NSAID Gastropathy
`A New Understanding
`Sanford H. Roth, MD
`
`Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is associated with substan-
`
`tial morbidity and mortality, which result in high costs to both the patient and so-
`ciety. The subset of patients who are at greatest risk for developing NSAID gastropa-
`thy continues to be better defined, but various risk factors, such as age and previous
`gastrointestinal tract disease, have been identified. In patients receiving older NSAIDs, the choice
`of NSAID should be based on differences in formulations at the lowest effective dose. Gastropro-
`tective cotherapy should be instituted if treatment with older NSAIDs is continued in at-risk pa-
`tients; misoprostol is currently the only agent approved for this indication. The impact of miso-
`prostol on clinical gastrointestinal tract end points has recently been documented. Newer NSAIDs
`may have an improved safety profile over older NSAIDs; some have a clinically documented re-
`duction in the incidence of adverse gastrointestinal tract effects. An understanding of these issues
`should enable the informed clinician to choose an NSAID on the basis of risk-benefit and cost-
`Arch Intern Med. 1996;156:1623-1628
`benefit considerations.
`
`By the turn of the century, aspirin had be¬
`come the most frequently used drug in the
`world. As an effective anti-inflammatory
`agent, aspirin was used to treat rheu¬
`matic disorders but was frequently asso¬
`ciated with adverse effects, such as "gas¬
`tric irritation" and tinnitus.1 By the 1950s,
`nonsteroidal anti-inflammatory drugs
`(NSAIDs) had been developed to provide
`alternatives to aspirin, primarily because
`of the perceived gastrotoxic effects of as¬
`pirin.2 To date, more than 100 NSAIDs
`have been tested; at least 18 have been mar¬
`keted in the United States and many more
`are marketed in other countries. There are
`70 million to 100 million prescriptions for
`NSAIDs per year, and approximately 15
`million patients in the United States re¬
`quire long-term NSAID therapy.1 In ad¬
`dition, the over-the-counter availability of
`NSAIDs is reported to exceed prescrip¬
`tion NSAID use by 7-fold.3
`The term NSAID gastropathy was first
`introduced into the medical literature in
`1986 in an effort to differentiate between
`classic peptic ulcer disease and the unique
`range of gastric mucosal lesions associ¬
`ated with long-term NSAID therapy.45
`Symptoms of NSAID gastropathy range
`
`From the Arthritis Center Ltd, Phoenix, Ariz.
`
`from dyspepsia and pain to the serious, si¬
`lent, and potentially deadly conse¬
`quences of perforations, ulcers, and hem¬
`orrhages. Gastropathy from NSAIDs
`usually occurs within the first few weeks
`of treatment6,7 but also seems to be asso¬
`ciated with long-term NSAID use.8
`Gastropathy from NSAIDs differs
`from classic peptic ulcer disease in sev¬
`eral aspects. Classic peptic ulcers are usu¬
`ally duodenal and symptomatic and are
`seen most frequently in younger men. In
`contrast, NSAID gastropathy includes mu¬
`lesions of the upper gastrointesti¬
`cosal
`nal (GI) tract and usually affects the el¬
`derly.5 In addition, there are important
`differences that are evident endoscopi-
`cally. Gastropathy caused by NSAIDs is
`characterized by lesions ranging from ery¬
`thema through diffuse erosions and mi-
`crobleeding to gastric crater ulcer.3 How¬
`ever, the subset of patients who take
`NSAIDs for a long period and develop se¬
`rious ulcer complications because of fail¬
`ure of normal mucosal adaptation re¬
`mains to be identified.Q
`Gastropathy from NSAIDs is recog¬
`nized as the most frequent serious com¬
`plication from medication therapy.1011
`Such complications as hemorrhage and
`perforation require hospitalization and/or
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`surgery, and up to 10% of these com¬
`plications can be fatal.12 An analy¬
`sis of data from the Medicaid Man¬
`agement Information System of
`Pennsylvania in 1985 suggested that
`the hospitalization of patients for the
`treatment of NSAID gastropathy
`costs $2000 for a 3-month period,
`compared with an average cost of
`$27 for outpatient treatment of
`NSAID-related GI tract effects.13 The
`annual cost of Gl tract complica¬
`tions is estimated at $3.9 billion, with
`at least 2600 deaths and up to 20 000
`hospitalizations per year.1114
`This article reviews new un¬
`derstandings in the epidemiology,
`pathogenesis, treatment, and pro¬
`phylaxis of NSAID gastropathy
`(Table 1)
`
`PATHOGENESIS OF
`NSAID GASTROPATHY
`
`Defensive gastric mechanisms in the
`face of the hostile acid pepsin envi¬
`ronment of the gastric lumen are
`now well understood. The phospho-
`lipid interface over a semiperme¬
`able mucin barrier, reinforced with
`bicarbonate ions in an unstirred wa¬
`ter layer, forms a neutral pH inter¬
`face between mucosal epithelial cells
`and the acid lumen. Critical micro-
`circulatory substrata reinforce the re¬
`silience of those mucosal cells.1'
`Under normal circumstances,
`the gastric mucosa adapts to compen¬
`sate for adverse conditions.16 In 1986,
`Graham and Smith8 defined the re¬
`siliency of the gastric mucosa under
`NSAID attack. They reported that
`continuing NSAID use ultimately pro¬
`duced an "invisible callus" that was
`seemingly resistant to NSAID insult.
`However, it appears that this resil¬
`iency fails in "at-risk" populations
`who are receiving long-term NSAID
`therapy, ie, there is a compromise of
`adaptive mucosal responses.9
`Adaptive mechanisms, so criti¬
`cal to organisms on a system-by-
`system basis, can indeed fail before
`aging and disease processes.17 More
`recent investigations indicating the
`possible amplification of ulcer com¬
`plication rates with NSAIDs re¬
`quire further study.18 Yet under¬
`standing the basis for that failure,
`and recognizing those mechanisms
`most likely to fail, provides the ra¬
`tionale for therapeutic response.
`
`Table 1. A New Understanding of NSAID Gastropathy4
`
`Issues
`Significant morbidity and mortality
`Identify those at greatest risk
`Choose safest NSAID
`
`Institute gastroprotective cotherapy
`if continuing therapy with older
`NSAIDs
`Cost-effectiveness
`
`Answers
`Results in high costs to patient and society
`Age, sex, medical history, endoscopy
`Based on pharmacological formulation differences
`lowest effective dose for older NSAIDs;
`at
`newer NSAIDs such as nabumetone appear to
`be gastroprotective
`is only approved agent for this
`Misoprostol
`indication
`
`Misoprostol demonstrated cost-effective;
`nabumetone demonstrated cost-effective
`compared with fixed-combination misoprostol
`and NSAID
`
`*NSAID indicates nonsteroidal anti-inflammatory drug.
`glandins is now available.22 Two
`The basis of gastrotoxic effects
`forms of COX enzyme are now rec¬
`is multifactorial. The NSAIDs com¬
`promise both platelet and coagula¬
`ognized as COX-I and COX-II.23-24
`The isoenzyme COX-I is specific to
`tion mechanisms. The generic de¬
`the stomach, intestine, kidney, and
`scription of cytoprotection must now
`platelets; COX-II is mitogen induc-
`include issues of restitution and re¬
`generative repair as part of adapta¬
`ible, mainly in inflammatory cells.
`Since the adverse GI tract events of
`tion and include new understand¬
`ings of the relevance of growth
`NSAIDs most often seem to relate to
`factors.16 Superimposed on preexist¬
`the inhibition of COX-I, a selective
`COX-II NSAID is thought to be gas-
`ing risk factors are interactions with
`aging, codisease and cotherapies, and
`trosparing. At least 1 such NSAID
`(nabumetone) has been identified by
`the effects of such compromise on
`neutrophil function and mucosal
`basic investigation (see below).
`blood flow. The role of prostagland-
`In 1974, Sun et al25 first re¬
`ported a 28% incidence of peptic ul¬
`ins, molecular energy interactions,
`and Superoxide radicals are all un¬
`cers with NSAID therapy and rheu¬
`matoid arthritis. In that study, we
`der continuing investigative scru¬
`tiny.16 It is a dynamic defensive role
`found esophageal dysfunction in one
`third of the 143 patients. They ex¬
`that responds to the additive offen¬
`sive punitive challenge from NSAIDs.
`hibited low esophageal sphincter
`When these morphologic barriers are
`pressure and motility derange¬
`ment, findings similar to those in
`compromised for a prolonged pe¬
`riod, gastropathy can evolve to clini¬
`scleroderma esophagus. This may
`cal complications.
`explain the dyspepsia and pyrosis
`commonly associated with NSAID
`The fundamental work of
`Vane19 demonstrated that the mecha¬
`use and not well correlated with en¬
`doscopie findings ofgastropathy. We
`nism of action of NSAIDs involves
`inhibition of prostaglandin synthe¬
`subsequently reported the high in¬
`sis via inhibition ofprostaglandin cy-
`cidence of mucosal lesions associ¬
`clooxygenase (COX). This inhibi¬
`ated with aspirin use in patients with
`tion of prostaglandin production
`rheumatoid arthritis.26
`results in anti-inflammatory ef¬
`fects, but it also compromises the
`normal protection of the gastric mu¬
`cosa. Individual NSAIDs have vary¬
`ing half-lives and renal clearance.
`They differ in topical mucosal tox-
`icity20 and potential for biliary re-
`circulation with reexposure to the
`gastric mucosa, and they have vari¬
`able gastric COX isoenzyme-
`sparing characteristics.21
`A more sophisticated apprecia¬
`tion of the isoenzymes of prosta-
`
`The following factors are associated
`with increased risk for developing
`NSAID gastropathy: increasing age
`older than 60 years712'27,28; female
`sex12; history ofprevious GI tract dis¬
`ease28; concurrent use of other ul-
`cerogenic substances, eg, corticoste-
`roids29 and anticoagulants30; and for
`older NSAIDS, higher dose.67'28
`
`RISK FACTORS FOR
`NSAID GASTROPATHY
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`There are conflicting data on
`the influence of smoking and alco¬
`hol on NSAID gastropathy, al¬
`though these elements are known to
`increase the risk of developing clas¬
`sic peptic ulcer disease.31
`It is now generally believed that
`Helicobacter pylori
`infection is
`associated with active chronic gas¬
`tritis and with the vast majority of
`duodenal and gastric ulcers. How¬
`ever, there is substantial evidence to
`suggest that H pylori is not a particu¬
`lar risk factor for NSAID gastropa¬
`thy.32"35 In 1 double-blind compari¬
`son of etodolac, naproxen, and
`placebo for 4 weeks in 46 healthy vol¬
`unteers, there was no evidence of
`worsening gastric mucosal histologi-
`cal injury with NSAID ingestion. In
`addition, the presence of Hpylori had
`no effect on the degree of gross GI
`tract damage induced by NSAIDs.33
`Thus, the authors concluded that it
`may not be necessary to determine
`H pylori status or to attempt to eradi¬
`cate H pylori before initiating NSAID
`therapy.
`The NSAIDs and salicylates are
`still the most accepted treatments for
`musculoskeletal and arthritic disor¬
`ders. However, in very high-risk pa¬
`tients with recent major hemor¬
`rhages or recurrent ulcer, alternative
`agents, such as topical and systemic
`analgesics, are recommended.5
`NSAID TOLERABILITY PROFILE
`
`Upper GI Tract Toxic Effects
`Extensive clinical and epidemiologi-
`cal evidence supports the associa¬
`tion of older NSAIDs with upper GI
`tract toxic effects.28 Relative risks for
`upper GI tract toxic effects be¬
`tween different NSAIDs have been
`determined by many investigators in
`randomized clinical studies, co¬
`hort studies, or case-control stud¬
`ies. Case-control studies may over¬
`estimate the risk because patients
`who present with GI tract hemor¬
`rhage are more likely than controls
`to be questioned about NSAID use.
`On the other hand, cohort studies
`may underestimate the risk by over¬
`estimating the duration of NSAID
`use. Finally, clinical studies usu¬
`ally lack statistically power to show
`clinically relevant differences.36 In
`addition, the endoscopie scoring sys-
`
`tern used in many studies empha¬
`sizes mucosal erosions, but recent re-
`evaluation suggests that this system
`may not be clinically relevant.37 Epi-
`demiological data appear to pro¬
`vide the best "real-life" estimate.5
`
`Salicylates. Aspirin is no longer a
`prototype for anti-inflammatory
`therapy because of its recognized
`high incidence of gastric symp¬
`toms as well as known gastric toxic
`effects. ' Mucosal adaptation has been
`shown to develop after short-term
`administration,38 but this adapta¬
`tion appears to fail after long-term
`administration.26 Failed mucosal ad¬
`aptation during long-term aspirin
`therapy in the elderly is supported
`by data from the Aspirin Myocar-
`dial Infarction Study.39
`Nonacetylated salicylates ap¬
`pear to be prostaglandin-sparing but
`are actually anti-inflammatory as well
`as analgesic.1 However, they may be
`less frequently prescribed for arthri¬
`tis and pain management because of
`concerns of allegedly lower efficacy
`and inferior analgesic benefits, tin¬
`nitus, and dosing issues related to
`salicylism.
`Older NSAIDs. The link between
`the use of older NSAIDs and gas¬
`tropathy is undisputed. The risks are
`generally similar for gastric and duo¬
`denal abnormalities.31 From the late
`1970s to the early 1980s, the in¬
`crease in NSAID prescriptions par¬
`alleled the increase in hospital ad¬
`missions for ulcer complications.27
`The Arthritis Rheumatism and Ag¬
`ing Medical Information System da¬
`tabase has documented a 1.5% an¬
`increase in the incidence of
`nual
`hospitalization associated with
`NSAID use in patients with rheu¬
`matoid arthritis.28 The US Food and
`Drug Administration and the UK
`Committee on Safety of Medicines
`have confirmed that the number of
`ulcer bleeding episodes reported in
`connection with NSAID use is in ex¬
`cess of all complications reported for
`all other drugs.40,41
`The overall relative risk for de¬
`velopment of upper GI tract bleed¬
`ing with older NSAID use is approxi¬
`mately 3 (2.5-10). Overall, there
`appears to be a 6.5-fold increased
`risk of hospitalization from GI tract
`illness in NSAID recipients.11
`
`Several studies and meta-
`analyses have attempted to evalu¬
`ate the relative risks of NSAID gas¬
`tropathy for individual NSAIDs
`(Table 2).7,30,42"44 Although the dif¬
`ferences in patient populations con¬
`found direct comparisons between
`studies, most data consistently sug¬
`gest that ibuprofen has the lowest
`relative risk and piroxicam the high¬
`est for gastropathy.7,30,43,44 This may
`in part result from the use of low-
`dose ibuprofen for short-term indi¬
`cations. These data are consistent
`with the Food and Drug Adminis¬
`tration and Committee on Safety of
`Medicines rankings among avail¬
`able NSAIDs.40,41
`
`Newer NSAIDs. Newer NSAIDs may
`demonstrate a more favorable GI tract
`tolerability profile than older NSAIDs.
`However, there are limited available
`data to rank individual NSAID GI
`tract tolerability accurately, espe¬
`cially in comparing older vs newer
`NSAIDs. Nabumetone has been stud¬
`ied in large enough patient cohorts
`to report a low incidence of NSAID
`gastropathy with 95% confidence in¬
`tervals (CIs).42 There are no data with
`oxaprozin from case or cohort stud¬
`ies and no data in large enough
`samples to report 95% CIs. Simi¬
`larly, the risks for adverse GI tract ef¬
`fects with etodolac have not been re¬
`ported with 95% CIs.
`Nabumetone is a nonacid pro-
`drug that is rapidly converted to its
`active metabolite, 6-methoxy-2-
`naphthylacetic acid, in the liver. It has
`no in vitro effect on prostaglandin
`synthesis in human gastric tissue45
`and is a weak inhibitor ofgastric pros¬
`taglandin synthesis in animals.46
`Nabumetone undergoes minimal en-
`terohepatic circulation, and, be¬
`cause of the lack of accumulation in
`gastric mucosal cells, it has been pos¬
`tulated to pose less risk for gastric
`damage than other NSAIDs.46 This re¬
`duced risk is supported by animal
`data47"'1 and also appears to be sup¬
`ported by recent clinical experience.
`Controlled clinical studies have
`documented the low ulcerogenic po¬
`tential of nabumetone in compari¬
`son with older NSAIDs.52"54 In addi¬
`tion, the ulcerogenic potential of
`nabumetone is comparable with that
`of fixed-combination ibuprofen-
`misoprostol.55 The cumulative inci-
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`Table 2. Estimated Risks for Gastropathy With Individual NSAIDs1
`
`GI Complications
`
`Cumulative Frequency, %
`(95% CI)
`
`4.8 (2.6-8.7)
`
`2.8(1.8-4.3)1
`2.1 (1.1-4.1
`2.5(1.5-4.1
`
`1.7(1.1-2.5)!
`
`0.7 (0.4-2.4)
`
`1.4(0.5-2.4)$
`
`0.2(0.01-0.3)$
`NA
`NA
`
`Relative Risk Ratios (95% CI)
`GI Hemorrhage
`Older NSAIDs
`18.0(8.2-39.6)§-|
`13.7(7.1-26.3)11 J
`3.1 (1.7-5.9)§ H
`9.1 (5.5-15.1)11 J
`2.9(1.5-5.6)§
`6.3(3.3-1.2)§ -|
`11.3(6.3-20.3)1.
`3.9(2.3-6.5)§
`4.2 (2.6-6.8)1
`2.9(1.7-5.0)§
`2.0(1.4-2.8)1
`Newer NSAIDs
`
`]]
`
`Peptic Ulcer Disease
`
`6.4 (4.8-8.4)$
`
`4.3 (3.4-5.4)$
`4.2(2.8-6.3)$
`3.8 (2.4-6.0)$
`
`2.3(1.8-3.0)$
`
`Piroxicam
`
`Naproxen
`Sulindac
`
`Indomethacin
`
`Diclofenac
`
`Ibuprofen
`
`Nabumetone
`Oxaprozin
`Etodolic acid
`
`* NSAIDs indicates nonsteroidal anti-inflammatory drugs; CI, confidence interval; GI. gastrointestinal tract; and NA, data with 95% CIs not available.
`\Lipani and Poland.'2
`XGriffin et al.7
`$García-Rodriguez and Jick.30
`\\Henry et al43
`%angman et al.44
`dence of gastric perforations, ul¬
`cers, and hemorrhages in more than
`6000 patients treated with nabum¬
`to 2 g daily, for 3 to 6
`etone, 1
`months in clinical trials is 0.1% at
`3 months and 0.2% at 6 months.42
`Pharmacoeconomic analyses ap¬
`pear to support the cost-effective use
`of nabumetone in arthritis. In 1 analy¬
`sis, the lower incidence of perfora¬
`tions, ulcers, and GI tract hemor¬
`rhages associated with nabumetone
`resulted in lower direct medical costs
`than comparable NSAID treat¬
`ment.56 In another study in patients
`with osteoarthritis, the lower inci¬
`dence of endoscopie lesions with
`nabumetone compared with fixed-
`combination ibuprofen-misopros-
`tol resulted in lower overall costs.57
`Etodolac is a member of the py-
`ranocarboxylic acid class ofNSAIDs.
`It appears to be well tolerated in both
`regular and sustained-release for¬
`mulations.58,59 In a recent review, the
`reported rate of GI tract complica¬
`tions was 0.8%.60 However, there are
`no data with 95% CIs. Further epi-
`demiological data are needed to con¬
`firm the long-term GI tract safety of
`etodolac.
`The propionic acid derivative
`oxaprozin has recently been ap¬
`proved in the United States for the
`treatment of rheumatoid arthritis and
`osteoarthritis. However, there are lim-
`
`ited published data available on the
`tolerability of oxaprozin.
`It is difficult to compare newer
`NSAIDs directly with older NSAIDs
`because doses, characteristics of pa¬
`tients, and study design have changed
`since the association between older
`NSAID use and GI tract hemor¬
`rhage, ulcers, and NSAIDs was rec¬
`ognized. Nabumetone appears to be
`the only NSAID with available data
`from large patient populations to give
`an estimated risk for gastropathy with
`95% CIs. Further postmarketing sur¬
`veillance data are required in similar
`patient populations to compare di¬
`rectly the relative risks of GI tract ad¬
`verse effects associated with indi¬
`vidual NSAIDs and to confirm the
`superior tolerability of any NSAID.
`
`Lower GI Tract Toxic Effects
`
`The effects of NSAIDs on the lower GI
`tract have been less well investigated
`and documented than those on the up¬
`per GI tract. However, there does ap¬
`pear to be an association between as¬
`pirin and lower GI tract hemorrhage.61
`In another study, Allison and col¬
`leagues62 showed that NSAID recipi¬
`ents have an increased risk ofnonspe¬
`cific ulcération ofthe smaller intestine
`(8.4% vs 0.6% in non-NSAID-treated
`patients). Although the risk of lower
`GI tractgastropathy is somewhat lower
`
`than that ofgastric or duodenal effects,
`these effects should not be overlooked,
`since life-threatening complications
`can result.
`
`PROPHYLAXIS AND
`TREATMENT OF NSAID
`GASTROPATHY
`
`The effectiveness of several agents as
`treatment or prophylaxis against
`NSAID gastropathy has been inves¬
`tigated. In general, while mucosal
`protective agents, such as antacids
`and sucralfate, are efficacious in pep¬
`tic ulcer disease, they have not been
`proved to be effective in NSAID-
`related GI tract complications.63 The
`effectiveness of antacids against
`NSAID gastropathy has recently been
`documented in a double-blind con¬
`trolled clinical study.64 However,
`while antacid use was associated with
`reduced dyspeptic symptoms, the risk
`of ulcer complications is not ad¬
`dressed by usual casual use of these
`agents. There are no data to support
`the use of sucralfate in NSAID-
`induced gastropathy.63
`The effectiveness of the hista-
`mine2-antagonist cimetidine against
`NSAID gastropathy has been stud¬
`ied extensively. These studies have
`failed to document successful pre¬
`vention of gastropathy when NSAID
`use is continued.5,37,65,66 Ranitidine was
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`effective against NSAID-associated
`duodenal, but not gastric, ulcération
`in 1 study,67 and a recent report also
`suggests that famotidine may effec¬
`tively prevent NSAID gastropathy.68
`Several studies suggest that the pro¬
`ton pump inhibitor omeprazole may
`treat and prevent gastropathy when
`administered concomitantly with an
`NSAID,69,70 although as with cimeti-
`dine, omeprazole appears to be more
`effective against duodenal than gas¬
`tric ulcération.71,72
`In the United States, misopros¬
`tol is the onlyagentcurrendyapproved
`as cotherapy with NSAIDs. Misopros¬
`tol has been documented as both ef¬
`fective treatment26,73 and effective long-
`termprotection38,74,75 against NSAID-
`associated GI tract effects. On the basis
`of these data, various pharmacoeco-
`nomic analyses ofmisoprostol data76
`suggested thatcotherapy with NSAIDs
`is cost-effective.77"80 These conclusions
`have been questioned because of the
`lack of evidence to link prospectively
`various GI tract end points to clinical
`outcomes.81 However, the recently
`published Misoprostol Ulcer Compli¬
`cations Outcome Study provides evi¬
`dence to support the conclusions of
`these pharmacoeconomic analyses. In
`this study, concurrent administration
`of misoprostol with NSAIDs signifi¬
`cantly reduced GI tract end points in
`patients with rheumatoid arthritis.75
`The results suggest that misoprostol
`would have an impact on the costs as¬
`sociated with NSAID gastropathy in
`patients with rheumatoid arthritis. Al¬
`though this study documented pro¬
`spective outcome data, it did not di¬
`rectly address economic issues. Eco¬
`nomic analyses of the data from the
`Misoprostol Ulcer Complications Out¬
`come Study may conclusively demon¬
`strate the cost-effectiveness of miso¬
`prostol as cotherapy with NSAIDs.
`Fixed-ratio combinations of mi¬
`soprostol with an NSAID are cur¬
`rently undergoing investigation. Di-
`clofenac-misoprostol
`is now
`available in the United Kingdom. It
`is anticipated that such fixed-
`combination treatment will be tar¬
`geted to patients at high risk for de¬
`veloping NSAID gastropathies.
`Other agents currently under¬
`going investigations as gastropro¬
`tective cotherapies with NSAIDs in¬
`clude rebamipide. Rebamipide is a
`quinolone derivative with topical
`
`gastric mucosal protective effects
`that is undergoing investigation for
`NSAID gastropathy.82
`Several agents may potentially
`afford gastroprotection when admin¬
`istered as cotherapy with NSAIDs, but
`there is a concern that these agents
`will lead to an increased financial bur¬
`den of such diseases as rheumatoid ar¬
`thritis. Careful identification of pa¬
`tients who are at increased risk of
`developing NSAID gastropathy
`should influence the choice of gas-
`trosparing NSAIDs or cost-effective
`cotherapies.
`CONCLUSIONS
`
`The NSAIDs remain the single most
`frequently used group of drugs in
`medicine, especially to relieve pain
`and suppress inflammation. Cost-
`benefit and cost-utility issues deter¬
`mine and limit therapeutic choices of
`NSAIDs including gastroprotective GI
`cotherapy or non-NSAID alterna¬
`tives in high-risk gastropathy pa¬
`tients. This includes oral and topical
`analgesics, or even nondrug manage¬
`ment. The serious outcomes of ul¬
`cers and hemorrhages drive the cost
`of NSAID gastropathy. Gastropathy
`symptoms require costly interven¬
`tion, including consultation, proce¬
`dural interventions, and possible
`short- and long-term cotherapy to
`permit continued NSAID manage¬
`ment. However, newer NSAIDs have
`been proved to be effective in both
`rheumatoid arthritis and osteoarthri¬
`tis. Of the newer NSAIDs, nabum¬
`etone appears to have an improved
`safety profile over older NSAIDs, with
`a clinically documented reduction in
`the incidence of serious adverse GI
`tract effects. Ultimately, the choice of
`an NSAID will be based on host re¬
`sponse with proper clinical monitor¬
`ing, and selection should be decided
`by safety data, which are now known.
`Cost-effective and risk-benefit con¬
`siderations are demanded not only by
`our managed care systems but by an
`informed medical conscience.
`Just as we entered NSAID gas¬
`tropathy into the medical literature
`through this journal a decade ago
`with the admonition "we started it,"
`so now through these new under¬
`standings, pharmacotherapies, and
`strategies, we can now more assur¬
`edly prevent and stop it.
`
`Acceptedfor publication April 19,1996.
`I acknowledge the many years of
`inspiration, support, and guidance of
`George E. Ehrlich, MD, including valu¬
`able opinion on the development of the
`manuscript, and also the technical as¬
`sistance of Tak Sato, MD.
`Reprints: Sanford H. Roth, MD,
`Arthritis Center Ltd, 3330 N Second
`St, Suite 601, Phoenix, AZ 85012.
`
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