NSAID-INDUCED GASTRIC ULCERS

Exatnining the risks for NSAID--induced gastropathy

SI lERINE E GABRIEL, MD, C LAIRE & )MBARL)IER, MD, FRC PC, LI ISA JAAKKIMAINEN, MSc

ABSTRACT: The medical literature describing the gastrointestinal risks as­sociated with chronic nonsteroidal anti-inflammatory drug (NSAlD) therapy is increasing rapidly. In spite of this, clinicians remain uncertain about how to translate this information into clinical practice. C linical decisions regarding the management of adverse reactions to medications have two components. The first involve~ risk to the patient, and the secoml an evaluation of available alternatives for managing that risk. Three research designs have been used to examine this association: ecological studies, case contro l studies and retrospective cohort studies. Although these designs do not provide the strongest evidence for causation, their results point toward the existence of a risk of serious gastrointes­tinal reactions of between 1.5 and 10 times greater for NSAID users than for nonusers. The wide variation in results is due to multiple factors, including different research designs, study populations and outcome measures. Several subgroups have been suggested to be at particularly high risk. Risk factors include advanced age, female sex, debilitating rheumato id disease, previous gastro intes­tinal disease, ethanol abuse and smoking. Only in the elderly has there been adequate data to support this associa tion. Although the data regarding females is compelling, this may be confounded by the documented increased NSAlD use among females. Decision analysis is a useful tool for the quantitative examination of the costs and benefits of management alternatives available for dealing with these risks. Research is needed to identify accurately subgroups ofNSAID users at high risk. CanJ Gastroenterol 1990;4(3):108-112

Key Words: Adverse gastrointestinal events, Nonsieroidal anti-infiammatary drugs, NSAIDs, Review

Examen des risques de la gastropathie provoquee par les AINS

RESUME: La litterature medicate fait de plus en plus frequemment etat des risques gastro-intestinaux associes aux therapies chroniques (anti-inflammatoires non stero'idiens). Les cliniciens ne savent neanmoins toujours pas comment traduire ces donnees clans leur pratique. Les decisions cliniques relatives au

Rheumauc Disease Unit and Clinical Epidemiology Unit , The Wellesley Hospiwl , Unwersity o{Taronw, Taronto , Omario

Correspondence and reprims: Dr C Bombardier, Suite 420A, Jones Building, Rheumatic Disease Unit , The Wellesley Hos/Jital , 160 Wellesley Street East, Toronto, O ntario M4Y 1)3

108

DESPITE TIIE RA PI DLY EXPANDING

meJical literature describing gastrointestinal ri sks associated wi th chronic nonsteroidal anti-inflam­matory drug (NSA!D) therapy, defin i­tive recommendations for cl inical practice c1re lc1cking. In order to rnc1 ke sound clinica l decisions regarding the management of NSAID-induced gastrointestinal effects, the risk to the patient must fi rst be defined; alterna­t ives for reducing that risk should then be examined (Figure 1 ). This con­troversy will be reviewed using these two issues as guidelines.

-

I. DEFINING THE RISK TO THE PATIENT

~ [ CLINICAL I DECISION

/ -

II. EXAMINING THE ALTERNATIVES FOR REDUCING THE RISK

-Figure I ) Components of clinical decisions regarding NSA ID-induced adverse grutrnin1es­tinal events

C AN J GASTRL)ENTEROI V OL 4 No 3 M AY 1990

traitement Jes reactions indesirables d 'origine medicamenteuse com portent deux elements. Le premier evalue quels sont les risques pour le patient et le second examine les solutions permertant de composer avec eux. T rois plans de recherche ont ete utilises pour ecudier cette association: etudes ecologiques, etudes cas­temoins, etudes re trospectives Jes cohortes. Bienque ces strategies ne constituent pas la fa~on la plus sure d'etablir la relation de cause a effet, les rcsultats indiquent que les usagers d' AINS sont l ,5 a 10 fois plus exposes aux reactions gastro-intes­t inales graves que les non-usagers. La la rge variation des resultats est due a des facteurs multiples. O n suggere que plusieurs sous-groupes etaient formes de sujets a risques particulieremenc eleves - les facteurs de risque comprenant I 'age avance, le sexe feminin, les maladies rhumato"ides debiliranres, les antecedents J'affec­tions gastro-intcstinales, les abus d'alcool er le tabagisme. Bien que les donnees re lat ives aux sujets feminins soienr impressionantes, ii faut prendre en con­sideration le fai t bien documente que les femmes sont grandes consommatrices d 'AlNS. C'esc done seulemen t chez les sujets ages que les resultats confirment !'association a l'etude. L'analyse des decisions est un instrument utile a !'examen quantitati f Jes coGts et des avantages que component les diverses strategies possibles pour aborder les risques en question. La recherche se doit d'identifier exactement les sous-groupes J'usagers des AINS qui sont a haur risque.

DEFINING THE RISKS Defining the risks to the patient in­

volves ;:inswering the following three questions. Do NSAlD users run an in­creased risk of adverse gastroincesnnal effects compared to nonusers? If so,

whar is chc magnitude of this risk? Which types of NSA!D user~ arc ac particularly high nsk' ls there a risk? The most important evidence for es1ablish111g a cau~e-cffcc1 relationship b chc strength of the re-

PROSPECTIVE COHORT STUDY:

RETROSPECT/VE COHORT STUDY: NSAIDS

? DISEASE

NO NSAIDS

CASE CONTROL STUDY :

? NSAID USE

? NSAID USE

PAST PRESENT

Figure 2) De.1ign of co/ion and case conrro/ qudic1

CAN J GN,TROCNTEROL VOL 4 NO 3 MAY 1990

NSAID gostropathy

search designs used co stu<ly that re­lationship ( I ). Randomi ze<l controlled rrials provi<le the strongest evidence but are seldom ethical in studies of causa­tion because they involve the random assignment of in<livi<luals to rccelve or not receive potentially harmful therapy. Well conducted, prospective cohort studies are the next best <lesign because they minimize the effects of selection and measurement bias. Fol­lowing in stre ngth of <les ign arc retrospective cohorts, case control studic~ and ecological studies; these have been use<l co examine the associa­tion between NSA l D use and gastropathy.

Ecological studies have associated the general rise in NSAID use in a population with the increased preva­lence of gastric ulcer or its complica­mms. Such Mudics have been conducted in the Uni ted States and the United Kingdom (2-7). Both countries have demonstrated a relationship be-1 ween rising prescription rates for NSAIDs cind increasing rates of ulcer

NSAIDS

? DISEASE

NO NSAIDS

109

GABRIEL et al

TABLE 1 Retrospective cohort studies

Reference Study population Outcome Rote ratio (Cl)

Jick 1985 GHC <65 years 1977-82 Hospitalization 1.05 (NA) (18) UGI bleed

Beard GHC >64 years 1977-83 Hospitalization 1.3 (-0.2. 3.4) 1987 (19) UGI bleed

Jick 1987 GHC 1977-83 Hospitalization 1.2 (0.5. 2.8) (15) UGI perforation

Carson COMPASS All members UGI bleed 1.5 (1.2. 2.0 1987 (20) Michigan and Minnesota 1980

Guess All members Fatal UGI bleed 3.1 (0. 1, 23.2) 1988 (21) or perforation All <75 years

Saskatchewan Health Plan 1983 5.3 (1.6. 17 4) F>75 years. no past history GI

Bloom Pennsylvania Medicaid 1984-85 All 2.52 (2.25. 2.82) 1989 (22) Gastric ulcer 2.36 (1.49. 3.74)

GI b leeding 3.27 (1 .40, 7.66)

Rate ratio Re/olive risk. users/nonusers: Cl Confidence intervals: GHC Group Health Cooperative, Puget Sound: COMPASS Computer/zed on-line pharmaceutical analysis and survelllonce system: UGI Uppergostrointesttnol

TABLE 2 Case control studies

Reference Rote ratio (Cl) Outcome

McIntosh 1985 (8) 6.4 (2.3, 18.0) Chronic gastric ulcer

Collier 1985 (9) 2.3 (0.84, 6.33) Admissions 11.5 (5.98. 22.31) Perforated peptic ulcer

Bartle 1986 ( 10) 4.3 (1 .5. 12.2) Admissions Upper GI bleeding

Duggan 1986 (11) 5.0 (1 .4, 26.9) Outpatient gastric or duodenal ulcer

SomeNille 1986 ( 12) 2.7 (1.7. 4.4) Admissions 3.8 (2.2. 6.4) Bleeding peptic ulcer

Armstrong 1987 (13) 13.7 (9.93, 18.06) Death or emergency surgery. peptic ulcer

Henry 1987 (14) 4.2 (0.9, 25.6) Fatal peptic ulcer complications 1.1 (0.6, 2.1)

Jlck 1987 (15) 1.2 (0.45, 3.5) Admission bleeding peptic ulcer

Levy 1988 (16) 9.1 (2.7, 31) Admission upper GI bleeding

Griffin 1988 ( 17) 4.6 (3.1. 7.2) Fatal peptic ulcer complications 5.2 (2. 7, 10.0) 4.2 (2.4. 7.1) 6.2 (3.1. 12. l)

Rote ratio Odds ratio, users/nonusers: Cl Confidence ,ntervol: GI Gostro,ntestinol

disease and its complications. Because both NSAID use anJ the development of ulcers were measured in the popula­tion rather than in individuals, it is possible that the NSAID users were not the ones who developed ulcers or ulcer complications. Ecological studies, therefore, cannot be regarded as strong evidence for cause and effect. Such studies, however, represent an impor­tant step in developing the hypothesis of causation.

Two ocher research designs have

110

been useJ to examine the association between NSA!Ds and gastropathy: retrospective cohort and case-control studies ; Figure 2 illustrates the differen­ces between these designs. The Jesign of prospective cohort studies is in­c luded for comparison.

In a cohort stu<ly, a group of people ( the cohort), al I of whom are ulcer-free, is followed over time to determine which members (NSAID users or non­users) <levelop ulcers or associated com­pl icacions. In retrospective cohort

studies, NSAID use is identified from pasr records con mined in healLh insur­ance registries. S uch data arc colleCLed for patient care purpose~ and therefore may 1101 he of sufficient qu::i li1y for rig­orous research. Alternatively, in pros­pective cohort studies, the data are collected specifically for the purpose of 1 he srudy and hence many biases are avoide<l, resulting in improved stu<lies examining rhe risk of NSA ID-induced gast rop;ithy.

Case control stu<lies retrospectively compare the frequency of NSAID use in people with and without gascro­pathy. lf patients with gastropathy were found more likely to be NSAlD users this would constitute some evidence for causation. Case control studies are sus­ceptible ro many more biases than co­hort studies. For example, patients receiving NSAIDs are more likely to be investigated for the presence of an ulcer than chose not receiving NSAIDs, leading to increased detection of ulcers in chis group.

Tables I and 2 summarize the main study characteristics and relative risks for adverse gastrointestinal events from case control (8-17) and cohort swdies (l 5,18-22). Eleven of the l6 studies reviewed show a statist ically significant increased risk of gastric ulcer or its com­plications for NSAID users compared to nonusers. The considerable vari­ability in the reported relative risks (from 1.05 to greater than LO) is largely due to differences in research design, study population ( eg, pre-paid group practice, elderly, med icaid) and out­come measures (cg, fatal upper gastro­intestinal bleed, gastrointestinal hospitalization, chronic gastric ulcer). The majority of studies point to a rela­tive risk for gastrointestinal events two co five times greater for NSAID users than nonusers.

Overall, the evidence for a causal relationship between NSA lOs and seri­ous gastrointestinal events is strong. Therefore, the answer to the fi rst ques­tion is yes, there is a risk. What is the magnitude of risk? The risks of gastrointestinal complications among NSAID users have been esti­mated from various sources. Prospec­ci vel y collecccc.l data from a la rge

CAN J GASTROENTEROL VOL4 No3 MAY 1990

computerized registry indicated risk of gastrointestinal hospita lizminn as l % per year for rheumatoid arthrius pa­tients (23 ). T he fond and Drug Admin­istration has quoted a risk for serious gastrointestinal events of 2 to 4% per year among NSAID users (24). A re­cent overview and meta-analysis wh ich combined the rates of gast ro in testina l complications from over 100 NSAID cl inical t riab reported an overall com­plication rate of 2°,{, (25). Estimated ahsolute risb of gastrointestinal com­plicarium from rhe six coh()rt studies rev iewed va ry from 0.02% to 0. 5<y.L Overall, rhe reported risb vary from two in 1000 LO four in JOO. T his varia­tion b due to differences in t he ascer­tai n ment nf NSA ID exposu re and o utcome nssessment. Who is particula rly at risk? Studies wh ich examine the types of patienh at risk yielJ somewhat inconsistent fi nd­ings due to the fact t!"iat most studies cxmnining risk factors fail to cont ml fur other potential confoundcrs. Fnr exam­ple, the evidence of an excessive risk in elderly females may he confounded hy the documented inc reased NSAID use in th is group ( 6). Other risk factors, such as h istory of previous gastroi ntestinal dis-

REFERENCES I. Sackett DL, I laynes RB, Tugwell P.

Cl111ical Eri<lcmiology: A Basic Science For Cl111ical Mcdic111e. Bostonfforonto: Little, Brown ,md Company, 1985:223-41.

2. ElashoffJO, Grossman Ml. Trends in hosrital admissions and death rates for pertic ulcer in the United States from 1970 to 1978. Gastroentcrology I 980;78:280-5.

3. Kurata JI I, Honda GD, Frankl H. Hospitalization and mortali ty rates for rertic ulcers: A comparison of a large health maintenance nrganizarion and United States data. Gastroemcrology 1982;83: I 008-16.

4. Kurata JI I, Corboy ED. Current peptic ulcer time trends. An epidemiological rrofile. J Clin Ga,trocnterol 1988; 10:259-68.

5. Baum C, Kennedy DL, Forbes MB. Utilization of nonsteroidal anti-inflam-marory drugs. Arthritis Rheum I 985;28(6):686-92.

6. Coggon D, Lambert P, Langman MJS. 20 years of hospital admissions for pertic ulcer in England and Wales.

case, alcohol use, smoking and severe rheumatic disease requ ire further study.

EXAMINING ALTERNATIVES FOR REDUCING RISKS

Having established the presence of a clin ically important risk, the next ster is w examine the alternatives for reduc­ing this risk (Figure l ). Some simple approaches to risk reduction in clude using the minimal dose of NSATD which wi ll control t he symplL)ms, switch ing to non-NSAID analgesia whenever possible, and carefully mon­itoring elderly patients. The dl'cision to

prescribe prophylaxis ts much more dif­ficult becat1se it involves not only po­tential hencfits hut abo potent ia l riob and additional co~t. Clinical decisinn nnalysis is useful because it qunntita­tivcly incorporates such information 111to the clinical decision making proceS5.

Using 'decision tree' methodl)logy, rhe aurhnrs have de,igned a c linical model representing clinical management dec1s1on.~ for physicians faced with these patien ts. This model can also he adapted for cost-effccnveness analyses. Prelimi­nary data indicate that determin ing the cost-effectiveness of prophylaxis with

7.

8.

9.

10.

11.

Lancet 1981 ;ii:1302-4. Walt R. K.irS(;himki B, Logan R, Ashley J, Langman MJS. Rising frcqunecy nf ulcer perforation 111 elderly people 111 the United Kingdom. Lancct;i:489-92. McIntosh JI I, Byth K, Piper DW. Environmenral factors in aetiology of chronic gasmc ulcer: A case control study of exposure var iables before the fim symptoms. Gut 1985;26:359-6'3. Collier DSJ, Pain JA. Non-steroidal ant i-inflammatory drugs and reptic ulcer rerformion. Gut l 985;26:359-63. Barde WR, Gupta AK, Lazor J. Non-steroidal anti -inflammatory drugs and gastrointestinal bleeding. A case control study. Arch Intern Med I 986;146:2365-7. Duggan J M, Dobson AJ, Johnson 11, Fahey P. Peptic ulcer and non-steroidal anti-inflammatory agents. G ut I 986;27:929-33.

12. Sommerville K, Faulkner G, Langman MJS. Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer. Lancet I 986;i:462-4.

13. Annstrong CP, Bl<1\VCr AL. Non­steroidal ant1-111flammatory drugs and

CAN J GASTROENTEROL VOL 4 No 3 MAY 1990

NSAID gastropothy

misoprostol. a syntheu c proswglanJin analogue, hinges tm a more accurate defin ition of the ulcer complicat inn rate.

SUMMARY In summary, most of the avai lable

li terature supports the existence of a

causal relationship between ch ronic NSAJD use and t he development of gastric ulcer and its subsequent com­plications. The magnitude of the risk can he estimated en be bet ween two in 1000 and four in I 00. A lthough several subgroups have been suggested to be at h igh risk, only 111 the elderly and per­haps in females have there been ade­quate data to support this associiition . Decisi,m analysis is c1 useful tool for the quantitative examination of the manageml'nt alternatives available for dea ling with these risks. Ir also repre­sents a model to study I he cost -effec­uveness of prophylactic therapy. Research 1s needed ro define accurately the natural hi,l()ry of NSAID-induced gastmincestmal mucosa! damage and particularly thl' ulcer complication rate, in both the general population anJ various suhgroups. Preventive strategies can then be targeted ro the high risk groups.

lite threatening complicat ion of rcptic ulcenniun. Gut I 987;28:527-32.

14. Henry DA. Johnston A, Dobson A, Duggan J. F;irnl reptic ulcer complic,1-nons and the use of nLm-steroi<lal anti­inflamm;itory drugs, aspirin and con icosteroids. Br Med J 1987;295: 1227-9.

15. Jick SS, Perera DR, Walker AM, Jick H. Non-steroidal anr i-111flammarory drugs and hospital admission for rcrforated peptic ulcer. LanCl't 1987;d80-2.

16. Levy M, Mi ller OR., Kaufman OW, ct al. Major urrcr gastmintewnal rrnct bleeding. Relation to the u,e of aspirin and other non-narcouc analgesics. Arch lncern Med 1988; 148:281 -5.

17. Griffin MR, Ray WA, Schaffner W. Nnnstcrnidal anti-intlammmory drug use :md Jeath from pcruc ulcer 111 elderly rcrsons. Ann Intern Med 1988; 109: 359-63.

18. J1ck H, Feld AD, Perm1 DR. Cerrn111 nonsteroidal a1111-inflammatory drugs and hospitaltzat1\m for urpcr gastmintestmal bl~eding. Pharmaco­thernry l 985;5:280-4.

111

GABRIEL et al

19. Bean! K, Walker AM, Perera DR, J tck H. Nonsteroi<lal anti-inflam­matory Jrugs anJ hospitalization for gastrointestinal bleeding in the elJerly. Arch lnrcrn Med 1987; 147: 1621-3.

20. Carson JL, S trom BL, Soper KA, West SL, Morse ML. The assoctatton of non­srcroiJal anti-inflammatory Jrugs with upper gastromtestmal tract blecJmg. Arch Intern Me<l 1987; 147:85-8.

21. Guess HA, West R, Srran<l LM, cc al. Fatal upper gastrmnrestmal hemor-

112

rhagc of performion among users anJ nonusers of nonstero1Jal anr1-intlam­mamry drugs m Saskmchewan, CanaJa 1983. J Clm Epi<lemt011988;4l:35-45.

22. Bl<X>m BS. Risk and cost of gastro­intestinal side effect, associated wtth nonsccro1dal ant1-111tlammacory drugs. Arch Intern Mc<l 1989; 149: IO 19-22.

2 3. Fries JF. TowarJ an cpiJ em1ology of gastropachy ,1ssocinted with non­stero idal anci -mtlammacory Jrug use. Ga,crocntcrolo!?) 1989;96:64 7 -5 5

24. Federal Rcgi.try. 22nd meeting of the Archnm AJv1sory Commtttce of chc US Food anJ Drttg Admmiscrat1on. Rockville, Maryland: US Food and Drug Admm1scra tion, 1988; May 16.

25. Cha Imm TC, Berrier J, I lewitr P, cc al. Meta-analysts of rnnJom1zed concmllcd triab as a method of cmmnt­mg rare compltcaltom of non-,tcro1dal anr1-intlammarory drug rhcrnpy. Aliment Pharmacol Ther I 988;2(Suppl I ):9-26.

CAN J GASTROENTEROL VOL 4 NO 3 MAY 1990

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