`tabulated separately in the National Vital Statistics
`reports, these effects would constitute the 15th most
`common cause of death in the United States. Yet
`these toxic effects remain largely a “silent epidemic,”
`with many physicians and most patients unaware of
` Furthermore, the
`the magnitude of the problem.
`12
`mortality statistics do not include deaths ascribed to
`the use of over-the-counter NSAIDs.
`In a recent survey of 4799 Americans, 807 were
`identified who had taken NSAIDs (prescribed or
`over-the-counter drugs) at least twice in the past
` Approxi-
`year for five or more consecutive days.
`12
`mately 45 percent of the group took NSAIDs for
`five or more consecutive days at least once per month,
`and 40 percent took both over-the-counter and pre-
`scribed NSAIDs. Nearly 75 percent of those who
`used NSAIDs regularly were either unaware of or
`unconcerned about possible gastrointestinal compli-
`cations. In addition, almost two thirds of the regular
`users indicated that they would expect warning signs
`before the development of serious NSAID-induced
`complications. Only a minority of patients who have
`serious gastrointestinal complications report any an-
` In a study of patients with
`tecedent dyspepsia.
`11,13
`serious gastrointestinal complications, Singh et al.
`11
`found that although the proportion of patients with
`prior symptoms was only slightly higher than the
`proportion with no prior symptoms (2.7 percent vs.
`2.0 percent), 81 percent of the patients reported no
`antecedent dyspepsia.
`
`RISK FACTORS FOR GASTROINTESTINAL
`COMPLICATIONS
`Because dyspeptic symptoms are not a reliable warn-
`ing sign, it is important to identify factors that in-
`crease the risk of serious gastrointestinal complica-
`tions and to determine methods for reducing this
`risk. A number of studies have been designed to
`identify patients who are most likely to have adverse
`effects of NSAID therapy (Table 1).
`Advanced age has been consistently found to be a
`primary risk factor for adverse gastrointestinal events.
`The risk increases linearly with age.
` Although
`15-20
`previous reports suggested that the risk diminishes
`over time, a recent study indicates that the risk of
`NSAID-associated gastrointestinal hemorrhage re-
`mains constant over an extended period of observa-
`tion.
` Other risk factors that have been identified in
`12
`multiple studies are higher doses of NSAIDs (in-
`cluding the use of two or more NSAIDs), a history
`of gastroduodenal ulcer or gastrointestinal bleeding,
`concomitant use of corticosteroids, serious coexist-
`ing conditions, and concomitant use of anticoagu-
`lants.
` However, many of these studies are based
`20-27
`
`Volume 340 Number 24
`Downloaded from www.nejm.org at Stanford University on May 23, 2003.
`For personal or educational use only. No other uses without permission. All rights reserved.
`
`·
`
`1889
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`Page 2 of 12
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`IPR2015-01773
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`The New England Journal of Medicine
`
`H. pylori. They found that the eradication of
`
`with
`
`H. pylori did not affect the rate of ulcer healing.
`However, six months after the end of combination
`therapy, the cumulative rate of recurrent ulcers was
`31 percent among the patients in whom
`H. pylori
`had been eradicated and 46 percent among those
`who were still infected. This difference was not sta-
`tistically significant.
`Chan et al.
` found that the use of a regimen that
`34
`included bismuth subcitrate to eradicate
`H. pylori
`significantly decreased the rate of ulcer development
`associated with the use of naproxen. In this study,
`gastroduodenal ulcers developed in 26 percent of
`
`H. pylori–infected persons, but in only 7 percent of
`those in whom the organism had been eradicated.
`The inclusion of bismuth in the drug regimen, how-
`ever, makes the findings somewhat ambiguous, be-
`cause bismuth can accumulate in the gastric mucosa
`and stimulate prostaglandin synthesis.
` Most recent-
`28
`ly, Hawkey et al.
`randomly assigned 285 patients
`35
`with current ulcers or a history of ulcers who were
`using NSAIDs to combined treatment with omepra-
`zole, clarithromycin, and amoxicillin or to treatment
`with omeprazole alone. They found that the eradi-
`cation of
`
`H. pylori did not affect the rate of recur-
`rent ulcer; in addition, ulcer healing was impaired
`even in the patients who were successfully treated
`
`H. pylori infection. It thus ap-
`with antibiotics for
`pears that infection with
`
`H. pylori increases the risk
`of gastroduodenal mucosal injury associated with
`NSAID use only minimally, if at all.
`28
`Singh et al.
` recently proposed a simple, point-
`36
`based algorithm that patients and their physicians
`can use to estimate the risk of an NSAID-related
`gastrointestinal complication. If confirmed by other
`investigators, this tool may help guide decisions about
`prescriptions for specific NSAIDs, the use of prophy-
`lactic agents, and the need for and frequency of pa-
`tient monitoring.
`36
`
`PATHOGENESIS OF NSAID-INDUCED
`GASTRODUODENAL MUCOSAL INJURY
`Gastroduodenal mucosal injury develops when the
`deleterious effect of gastric acid overwhelms the nor-
`mal defensive properties of the mucosa. Concepts
`about NSAID-induced gastroduodenal mucosal inju-
`ry have evolved from a simple notion of topical injury
`to theories involving multiple mechanisms with both
`local and systemic effects (Fig. 2). The systemic effects
`are largely the result of the inhibition of endogenous
`prostaglandin synthesis.
` Prostaglandin inhibition, in
`37
`turn, leads to decreases in epithelial mucus, secretion
`of bicarbonate, mucosal blood flow, epithelial prolif-
`eration, and mucosal resistance to injury.
` The im-
`38,39
`pairment in mucosal resistance permits injury by en-
`dogenous factors, including acid, pepsin, and bile
`salts, as well as by exogenous factors such as NSAIDs
`and possibly ethanol and other noxious agents.
`
`1890
`
`·
`
`June 17, 1999
`
`Topical Injury
`Mucosal injury is initiated topically by the acidic
`properties of aspirin and many other NSAIDs. Be-
`cause of a low dissociation constant, which varies ac-
`cording to the particular agent, these weak acids
`remain in their nonionized lipophilic form in the high-
`ly acidic gastric lumen. Such conditions favor migra-
`tion through the gastric mucus across plasma mem-
`branes and into surface epithelial cells, where NSAIDs
`are dissociated into the ionized form, resulting in
`trapping of hydrogen ions.
` NSAIDs can also cause
`37
`topical mucosal damage by diminishing the hydro-
`phobicity of gastric mucus, thereby allowing endog-
`enous gastric acid and pepsin to injure the surface
`epithelium.
` In addition, topical mucosal injury may
`39
`occur as a result of indirect mechanisms, mediated
`through the biliary excretion and subsequent duode-
`nogastric reflux of active NSAID metabolites.
` For
`40,41
`example, although sulindac is administered as a non-
`toxic prodrug, its active metabolite, sulindac sulfide,
`is excreted into the bile. On entry into the duode-
`num, sulindac sulfide causes topical injury to the mu-
`cosa by virtue of its acidic properties.
`
`The Role of Prostaglandins
`Topical injury caused by NSAIDs contributes to
`the development of gastroduodenal mucosal injury.
`However, the systemic effects of these agents appear
`to have the predominant role,
` largely through
`37,42,43
`the decreased synthesis of mucosal prostaglandins.
`44
`The use of enteric-coated aspirin preparations
` and
`44
`parenteral
` or rectal
` administration of NSAIDs in
`45
`46
`order to prevent topical mucosal injury has also failed
`to prevent the development of ulcers. Moreover,
`doses of aspirin as low as 30 mg are sufficient to sup-
`press prostaglandin synthesis in the gastric mucosa.
`47
`Prostaglandins are derived from arachidonic acid,
`which originates from cell-membrane phospholipids
`through the action of phospholipase A
` (Fig. 3). The
`2
`metabolism of arachidonic acid to prostaglandins
`and leukotrienes is catalyzed by the cyclooxygenase
`pathway and the 5-lipoxygenase pathway, respective-
`ly.
` Two related but unique isoforms of cyclooxy-
`1,37
`genase, designated cyclooxygenase-1 and cyclooxy-
`genase-2, have been demonstrated in mammalian
`cells.
` Despite their structural similarities, they are
`48,49
`encoded by distinct genes and differ with regard to
`their distribution and expression in tissues.
` The
`50,51
`cyclooxygenase-1 gene contains a promoter region
`without a TATA sequence and is primarily expressed
`constitutively. In contrast, the cyclooxygenase-2 gene
`is thought to be the inducible form that is nearly un-
`detectable in most (but not all) tissues under normal
`physiologic conditions.
`Cyclooxygenase-1 appears to function as a “house-
`keeping” enzyme in most tissues, including the gas-
`tric mucosa, the kidneys, and the platelets, whereas
`the expression of cyclooxygenase-2 can be induced
`
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`For personal or educational use only. No other uses without permission. All rights reserved.
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`Page 3 of 12
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`Patent Owner Ex. 2008
`Lupin v. Pozen
`IPR2015-01773
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`MEDICAL PROGRESS
`
`NSAID
`
`Hepatic metabolism
`
`Systemic effect
`
`Active NSAID(cid:1)
`metabolite
`
`Decrease in gastric(cid:1)
`mucosal prostaglandins
`
`Figure 2.
` Mechanisms by Which NSAIDs Induce Gastroduodenal Mucosal Injury.
` NSAIDs have direct toxic effects on the gastroduodenal
`According to the dual-injury hypothesis of Schoen and Vender,
`37
`mucosa (solid arrows) and indirect effects through active hepatic metabolites and decreases in mucosal prostaglandins
`(broken arrows). Hepatic metabolites are excreted into the bile and subsequently into the duodenum, where they cause
`mucosal damage to the stomach by duodenogastric reflux and mucosal damage to the small intestine by antegrade pas-
`sage through the gastrointestinal tract. Adapted from Schoen and Vender.
`37
`
`Membrane Phospholipids
`
`Phospholipase A2
`
`Arachidonic Acid
`
`Lipoxygenase
`
`Cyclooxygenase-1
`Housekeeping gene(cid:1)
`(constitutive)
`
`¡
`
`¡
`
`Cyclooxygenase-2
`Inflammatory gene(cid:1)
`(inducible)
`
`¡
`Corticosteroids
`
`NSAIDs
`Gastrointestinal mucosal integrity(cid:1)
`Platelet aggregation(cid:1)
`Renal function
`
`Mitogenesis and growth(cid:1)
`Regulation of female reproduction(cid:1)
`Bone formation(cid:1)
`Renal function(cid:1)
`Other functions?
`
`Figure 3.
` Biosynthesis of Prostaglandins through the Cyclooxygenase Pathways.
`The immediate precursor of prostaglandins, arachidonic acid, is derived from membrane phospholip-
`ids and is catalyzed by the two cyclooxygenase isoenzymes (also designated as prostaglandin H syn-
`thase), cyclooxygenase-1 and cyclooxygenase-2. The gene for cyclooxygenase-1, the housekeeping en-
`zyme, is expressed constitutively and maintains the homeostasis of organs, including gastric mucosal
`integrity. In contrast, the gene for cyclooxygenase-2, the inflammatory enzyme, is inducible. Although
`both pathways can be variably inhibited by different NSAIDs, only the gene for cyclooxygenase-2 con-
`tains a corticosteroid-responsive repressor element in its promoter region. The broken arrows indicate
`the inhibitory effects of pharmacologic agents.
`
`Volume 340 Number 24
`Downloaded from www.nejm.org at Stanford University on May 23, 2003.
`For personal or educational use only. No other uses without permission. All rights reserved.
`
`·
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`1891
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`Page 4 of 12
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`Patent Owner Ex. 2008
`Lupin v. Pozen
`IPR2015-01773
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`The New England Journal of Medicine
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`by inflammatory stimuli and mitogens in many dif-
`ferent types of tissue, including macrophages and
` It has thus been suggested that the
`synovial cells.
`43
`antiinflammatory properties of NSAIDs are mediat-
`ed through the inhibition of cyclooxygenase-2, where-
`as adverse effects, such as gastroduodenal ulceration,
`occur as a result of effects on the constitutively ex-
` As discussed below, cur-
`pressed cyclooxygenase-1.
`43,49
`rent strategies for developing NSAIDs with an im-
`proved safety profile include the selective inhibition
`of cyclooxygenase-2, with the sparing of cyclooxy-
`genase-1.
`Although there is substantial evidence that the sup-
`pression of gastric prostaglandins is the fundamental
`mechanism responsible for the gastrointestinal toxici-
`ty of NSAIDs, some studies suggest that other mech-
`anisms may be involved. For example, ulcers do not
`develop spontaneously in mice with a disrupted cy-
` and Wallace et al.
` reported
`clooxygenase-1 gene,
`52
`53,54
`that NSAID-induced injury occurred in association
`with enhanced adherence of neutrophils to the gastric
`vascular endothelium, as the result of an increase in
`the expression of intercellular adhesion molecule 1 in
` Neutrophil adherence,
`the basal endothelium.
`55-58
`in turn, causes mucosal injury through the release of
`oxygen-derived free radicals and proteases.
`1
`
`CLINICAL SPECTRUM OF INJURY
`In the majority of patients, NSAID-induced gas-
`troduodenal mucosal injury is superficial and self-lim-
`ited. However, peptic ulcers develop in some patients,
`and they may lead to gastroduodenal hemorrhage, per-
`foration, and death. Serious complications of NSAID
`use that are less commonly recognized include pill
`esophagitis, small-bowel ulceration, small-bowel stric-
`tures, colonic strictures, diverticular disease, and ex-
`acerbations of inflammatory bowel disease.
`9
`The spectrum of NSAID-related gastroduodenal
`injury includes a combination of subepithelial hemor-
`rhages, erosions, and ulcerations that is often referred
`to as NSAID gastropathy. The distinction between
`erosions and ulcerations depends on pathological def-
`initions, with ulcers defined as lesions that penetrate
`to the level of the submucosa and erosions defined
`as lesions confined to the mucosa. For practical
`purposes, an endoscopic definition is used, which is
`based on a subjective assessment of the size, shape,
`and depth of the lesion. Erosions are likely to be
`small and superficial, whereas ulcers tend to be larg-
`er (more than 5 mm in diameter) and deeper.
`9
`After ingestion of an NSAID, ultrastructural dam-
`age to the gastric surface epithelium occurs within
`minutes, and gross, endoscopically detectable hem-
`orrhages and erosions in the gastroduodenal epithe-
`lium occur within several hours.59 However, mucosal
`adaptation appears to occur in response to long-term
`administration of aspirin in most persons.60,61 No
`area of the stomach is resistant to NSAID-induced
`
`1892
`
`·
`
`June 17, 1999
`
`mucosal injury; the most frequently and severely
`affected site is the gastric antrum.59 Although the
`prevalence and severity of acute injury vary accord-
`ing to the drug formulation,62-64 the acute injury
`commonly observed during short-term administra-
`tion of NSAIDs is not closely correlated with the
`subsequent development of the more clinically rele-
`vant process of mucosal ulceration20,21,65,66 or with
`serious complications.10,67,68 Duodenal mucosal inju-
`ry occurs less commonly than gastric damage; how-
`ever, ulcer complications associated with NSAIDs oc-
`cur with nearly equal frequency in these two sites.51,66
`Prospective, cross-sectional endoscopic studies have
`shown that the combined prevalence of gastric and
`duodenal ulcers is 10 to 25 percent in patients with
`chronic arthritis treated with NSAIDs,10,67 which is
`5 to 15 times the expected prevalence in an age-
`matched healthy population.
`
`TREATMENT OF NSAID-RELATED
`DYSPEPSIA
`At least 10 to 20 percent of patients have dyspep-
`tic symptoms during NSAID therapy.10,11 However,
`such symptoms are poorly correlated with the endo-
`scopic appearance and severity of mucosal injury,
`since up to 40 percent of persons with endoscopic
`evidence of erosive gastritis are asymptomatic,10,68 and
`conversely, as many as 50 percent of patients with
`dyspepsia have normal-appearing mucosa.10
`
`Histamine H2–Receptor Antagonists
`Several studies using different methods have shown
`an improvement in dyspeptic symptoms when hista-
`mine H2–receptor antagonists are given to patients
`taking NSAIDs.69-73 A recent prospective, observa-
`tional cohort study by Singh et al.,11 however, found
`that asymptomatic patients with rheumatoid arthri-
`tis who were taking H2-receptor antagonists had a
`significantly higher risk of gastrointestinal complica-
`tions than those not taking these drugs. The expla-
`nation for this surprising observation is unknown,
`but it might be due to the masking of dyspeptic
`symptoms associated with mucosal injury. There-
`fore, although H2-receptor antagonists are effective
`in reducing NSAID-related dyspepsia, their routine
`use in asymptomatic patients taking NSAIDs cannot
`be recommended. Patients receiving H2-receptor an-
`tagonists for the treatment of dyspepsia must be
`monitored carefully for the development of serious
`complications. The initial dose should generally be
`low (e.g., 400 mg of cimetidine, 150 mg of raniti-
`dine or nizatidine, or 20 mg of famotidine, admin-
`istered twice daily in each case), and the dose should
`be tailored to the needs of each patient.
`
`Proton-Pump Inhibitors
`In two recent studies, the proton-pump inhibitor
`omeprazole was compared with ranitidine74 or mi-
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`MEDICAL PROGRESS
`
`soprostol,75 a prostaglandin E1 analogue, for the
`treatment and prevention of NSAID-related gastro-
`duodenal ulcers. A secondary goal in both of these
`multicenter trials was to assess the effects of therapy
`on dyspeptic symptoms. In both studies, although
`different methods were used to assess the clinical re-
`sponse, omeprazole provided greater symptomatic
`relief. After four weeks, only 6 percent of patients
`treated with omeprazole had moderate-to-severe
`symptoms, as compared with 52 percent at base line,
`whereas 12 percent of those treated with ranitidine
`had such symptoms, as compared with 50 percent at
`base line.74 A quality-of-life evaluation showed that
`the patients receiving omeprazole had significantly
`greater improvement in scores on the Gastrointesti-
`nal Symptom Rating Scale than the patients receiv-
`ing misoprostol.75 Because proton-pump inhibitors
`represent a suitable means of preventing the devel-
`opment of gastroduodenal ulcers associated with the
`use of NSAIDs,76 they appear to provide a safe and
`effective form of therapy for NSAID-associated dys-
`pepsia.
`
`MANAGEMENT OF NSAID-RELATED
`GASTRODUODENAL ULCERS
`The optimal treatment for patients with NSAID-
`induced gastroduodenal ulcers should include the
`elimination of any potentially aggravating factors.
`Nontoxic analgesics such as acetaminophen should
`be substituted for NSAIDs when possible, and in
`patients with inflammatory arthritides, disease-mod-
`ifying (or slow-acting) antirheumatic drugs have been
`recommended as first-line treatment. If NSAID ther-
`apy is discontinued, effective treatment aimed at heal-
`ing the acute ulcer can be instituted with one of sev-
`eral antisecretory agents or with sucralfate. If the use
`of NSAIDs must be continued, ulcer healing is en-
`tirely dependent on the specific agent chosen for ul-
`cer treatment.
`
`Mucosal Protective Agents
`Sucralfate, a basic aluminum salt of sucrose octa-
`sulfate, is effective in the treatment of both NSAID-
`related duodenal ulcers and those unrelated to
`NSAIDs, and the agent appears to be as effective
`as H2-receptor antagonists in the healing of non–
`NSAID-related gastric ulcers.77 However, sucralfate
`has no proven benefit in the treatment or prevention
`of NSAID-related gastric ulcers. Prostaglandins exert
`their therapeutic effects both by enhancing mucosal
`defensive properties and by inhibiting gastric-acid se-
`cretion.39 Although they are effective in preventing
`NSAID-induced gastroduodenal mucosal injury, their
`role in the treatment of NSAID-associated ulcers is
`unclear. Hawkey et al.75 recently compared the ca-
`pacity of misoprostol (200 µg given four times daily)
`and omeprazole (20 mg or 40 mg given once daily)
`to heal gastroduodenal ulcers in patients receiving on-
`
`going NSAID therapy. After eight weeks of therapy,
`89 percent of the patients with duodenal ulcers who
`received omeprazole at either dose had healing, as
`compared with only 77 percent of those with duo-
`denal ulcers who received misoprostol. Among the pa-
`tients with gastric ulcers, healing was detected in 80
`percent of those receiving 40 mg of omeprazole, in
`87 percent of those receiving 20 mg of omeprazole,
`and in 73 percent of those receiving misoprostol.75
`
`Antisecretory Drugs
`The efficacy of H2-receptor antagonists in the treat-
`ment of NSAID-related ulcers has not been assessed
`extensively. Both open, uncontrolled, nonrandom-
`ized studies78 and prospective, randomized studies79
`have suggested that treatment with conventional dos-
`es of H2-receptor antagonists for 6 to 12 weeks re-
`sults in the healing of approximately 75 percent of
`gastric ulcers (range, 50 to 88 percent) and 87 per-
`cent of duodenal ulcers (range, 67 to 100 percent),
`despite the continued use of NSAIDs. When the use
`of NSAIDs is continued, healing appears to be de-
`layed and is largely dependent on the initial size of
`the ulcer. O’Laughlin et al.80 reported a 90 percent
`healing rate for small gastric ulcers (less than 5 mm
`in diameter) after an eight-week course of treatment
`with cimetidine, whereas only 25 percent of larger
`ulcers healed.
`In a multicenter trial that included a small sub-
`group of patients with NSAID-related gastric ulcers,
`Walan et al.81 reported that among the patients who
`continued to receive NSAIDs, the healing rate was
`higher for those treated with omeprazole than for
`those treated with ranitidine. A more recent multi-
`center trial by Yeomans et al.74 also demonstrated
`the superiority of omeprazole over ranitidine in the
`treatment of NSAID-related gastroduodenal ulcers.
`In this study, the rates of ulcer healing at eight weeks
`were 79, 80, and 63 percent in the groups receiving
`40 mg of omeprazole, 20 mg of omeprazole, and
`150 mg of ranitidine twice a day, respectively. A study
`by Agrawal et al.82 compared the efficacy of lanso-
`prazole with that of ranitidine in the healing of gas-
`tric ulcers during continued NSAID therapy. After
`eight weeks, ulcers were healed in 57 percent of the
`patients receiving 150 mg of ranitidine twice daily,
`whereas ulcers were healed in 73 percent of those re-
`ceiving 15 mg of lansoprazole once daily and 75 per-
`cent of those receiving 30 mg of lansoprazole once
`daily. These observations suggest that proton-pump
`inhibitors can heal gastroduodenal ulcers more effec-
`tively than H2-receptor antagonists, whether or not
`NSAIDs are continued.
`
`PREVENTION OF NSAID-ASSOCIATED
`GASTRODUODENAL ULCERS
`Because of the prevalence and severity of NSAID-
`related gastrointestinal complications, recent efforts
`
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`· 1893
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`Lupin v. Pozen
`IPR2015-01773
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`
`The New England Journal of Medicine
`
`have been directed at the prevention of mucosal in-
`jury induced by NSAIDs. As discussed above, the
`best way to prevent mucosal injury is to avoid the
`use of NSAIDs and to substitute an agent less toxic
`to the gastroduodenal mucosa, such as acetamino-
`phen, salsalate, or magnesium salicylate. Neverthe-
`less, a potent NSAID is commonly preferred, and two
`strategies have been used to improve their safety: the
`administration of concomitant medication to protect
`the gastroduodenal mucosa from injury and the de-
`velopment of safer antiinflammatory agents.
`
`Concomitant Therapy
`
`Sucralfate
`Early, small studies suggested that sucralfate might
`reduce gastroduodenal mucosal injury associated with
`the use of NSAIDs.83 However, a large, controlled,
`randomized trial conducted by Agrawal et al.84 showed
`no significant benefit of sucralfate in preventing gas-
`tric ulcers in patients with osteoarthritis who were
`receiving NSAID therapy.
`
`H2-Receptor Antagonists
`Two large, placebo-controlled, prospective trials in-
`vestigated the protective effect of ranitidine in pa-
`tients with arthritis who were receiving NSAID ther-
`apy.85,86 Ranitidine (150 mg given twice a day) was
`effective in preventing duodenal ulcers, which devel-
`oped in 0 percent and 1.5 percent of the ranitidine-
`treated patients in the two studies, as compared with
`8 percent of the placebo-treated patients in both
`studies. In contrast, the same dose of ranitidine was
`ineffective in preventing gastric ulcers in both studies.
`Taha et al.73 recently reported a benefit of high-dose
`famotidine (40 mg given twice a day), as compared
`with placebo, in preventing both gastric and duode-
`nal ulcers in patients with arthritis who received
`NSAIDs for 24 weeks. Symptomatic relief was also
`observed in the group randomly assigned to famoti-
`dine, but the benefit, although statistically signifi-
`cant, was only moderate, and the cost of such doses
`of H2-receptor antagonists is considerable. Thus, the
`use of H2-receptor antagonists for the prevention of
`N