Epidemiology of Nonsteroidal Anti-inflammatory Drug–Associated Gastrointestinal Injury

Epidemiology of Nonsteroidal Anti-inflammatoryDrug–Associated Gastrointestinal Injury

Marie R. Griffin, MD, MPH, Nashville, Tennessee, USA

Nonaspirin, nonsteroidal anti-inflammatory drugs(NSAIDs) are among the most frequently useddrugs in many countries. Use of the majority ofNSAIDs increases with age, primarily for symp-toms associated with osteoarthritis and otherchronic musculoskeletal conditions. Population-based studies have shown that, on any given day,10 –20% of elderly people (≥65 years old) have acurrent or recent NSAID prescription. Over a6-month period in Alberta, Canada, 27% of elderlypeople were prescribed NSAIDs. Furthermore, inTennessee (USA), 40% of elderly people receivedat least one NSAID prescription annually, and 6%had NSAID prescriptions for >75% of the year.NSAIDs cause a wide variety of side-effects. Themost clinically important side-effects are uppergastrointestinal tract dyspepsia, peptic ulceration,hemorrhage, and perforation, leading to death insome patients. Gastrointestinal side-effects arecommon; the most common NSAID-associatedside-effect is epigastric pain/indigestion. Gastroin-testinal side-effects are also a frequent reasonboth for withdrawal of NSAIDs and for co-treat-ment with another drug. Indeed, in two population-based studies of people aged ≥65 years, the use ofagents to prevent peptic ulcers or relieve dyspep-sia was nearly twice as common in regular NSAIDusers (20 –26%) than in non-NSAID users (11%). InAlberta, Canada, it has been estimated that NSAIDuse accounts for 28% of all prescriptions for anti-ulcer drugs in people aged at least 65 years. Manystudies have now shown that NSAIDs increase therisk of peptic ulcer complications by 3–5-fold, andin several different populations it has been esti-mated that 15–35% of all peptic ulcer complica-tions are due to NSAIDs. In the United States alone,there are an estimated 41,000 hospitalizations and3,300 deaths each year among the elderly that areassociated with NSAIDs. Factors that increase therisk of serious peptic ulcer disease include olderage, history of peptic ulcer disease, gastrointesti-nal hemorrhage, dyspepsia, and/or previous NSAIDintolerance, as well as several measures of poorhealth. Am J Med. 1998;104(3A):23S–29S. © 1998 byExcerpta Medica, Inc.

Nonaspirin, nonsteroidal anti-inflammatorydrugs (NSAIDs) are among the most frequentlyused drugs in many countries, and their use in-

creases with age,1 primarily for symptoms associated withosteoarthritis and other chronic musculoskeletal condi-tions. Population-based studies in the United States,2– 4

Canada,5 England,6 and Australia7 have shown that non-aspirin NSAID use is common in the elderly ($65 yearsold) and that 10 –20% of these people have a current orrecent NSAID prescription. Over a 6-month period inAlberta, Canada, 27% of elderly people were prescribedNSAIDs.8 Furthermore, among elderly Medicaid enroll-ees in Tennessee (USA), 40% received at least one NSAIDprescription that covered .75% of the year.9,10

NSAIDs cause a wide variety of reported adverseevents, the most clinically important of which are uppergastrointestinal side-effects.9 Many studies have shownthat NSAIDs increase the risk of peptic ulcer complica-tions by 3–5-fold,11–13 and in several different popula-tions it has been estimated that 15–35% of all peptic ulcercomplications are due to NSAIDs.2,5,6,14 –17 Indeed, in theUnited States alone, there are an estimated 41,000 hospi-talizations and 3,300 deaths each year among the elderlythat are attributable to NSAIDs.9

The high use of NSAIDs, particularly in elderly popu-lations (who are at a high risk for developing complica-tions), may be viewed as an important public healthproblem. NSAIDs, however, are now being considered bymany as second-line therapy for symptoms associatedwith osteoarthritis.18,19 The reason for this shift awayfrom first-line NSAIDs therapy in osteoarthritis is pri-marily due to the adverse events associated with NSAIDuse, coupled with the modest overall efficacy of NSAIDs.Of note is the fact that NSAIDs have not been demon-strated to have a positive influence on the natural historyof osteoarthritis or other musculoskeletal conditions;they are used for symptom control, and not for treatmentof the disease itself.

UPPER GASTROINTESTINAL SIDE-EFFECTS ASSOCIATED WITH NSAID USE

Although NSAIDs may produce a wide variety of adverseevents, it is the upper gastrointestinal side-effects that arethe primary reasons for discontinuation of therapy, forserious morbidity, and for co-treatment with anotherdrug. Upper gastrointestinal side-effects associated withNSAID use include dyspepsia, peptic ulceration, hemor-

From the Departments of Medicine and Preventive Medicine, Vander-bilt University School of Medicine, Nashville, Tennessee, USA.

Requests for reprints should be addressed to Marie R. Griffin, MD,MPH, Department of Preventive Medicine, Vanderbilt UniversitySchool of Medicine, A-1124 MCN, Nashville, Tennessee 37232, USA.

© 1998 by Excerpta Medica, Inc. 0002-9343/98/$19.00 23SAll rights reserved. PII S0002-9343(98)00207-6

rhage, and perforation, leading to death in some pa-tients.2,6,10,12,14,20,21 In a typical clinical trial in which pa-tients with known peptic ulcer disease or NSAID intoler-ance were excluded, 17% of patients randomized toreceive diclofenac reported gastrointestinal side-effectswithin 4 weeks of starting treatment, compared with only0.8% at baseline; furthermore, 7% of patients withdrewfrom the trial because of these side-effects.22 The mostcommon side-effect was epigastric pain/indigestion.

In practice, many patients are co-prescribed H2-re-ceptor antagonists, antacids, sucralfate, or misoprostolto treat such side-effects and/or prevent peptic ulcercomplications. In two population-based studies of pa-tients aged $65 years, the use of these agents wasnearly twice as common in regular NSAID users (20 –26%) than in non-NSAID users (11%).8,23 In Alberta,Canada, it has been estimated that NSAID use accountsfor 28% of all prescriptions for antiulcer drugs in peo-ple aged $65 years.8

Gastrointestinal side-effects are poor predictors ofthose NSAID users with endoscopic erosions or pepticulcers.24,25 However, a recent study has reported that pa-tients who switch from one NSAID to another are at highrisk of developing peptic ulcer complications,5 suggestingthat this strategy may not be an appropriate way to treatgastrointestinal side-effects.

RISK FACTORS FOR NSAID-ASSOCIATEDGASTROINTESTINAL INJURY

Although dyspepsia is a common side-effect that bothdecreases quality of life22 and increases the cost of treat-ment,8,23 it is the more serious gastrointestinal complica-tions that have led to the reconsideration of NSAID ther-apy as first-line treatment for osteoarthritis.18,19,26,27

Many studies have now shown that NSAID use increasesthe risk of peptic ulcer complications by 3–5-fold.11–13

Differences in NSAID exposure (dose and duration), theuse of other drugs, and variations in host factors are allimportant in determining the rates of gastrointestinalside-effects in individual people. The host factors thatincrease the risk of serious peptic ulcer disease includeolder age,5,28 history of peptic ulcer disease, gastrointes-tinal hemorrhage, dyspepsia, and/or previous NSAID in-tolerance,5,28 –30 as well as various measures of poorhealth.2,29,30

AgeHospitalization rates for peptic ulcer disease have beenreported to be ,1 per 1,000 per year in most populations,50 years of age.21,31–33 Hospitalization rates for pepticulcer disease increase with age, however: for patients .65years, the reported rate of hospitalization is 2– 6 per 1,000per year,10,17,21,32–34 and this higher absolute rate of pep-tic ulcer complications in older people has been consis-tently observed.5,21,29,30,35

Age does not appear to modify the relative risk of pep-tic ulcer complications associated with NSAIDs.11 How-ever, because the baseline risk of peptic ulcer disease ismuch higher in older people, multiplying this relativelyhigh rate by a factor of 4 (the increased risk of pepticulcer complications associated with NSAID use) gives amuch higher rate than for those populations with a lowbaseline risk.

For people aged $65 years who enrolled in the Tennes-see Medicaid program, the annual rate of hospitalizationfor peptic ulcer disease was approximately 4 per 1,000 innon-NSAID users, compared with 16 per 1,000 in NSAIDusers. The attributable incidence—i.e., the amount ofpeptic ulcer disease due to NSAIDs—was therefore 12 per1,000 (i.e., [16 2 4] per 1,000). This means that for every83 elderly persons prescribed NSAIDs for 1 year, therewas one additional hospitalization for a peptic ulcer com-plication. Similar results have been reported from a co-hort of patients with rheumatoid arthritis who were tak-ing NSAIDs. The incidence of hospitalization or deathfrom acute gastrointestinal adverse events increased from3 per 1,000 person years of use in those aged ,63 years, to19 per 1,000 in those aged 63–75 years, and to 42 per 1,000in those .75 years.29 If one assumes that these rates arefour times the baseline rate, the attributable incidence inthese three age groups can be calculated to be 2, 14, and 32excess hospitalizations, respectively, per 1,000 NSAID us-ers each year. It is therefore obvious that the impact ofNSAIDs increases markedly with age due to the higherbaseline risk in this age group.

History of Peptic Ulcer DiseaseIn most studies, NSAID use in patients with a history ofpeptic ulceration, hemorrhage, or dyspepsia has been as-sociated with a lower relative risk of peptic ulcer compli-cations, than in patients without such a history. For ex-ample, in a meta-analysis of five studies, the relative riskwas 2.5 (1.9 –3.2) in patients with a history of peptic ulcerdisease, compared with 4.9 (4.0 – 6.1) in patients withouta history.11 However, the absolute rate of peptic ulcercomplications in these patients is very high because oftheir high baseline risk. In fact, in two studies, patientswho both used NSAIDs and had a history of peptic ulcerdisease had a risk of peptic ulcer complications that was14 –17 times greater than that in patients who had neitherof these factors.5,28 If one assumes a baseline rate of pepticulcer complications of 4 per 1,000 (as in patients aged$65 years), then a person with a history of peptic ulcerdisease who uses NSAIDs would have a complication rateof 6 –7% per year ([4 per 1,000] 3 14 –17). These esti-mates are consistent with the annual incidence of gastro-intestinal hospitalizations or death (4 – 8%) that were ac-tually observed among a cohort of arthritis patients withboth of these risk factors.29

A Symposium: Managing NSAID-Associated Ulcers/Griffin

24S March 30, 1998 THE AMERICAN JOURNAL OF MEDICINEt Volume 104 (3A)

Helicobacter pyloriHelicobacter pylori and NSAIDs are the major indepen-dent causes of both gastric and duodenal ulcers.36 –38 Al-though H. pylori infection does not appear to increase therisk of developing an NSAID-associated peptic ulcer,39,40

infection with the bacterium does identify people with ahistory or higher risk of peptic ulcer disease. Further-more, people with both of these factors have a muchhigher risk of peptic ulcer disease than those with neitherof these factors.41

OtherSeveral measures of poor health have been associatedwith an increased risk of peptic ulcer complication. Thesemeasures include recent hospitalization,2 level of disabil-ity,29 and history of heart disease.30 The relationship be-tween cigarette smoking or alcohol consumption andpeptic ulcer disease has been found to be inconsistent,however.15,28,42,43

SummaryAmong NSAID users with other risk factors for develop-ing peptic ulcer complications, the incidence of seriouscomplications may be as high as 1– 8% per year. Welldocumented host factors that increase the risk of NSAID-associated gastroduodenal damage include increasingage, history of peptic ulcer disease, and poor health.Other factors such as high NSAID dose, and the concom-itant use of glucocorticosteroids and anticoagulants alsoincrease the risk. In-hospital fatality rates associated withpeptic ulcer disease are 2–10%,5,7,17,28 with the estimatesat the higher end derived from older populations. Forelderly NSAID users, fatalities are close to 1 per 1,000person years of NSAID use and are even higher in thosepatients with additional risk factors such as a history ofpeptic ulcer disease.

EXCESS COSTS FOR THE DIAGNOSISAND TREATMENT OF NSAID-ASSOCIATED GASTROINTESTINALDISEASESmalley et al23 attempted to quantify the costs for thediagnosis and treatment of gastrointestinal disease thatwere attributable to the use of nonaspirin NSAIDs in el-derly people. A retrospective cohort study was performedon 75,350 people aged at least 65 years who enrolled in theTennessee Medicaid program. The cohort was classifiedby baseline NSAID use: non (no NSAID use in the pre-ceding year [1988]), occasional (use ,75% of days), orregular use $75% of days) NSAID users. For the fol-low-up year (1989), the annual rates of utilization of, andpayments for, medical care were calculated for NSAID-associated gastrointestinal disease: hospitalizations/emergency room visits for peptic ulcers, gastritis/duode-nitis, and gastrointestinal bleeding; outpatient upper andlower gastrointestinal radiologic and endoscopic exami-

nations; and prescriptions for H2-receptor antagonists,sucralfate, or antacids. The rates were adjusted for demo-graphic characteristics and baseline healthcare utiliza-tion.

In non-NSAID users, the adjusted mean annual pay-ment for all types of medical care for the study of gastro-intestinal disease was US$134. This sum increased toUS$180 in occasional NSAID users, an excess of US$46 (P,0.001), and to US$244 in regular NSAID users, an ex-cess of US$110 (P ,0.001, comparison with both non-NSAID users and occasional NSAID users). Cohortmembers with any baseline NSAID use had an adjustedmean annual payment of US$191, which was US$57 (P,0.001) higher than that for non-NSAID users. In bothNSAID users and non-NSAID users, medications and in-patient care accounted for the largest component of thecosts. In regular NSAID users, excess payments increasedwith the baseline NSAID dose: US$56, US$120, andUS$157 for ,1, 1–2, .2 standard units per day, respec-tively (P ,0.01, linear trend).

As the costs in this study were defined as Medicaidpayments to vendors, which are generally substantiallylower than reimbursement from other third-party payersor charges to patients,44 the results from this study mayunderestimate the impact of NSAIDs on the cost of treat-ment of gastrointestinal disease in other populations. An-other source of underestimation includes the fact thatthis study identified only those physician visits duringwhich specific diagnostic procedures were performed:other types of outpatient physician visits were notcounted. In addition, the current costs for drug treatmentof the gastrointestinal disease in the study may havechanged since the introduction, and wider use, of ome-prazole and misoprostol.

Other economic analyses of the gastrointestinal ad-verse events associated with NSAID use have been of nar-rower scope than the above study, utilizing decisionmodels to evaluate the cost-effectiveness of prophylactictreatment with misoprostol for the prevention of gastriculcers.45–50 Cost estimates (annualized) vary substan-tially, ranging from US$211 for the treatment of uppergastrointestinal bleeding in NSAID users46 to US$1206for the treatment of gastric ulcer in osteoarthritic patientsreceiving NSAIDs who have abdominal pain.47 This het-erogeneity stems from differences in the populationsstudied, as well as from different assumptions that havebeen made when evaluating the decision models, includ-ing the rate of clinically apparent peptic ulcers in NSAIDusers, the proportion of patients treated in ambulatory orinpatient settings, and the costs of treatment. The esti-mate of US$244 for the elderly regular NSAID users in theMedicaid population, who had a much wider range ofgastrointestinal diseases than in many other studies, wasbased on direct measures of utilization and payments andis most consistent with the lower estimates from other


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studies. This suggests, therefore, that the findings fromsome studies that misoprostol is cost saving45,47–50 aretrue only for very high-risk populations.

The applicability of findings from the study by Smalleyet al23 to other populations depends on several parame-ters, including the prevalence of NSAID use, rates of gas-trointestinal diseases that are attributable to NSAIDs,treatment practices, and reimbursement rates. The lim-ited data available suggest that among the 33 million peo-ple in the United States who are aged at least 65 years, thepatterns of NSAID use3,4 and gastrointestinal diseas-es12,51 are very similar to those in the elderly TennesseeMedicaid population; that utilization of outpatient diag-nostic procedures is higher among all U.S. elderly citizensthan those enrolled in the Medicaid program,52 whereasrates of utilization of medication use are lower.53,54 Ex-trapolation of our findings to all U.S. residents aged $65years (with adjustment for utilization differences) yieldsestimates of excess medical care costs for NSAID-associ-ated acute gastrointestinal diseases of US$500 million.

OTHER SIDE-EFFECTS OF NSAIDs

Other Gastrointestinal Side-EffectsNSAIDs have been associated with deleterious effects onthe small intestine, including inflammation associatedwith blood and protein loss,55 stricture,56 ulceration, per-foration, and diarrhea.57 Large bowel perforation andhemorrhage are also associated with NSAID use.58 Al-though poorly quantitated, the effects of NSAIDs on thesmall and large bowels are probably less frequent than areupper gastrointestinal tract problems associated withNSAID use.

Renal Side-EffectsNSAIDs have been shown to produce a wide variety ofundesirable renal effects.59 Many experimental studieshave shown that a large proportion of patients with con-ditions that cause a dependence on prostaglandins tomaintain renal perfusion (e.g., congestive heart failure,dehydration, cirrhosis) will suffer a decline in renal func-tion when exposed to several specific NSAIDs.60,61 Thereis some debate over whether all NSAIDs have similar del-eterious effects and specifically whether sulindac is lesslikely to cause deterioration in renal function than otherNSAIDs.62 However, it is clear that all NSAIDs, includingsulindac, can both decrease renal prostaglandin produc-tion and cause deterioration in renal function under con-ditions of decreased effective circulating volume.63– 67

Blood Pressure RegulationThere is considerable support for a role of prostaglandinsin arterial blood pressure regulation.68 In experimentalmodels, acute administration of a variety of NSAIDs in-creases both arterial blood pressure and peripheral resis-tance,68 although the role of chronic NSAID administra-

tion has been less certain. However, more recent datasuggest that a variety of NSAIDs interfere with the effi-cacy of antihypertensive drugs,69 –72 raise blood pressurein hypertensive patients,73,74 and may result in the initi-ation of antihypertensive treatment in older people.75

Other Side-EffectsNSAIDs have been reported to cause a wide variety ofother side-effects; for example, hepatotoxicity,76 cutane-ous toxicity,77 pneumonitis, and neurological problemsincluding headaches and aseptic meningitis.78

ARE NSAIDs APPROPRIATE ASCHRONIC THERAPY FOR SYMPTOMSASSOCIATED WITH OSTEOARTHRITIS?

Two 2-year trials of NSAIDs have demonstrated modestlong-term efficacy of both NSAIDs and acetaminophenin osteoarthritis.79,80 These results suggest that, althoughNSAIDs are clearly superior to placebo overall, the ad-vantages of NSAIDs over acetaminophen are not so clear,a finding that has also been supported by shorter-termstudies.81,82 In addition, a small number of clinical trialshave reported benefits from a variety of exercise pro-grams and topical capsaicin that are similar in magnitudeto that achieved with NSAID therapy.83 Several studies ofNSAID withdrawal in elderly people suggest that manypatients (up to two-thirds) using NSAIDs chronicallymay do just as well without the NSAID if other analgesicsare available.84,85 Although acetaminophen is probablymuch safer than NSAIDs in most people, the substitutionof narcotic analgesics may increase the risk of falls86 andmay have other undesirable effects, particularly in frailelderly patients.87

Nonmedical therapies including behavior modifica-tion and exercise should be considered as primary strat-egies to relieve symptoms associated with osteoarthritisand other noninflammatory conditions.88 Simple analge-sics such as acetaminophen are then preferable as the ini-tial choice of oral therapy. Furthermore, NSAIDs shouldnot be continued in patients who clearly do not benefitsymptomatically.

If NSAIDs Are Used, Which One Is Best?Although there are good data to show that many patientsdo well after NSAID withdrawal, there are clearly somepatients who benefit from NSAID therapy. For these pa-tients, it is important to minimize the risks of adverseevents. Ibuprofen, particularly at daily doses of ,1,600mg, or perhaps ,2,400 mg, is a reasonable first-choicetherapy because it has consistently been associated with alower rate of gastrointestinal side-effects than otherNSAIDs.11 Salsalate (and probably other nonacetylatedsalicylates) has been less well studied but also appears tohave a lower rate of gastrointestinal side-effects thanmany other NSAIDs.89 It is likely that the favorable pro-



file of both of these drugs is due, in large part, to their useat relatively low doses. Differences in the rates of gastro-intestinal complications observed between other NSAIDsvary but usually have not been statistically different.11

However, it is reasonable to try to avoid NSAIDs thathave consistently been shown to cause high rates of seri-ous gastrointestinal side-effects, and these NSAIDs in-clude piroxicam, ketoprofen, and tolmetin,11 particularlyin patients with other risk factors for peptic ulcer disease.It is also reasonable to try to avoid NSAIDs that causeother frequent side-effects, such as indomethacin (cen-tral nervous system) and meclofenamate (diarrhea), orthat appear to cause an increased risk of rare, but serious,side-effects, such as phenylbutazone (blood dyscrasias).For some of the newer NSAIDs, however, there is muchless experience with regard to side-effects.

Is a Patient at High Risk of ExperiencingSide-Effects?Increasing age and history of peptic ulcer disease or dys-pepsia are both common factors in patients with osteoar-thritis. Therefore, patients who are $65 years, particu-larly those with a history of peptic ulcer disease, shouldunderstand that 1– 8% of patients are hospitalized forpeptic ulcer complications within 1 year of starting suchtreatment. Other factors that increase this risk include theuse of anticoagulants or glucocorticosteroids. High dosesof NSAIDs should be used with caution, particularly inpatients with other risk factors for peptic ulcer disease.Chronic renal failure must be viewed as a relative contra-indication to the use of NSAIDs. NSAIDs should also beconsidered as a possible factor in poor blood pressurecontrol, fluid overload, edema, and the development ofrenal insufficiency. An attempt to discontinue NSAIDtherapy in response to these signs and symptoms iswarranted.

Can Side-Effects Be Prevented in PatientsTaking NSAIDs?As noted above, many patients taking NSAIDs are co-prescribed antiulcer drugs. However, while H2-receptorantagonists, the most common class of drug to be co-prescribed, may relieve symptoms, they have not beenshown to prevent NSAID-associated gastric ulcers. Onlymisoprostol has so far been demonstrated to preventboth gastric and duodenal ulcers associated withNSAIDs.30 However, the co-prescription of misoprostoland NSAIDs is controversial90: misoprostol is expensive;its efficacy is by no means complete with an estimateddecrease in peptic ulcer complications of 40%; it causesrelatively frequent adverse events, predominantly diar-rhea30,91; and often it does not relieve dyspeptic symp-toms. Thus, the daily quality of life of patients takingmisoprostol may actually be worse than those takingNSAIDs alone.92 However, for patients with a high risk ofpeptic ulcer complications who receive considerable ben-

efit from NSAID therapy, and not from alternative anal-gesics, it is reasonable to coprescribe misoprostol.

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Epidemiology of Nonsteroidal Anti-inflammatory Drug–Associated Gastrointestinal Injury