NSAID-INDUCED GASTRIC ULCERS

The assesslllent of evidence associating nonsteroidal

anti~inflammatory drugs with complications of peptic ulcerations

MJS LANGMAN, MO

ABSTRACT: A causal relationship is now finnly established between non­steroidal anti -inflammatory drug (NSAlD) use a nd the occurren ce of peptic ulcer complications. In the United Kingdom, rising NSAID use has been matched by rises in ulcer mortality and perforation rates, particularly in o lder women. It is n ot likely, h owever, that drug use accounts for the entire increase. The reasons why some people deve lop ulcer complications and others do not are poorly understood. It is plausible to propose that oth er factors, such as history of ulcer o r imJigestion, current smo king, and alcoho l consumption, might raise this risk; however, supportive evide nce is lacking. Can} Gastroenterol 1990;4(3 ):91-94

Key Words: NSA/Ds, Peptic ulcer complications

Evaluation des donnees associant anti,inflammatoires non steroi:diens et complications des ulcerations gastro,duodenales

RESUME: U ne relation causale est desorma is fcrmement etablie cntre l'usage des anti-infla mmatoires nonstero"idiens (AINS) ct la survenueJes complications de l'ulcere gastro-duodena l. Au Royaume-Uni , ii a ete demontre que la consom­mation accrue des AINS correspond a une hausse de la morta lite a ttribuablc aux ulceres et des taux de perforation, surrout chez la femme agce. ll n'est toutefois pas probable que ]'usage J e ce medicamem explique cette augmentation tout entie re. Les ra isons pour lesquelles certains sujets souffrent de complications de l'ulcere et d'autres pas restent obscures. Il est plausible que d'autres facteurs, tels l'histoire de l'ulcere ou de ('indigestion , le tabagisme actif et la consommation d'alcool, augmentent ce risque; les preuves concluantes font cependant defaut.

CLINICALLY, IT IS WELL ACCEPTED

that the use of nonsteroidal anti­inflammatory drugs (NSAIDs) will pre­dispose to peptic ulcer complications of bleeding and perforation. The strength of evidence support ing this view va ries, however, as it derives from a variety of sources, including anima l and human

experimen tal studies, clinical reports of suspected adverse responses, retrospec­tive studies with o r without controls, and prospective surveillance programs. The value of these findings must there­fore be judged by sta ndard c riteria which can be employed in assessing any set of evidence bearing upon Jisease

Department of Medicine, Queen Elizabeth Hospiwl, Birmingham, United Kingdom Correspondence and reprints: Dr MJS Langman, Department of Medicine, Queen Elizabeth

Hospiwl , Birmingham Bl5 2TH, United Kingdom

CAN J GASTROENTEROL VOL 4 No 3 MAY l 990

causat ion regardless of the factors in­volved. The basic criteria include: con ­sistency of disease occurrence fol lowing exposure, strength of association, dose response, t iming, logic and accommo­dation of con founding variables.

DESCRIPTION OF BASIC C RITERIA

Consistency of disease occurrence fol­lowing exposure: Confirmation of a n associat ion requi res the occurrence of d isease in individuals exposed with at least reasona ble frequency co t he et io­logical faccor under consideration . In addition , exposure to this factor should be detected more frequendy in indi­viduals with the d isease under consid­e rat ion than in contro l individuals without it. The possibility that the etio­logical association is due co the effect of another associated factor ( referred to as a 'confounding variable' ) should a lways be examined. For example, in assess ing th e importance of smok ing habits, the confounding influence of concurrent alcoho l con sumption must be consid­ered. Furthermore, it is necessary to

conside r whether the control group chosen represents a fai r comparator. Controls should be chosen to be as sim­ilar as possible to the disease group ex­cept for being free from the d isease in question. This implies similari ty in age, sex and other factors, such as social class distribution.

91

LANGMAN

Strength of association: The strength of an association is typically expressed as the 'odds ratio' or 're lative risk'. These ratios state how many Limes more likely an individual exposed to a par­ticular factor is to develop a disease than one who is not exposeJ to the sa me factor. Although a raised risk shows association, it does not necessari­ly imply causation; raised risks can also be associated with confounding influ­ences. In general, the higher the risk, the greater are the chances thal the relevant factor is causal. Dose response: In order co measure dose response, the intensity of exposure must be graded. Generally speaking, the greater the intensity of exposure, the greater the risk. A good example of this is c igarette smoking in relation to the occurrence of lung cancer. Timing: Exposure to the relevant factor should occur at an appropriate Lime in­terval. Confounding may often occur because disease occurrence alters habils or behaviour in a way which intensifies exposure ro a suspected risk factor. Thus cimetidine or other anti-ulcer drug use commonly occurs in the period imme­diately preceding gastric cancer diag­n os is, but the relationship can be readily explained by drug taking for the relief of dyspepsia caused by the cancer itself. Logic: A logical basis for an association, though not in itself a prime criterion, provides reassurnnce and strengthens the belief chat a proposed association is likely to be causal. It should be noted, however, chat in cases where the under­lying cause of disease 1s not understood, muc h epidemiological evidence is ob­tained in an effort to ascerta in clues m likely etiologic::il factors. In such c ir­cumstances the consistency of findings from one study to anothe r becomes esp­ecially important, particularly wh ere methodo logy differs, for instance from retrospective case control to prospec­tive surveillance. Confounding: Few environmental in­flu ences upo n disease occ urrence operate without the coinc idcmal ap­pearance of associated factors. These may be non -noxious or, although harm­ful in themselves, independently oper­ating factors. The importance of the

92

fonner lies in their ability to confuse the nature of the true noxious influence. For example, ma rital srarus can inllu­e ncc disease occurrence through change in habits. The latter can a lLer risk estimates for the influences under prime consideration. For instance, al­cohol and tobacco can independently affecl the occurrence of esophageal cancer.

RELATlNG NSAIDS AND GASTRODUODENAL MUCOSAL DAMAGE

Consistency of evidence: A large body of evidence now exisls with regard to

NSA!D use and gnstrodmxknal mu­cosa! damage, deriving from a variety of sources and with varying stre ngth. Spontaneous adverse reaction reports: NSAID~ have appeared prominently in the spontaneously rcporte<l adverse re­action registers of many counLries and have been responsible for one-quarter to one-fifth of all such reports in Lhe United Kingdom and the United States ( 1-3 ).

These darn ::ire difficult Lo assess. Sromaneous reports represent a biased sample. These biases lead to reporting or, much more frequently, nonrepon­ing, which is poorly underst0od. Re­ports, however, arc much more likely to

be generated for new rather than old drugs. This of itself invalidaLes compar­isons between individual agents which are based upon spontaneous reports and, with NSAID-associated gastroinL­estinal nd versc events, the occurrences are in commlm for the class. Neverthe­less, reports of serious adverse events of ulcer bleeding, perforation, and death have been so frequen t thal an impor­tant clinical problem must be assumed. Complication rates: Little controlled informaLion is available with regard to

pcrforntion of ulcers. In the Un ited Kingdom, a higher rnte of prior NSAIO use was found among pariems wiLh per­forated ulcers than among inpatient controls in two studies (4,5). O n e of these studies included a suhsrantial ad­mixture nf paLicnts wi1 h ulcer bleeding but focused on thnse whn had heen opera Led upon ( 5 ). Furthermore, deta i Is of Lhe expcrimen rn l methods indicaLed Lhat controls were nrn collecLed con-

temporancously and were not mmched for age. Surve illance studies in the U niLed Kingdom (6) and the Unned St.Hell (7) have suggested tha1 the nsks of ulcer perfora1 ion m,1y have hecn ex­aggerated. The former sLUdy, however, may nol have included sufficil:nt ly large numbers of elderly people LO detect ul­cercomplicalions, whereas in the latter swdy, rhc numhcr of subjeCLli who de­veloped ulcer complicat ionl, wal, rmher small and Lhc observed dma set in­cluded many cases wiLh coding errors. The relative risk, although rnbed at 1.6 , had wide confidence intervals, rellect­ing the small numhers sLUdied, and the even smaller number with NSAID-a~­sociaLcd com pl ,cat ions. Bleeding: Many of Lhe Jara se ts for ulcer bleeding arc uncontrolled. I low­ever, data from one l,llldy (8), which employed matched Cl>mmunity and hospital inpatient controb, suggested that chose with ulcer bleeding, both gaslric and duodenal , were belwccn two and five times as likely to have hecn NSAID users as e ither cont ro l. Risks also differed liLLlc for aspirin and non­aspirin NSAIDs. S urveill a nce o f Medica id script rccipienls in Michigan and Minncsorn revealed a raised rela­tive risk ( l. 5) with a 95% confidence interval of l.l LO 1.9 for upper gastrointestinal bleeding from all sour­ces (9). By contrnsr, no mmcrial risk for upper gastroinleslinal hleeding was found at Puget Sound, Washington, USA, in individuals aged 65 or less. Of the 301 patients admiucd to hospital , 14 had filed a prescripl ion for an NSAID in the previous 90 days; all paLients bleeding from duodenal ulcer in the period under review were ex­cluded (10). Ulcer death: The same raised risk of dcalh from ulcer in NSAID recipient:,, (relaLive rbk 4.7) was found in Lwo North American Mudies; nne from Sas­katchewan ( 11 ), and the tither from Tennessee ( 12). This risk, however, was limited to rho:,,c aged 75 and over in the former study. Strength of association and dose re­sponse: T he strength of an a,sociation b conventiona lly mca,ured hy Lhc rela­ti ve risk or odds raLio, which ,tale~ how much more or less likely it is for an

CAN J GASTR0ENTEROL VOL 4 Nl) 3 MAY 1990

inJtviJual who possesses a paruculm characterisr rc 11> Jevelnp a specific u1n ­dn1on than for ,mL' withou t such a char­acteristic. W here NSAID use is con­cemed , this rbk, when raised, has been

founJ co hi.' of the order of two- tn fou rfold. Such a figure, however, docs

nm measure the .ihsolu te risk. This can­not he obtnined without e ither some accrnnp,mymg measure nf the actual risk in the ordinary popularion or an

odds ratio, 1c, a mea~ure of the actual risk m NSA I l) users and the difference compared wnh rhe base population. In Michigan and Minnesota (9), cwocascs of hemorrhage were estim ated en occur for every I 1,000 individual months of tn:aun1::nt, a figure \\'hich corre,ponds with est1m,1te, of n,k in t he U1111ed

Kmgdnm (8,13). Increased risk, c1ccording w rntens11 y

or durauon nf exposure w a ,uspccted

en ological agent, usually provides con ­

fi rmatory ev1dl.'nce of causation. This type of ev 1de11Le, however, b nm avml­

ab!..:; variaunn 111 the anti -inflamma­tory strengt h and pharmacokinetic pniperues nf individual drugs makes it impossible tu crente logical compil,1-t iom for di rL'Ct comparisom. Timing: A ll available darn sets h:,w been col lectl'd with cnns1deratinn given to drug intake 111 the imml.'diare preceding time period. It 1s therefore

not poss1hle tu dissect the mformat ion

fun her. Logic: NSA!Ds have been comnwnly associatd with dyspepsia. Furthcrmnre, expernnenrnl otud ics and clinical triab

have shown that NSAID treatment is associated with the appearance of upper

gastrointcsunnl lesiom, mainly gastric antral in site and varying Ln degree from hemorrhagic spots to 1::rosions or ulcers

(14-17). What is k ss clear is the basis for the

occurrenct: of ulcer comp I icarions, as­suming that NSA !l) treatment has a causal role. A th ird or more ofNSA JL) recipients may develop dyspepsia ( 18), but ulcer complirn tiom seem to occur in less than one in LOOO. NSA ID rreat­mcnt inhibits p latel e1 function, which

c~iuld account for th e tendency I ll

hemnrrhage. It does not, hl1wever, n.­plain ulcer pe1forntion.

C linic.1! experience in the United

Kingdom and elsewhere have suggested

t hat the occurrence of dyspepsrn com~­lates poorly with l1abil1ty tn ulcer com­

plicatiom ( 19,20). Ry contrast, tn the U nited States rheumc1w1d anhriris pa­

tients receiving NSA!Ds appeared to he at six times the risk ,if hospita l adm1:,­

s11m due tn gastrointestinal disease co m pa red to nonrec ipients with

rhc11matrnd anhrn 1s (21 ). C haractcris­u cally, rhts association held fnr o lder 111dividuals who had previous histories of NSAI D intolerance. Ph,mnac.olo­g1cally, it might he expecred that ad­

verse even ts would occur in those with undul y slow NSA[L) metablllism or

those taking drugs with long half-lives. The l11111ted avnalable evidence, how­

ever, gives no ind1cat 1011 that pharm­ac,ik I ne 11c properties can predH:t symptom occurrence, and clear differ­ences m relanve risks hetween d rug:,

have yet to emerge (22,2 3). Confounding: Curre nt cl inica l evi­dence suggests that the elderly are pm­t icularly prnne to develop NSA ID, assoc iated complicatinm and may alw he the gn)up most prone to peptic ul­ccrat1on . Most fonnal st ud ies, there­fore, account for confounding hy age. Another important fac tor is confound­ing hy disease indication. There ts ,time reason to bel1<.'ve that paricnts with rheumawid arth ri tis may he more prone

to peptic ulceration than expected. However, the hulk of NSAID -as­

socaated ulcer complica tions seem ro occur in individuals who dn not have rheumatoid arthritis. Disability asso­

c iated with rheumatoid anhriris has heen associated with liab ility to peptic

ulceration, hut multivaria te a na lysis h as not been used to separate disahility from drug treatment (21 ); indeed, they may

not he separable by formal study. The degree of disability associated with os­teoarthritis, the most common indica­tion for NSA I D treatment, has nnt been aSsllCiated with susceptibility to

ulcer.

DISCUSSION There seems good reason to accep t

that NSAIL) treatment is frequently as­

soc iated wi th the onset of dyspepsia and tha t peptic ulceration may emue. Fur­ther oimplications, however, arc rare.

CAN J GASTRllENTEROI VI.Ji 4 Nl1 3 MAY 1990

Peptic ulcer complications

Snme clinical studies, hut not al l, have shown thar patients 1n whom compli ,

cared ulceration develops may have had no prior symptoms. The reasom arc un­clear; thus, we do not know 1f rhe cnm­

plicaunn nccurs in a newly developed or an esrnhlbhed ulcer. Nevertheless,

there seems tll Ix adequate evidence for accepting that NSA ID treatment 1s as­sociated with the development of ulcer crnnplicar1ons and tha1 the assm.1.1t ion

1s c.iusal. W hat remams unclea r 1s v. h y some

111d1viduab develop ulcer compl1ca­nons and others dn not, and whether there are matenal differences 111 gastric

and duodern1I susceptibility to damage. Experimental stud ies a nd short 1erm human investigat11ms in ntirmal volu n­

teers sugge,t that the ga,tnc ant rum may he the prune , arc 1i damage ( 14-17). Whether mvesugauons Ill healthy

volunteer, ( who ,ire usually young) c.in be u~ed t1l predict the s1u: and pmtern of damage 111 o!dl.'r people with ch niniL diseases 1s uncerta111. In the Unned S tai es the hroad assumption tends to he made that danrnge is mainly ga,mc. Evidence fnim elsewhere 1s contl1cung. Thu,, n11 d1fferenLe was found in the risks nf gastric and duodenal ulcl.'r

hleed111g which were equally r,1ised 111 N!:,A[l) taker, (8). By contrast, 111

Australw a raised rbk of developing gas­

t f!L ulcer was detected 111 l,ne stuJy wnhoul a parallel risk for d11ndena l ul­

cer (24). Kurata (25), in reviewing the ,l\"ail ­

able U nited Srnu:s and United King­dom studi es , noted that differing physician prac tice study designs mid

populatiom which were examml.'d could have contributed to the variable results obrnined from one ,tudy w ,m­other. Another factor may he a differ­

ence in underlying trends ill ulce r frequency and behaviour. Thus, 111 the

United Kingdom ulcer perforat inn ratl.'s, used as proxy for mcide11Lc data, have fa llen steeply Ill men, whereas rates, panilularly uf duodena l ulcer, have risen in elderly women ( 13). The reas1ms for the rise were uncle.ir am.I could not he ascribed to ei t her smoking habits or changes in NSA lD use, a l­

though these could have accoun ted for part of the rise. Despite decr1::as1ng

-

LANGMAN

Uni led Slates 11llspicalizmion and m,ir­calicy rates over the past 30 year,, self­reported ulcer prevalence ha~ ri~en (25). These trend~ may he related to a ~hifL to outpauenc management usmg new drugs. A lternalivcly, United Stales data show a sex ratio corresponding to

the rising rate for women found in Lhc Nalional Health Imerview Survey (25,26). Analytical stuJ1es suggest a

strong correlation in men and women with :,moking habits (27). Although the differences in findings between dif­fe rent area~ seem irreconcilable 111 the main, limited agreement exists in sug­gesting chat differences in ulcer fre­quency between men and women may be d isappearing, anJ that NSAI L) use

REFERENCES l. Griffin JP. Survey uf rhe ,pum.meous

adverse reactinn rcpon111g ,chcrne, in fifteen countries. Br J Cl111 Pharmaw l 1986;22(Surrl):853-1005.

2. Committee on the Safety cif Medicine Update. 1. Non,rero1dal ant ,-mflam-matory drug,. Br Med J I 986;292:614.

). Rossi AC, l l~u JP, F,11ch GA. Ulu:rn-gcntcity nf p1rox1cam and analy,i:, of spontc1ncously reported data . Br Med J 1987;294: 147-50.

4. Collier DS, Pain JA. Nonstermdal ,lllfl• inflammatory drug:, ,tnd pcp11, ulcer r,·rfornti<ln. Gut 198'i;26: 159 61

5. Armstrong CP, P.lower JL. Non-srcrnidal ;111n-1nfl,1mm,11,,ry drug, ,md life threaten mg compl11 .. au,m, of pep-t ic ulccrati,>n. Gut l 987;28:527-12.

6. Inman WI IW. Comp,1rauvc study nf five NSAIDs. PEM News 1985;H-l 3.

7. J,ck SS, Perera DR, Walker AM, ct al. Nomternidal ,1nt1-inflammarory drug:, and ho,pital admis,1om, for perforated pepuc ulcer. Lmcet 1987;11: l80-2.

8. Somerville KW, Faulkner G, Langman MJS. Nnmteroidal ann-inflammatl>ry drugs and hleeding peptic ulcer. Lancet I 986;1:462-4.

9. Can.on JL, Stmm RL, Soper KA, c1 al. The associauon of nnmrerrnJal anti· inflammatory drugs with upper gastm-intestinal hlccding. Arch lmcrn Med 1987; 147:85-8.

LO. Jick H, Feld AD, Perera DR. Certam nonsremidal ant1-inflamm,1rory drugs and hosp1caliza1ion for upper gastro-intestinal bleeding. Pharmacuthcrapy I 985;5:280-4.

11. Guess HA, West R, Strand LM, ct al. Fara I upper gascromrcst in,11 hcmnr-rbage or pcrforamm among users :ind non-users of mmsteroidal anti-i

94

c.m ,lCCl>UnL for a minor progressinn only, perhaps onC·ljWHtcr of the uh­served change.

The h,1s1s for 111div1dual susccpuhil­ity i~ unclear. Ulcer complicatiom as­sociated with NSA!D use seem to be particularly prevalent in the elderly. hut NSAlD use increases with age. Armstrong ;iml Blower (5) suggested that NSAl D users might he at particular rbk uf dymg, hut this evidence is dif­ficult to evaluate because cases and contrnb were not age-matched. In an­other study in Australia, however, there wa~ m, evidence chat NSAID use af­fected Lhe chances of dying with ulcer disease over and above that nf develop­ing ulcer compl,cat iom (28).

ntlarnmalllr) drug, m Sa,katchcwan. CanaJ,1 198 l. J Cl111 Epidernl()l 1988;4 I : '35-45.

12 . Cinffin MR, Ray WA, Schaffner W. N1m~tem1dal anr1-inf1ammatory drug use and death fn)m pep1 tc ulcer m elderly pemm;. Ann ln1ern Med 1988; 109: '359-61.

I 3. Wair R, Katschmsk1 B, Logan R, Cl al Rising frequency of ulcer pcrforauon 111

ckll'rly pel1ple 111 the United Kingdom. Lancet l 986;1:489-92.

14. Sato 11, Guth Pl I, Grl1s:,man Ml. Rl,lc of food m gastm111tcst111al ulc,·rat1on pwdw.:cd hy 111dume1haun in the rnt c;a,trocn1erol,,gy 1982;83:2 I 0-5.

15. Lanza FL, Royer GL. Nelson RS, et al. The diccts ll( ,hupmfon, indo-mel hacin, ,t:,pirin, naprnxcn ,ind placehn 1m 1he gas1nc mucosa nf 1111r-ma! volunteer:,. A ga~trosu>pic and photographic Mudy. Dig D1, Sc, l 979;24:823-9.

16. Larka1 EN, Smith JL, Lidsky MD, Graham DY. Ga:,troduodcn,t l mucosa and dyspeptic ,ymptoms in arthritic patients during chronic nonsterrndal anti-inflammatory drug use. Am J Gastmentcml 1987;82: 1153-8.

J 7. Graham DY, Agrawal N, Roth S. Prevention nfNSAID induced g..i,mc ulcer with the synthcric prmcaghm,lin 1111,opmsml. A mulricentre double-hi ind placeh1l·COntrollcd trial. Lmcet 1988; ii: 1277 -80.

18. I lush) G, I lolme I, Rug,rad HE. c1 al. A d,,uhle-hlmd multiccntrc tnal of p1mxicam nnd napmxen 111 ostco-arthritis. Clm Rhcumawl J 986;5:84-91.

19. Mcllem M, Sravc R, Myers], cl ,11. Symptoms in patients \\'1th peptic ulcer and haematemes1> ,md/nr mclaena re-tared rn rhe use ot nonstemidnl ant1-111-

CONCLUSIONS Despite widely varymg re~ult~ of

retrospective case control and surveil­lance studies, the body 01 evidence gen­erally poinb LP n raised mk of ulcer complications associated wllh NSAID drug use. The reasons f1)r the discrepan­cy between the common ()Ccurrencc of dyspepsia and the much rarer advent of ulcer bleeding or perforauon are nm

understood. A !though elderly indivi­duals appear tn he at particular risk, they are not frequent user~. Funhermnre, there is no convincing evidence 1n I he majori ty who take this drug, 11lllirheum­ato1d anhm1s patients, which permits the predict ion of the ind ividuab at par­ticular risk.

tbmmmory drug,. Sc,md J Gamocntcml 1985;20: 1246-8.

20. Clinch D, P.ancrJCl'. AK. Oslil'k G. Ah,cncc of ;ihdorninal pam 111 clJcrl) patients w1th pcpnc ulcer. Age Ageing 1984; 13: 120-1.

21. Fries Jr, M ,lier SR, Spitz PW, Cl al Towards an epidemiology of J.:a:,tropathy asMK 1atcd with non-, teroiJal anti -inflammatory druJ.! u:,c. G,1,1 roenrerology 1989;96:64 7 -5 5.

22. Rugstad I IE, I lundal O. I lolnw I. er al Pimxicam and naproxen pl,1,ma con-centn11 ion, 1n p,111cni:, w11h o:,icn-arthritb rclauvc to age, ,ex, cft,cacy and adwrsc cffou,. Clin Rheum;11ol 1986;5: 189-98.

23. Carson J L, Strnm RL, Ml>rM' LM, ct al. The rchmvc gaMrointcMinal l<lX1cit~ of the nomtero1dal ant1-mflammm11ry drugs. Arch Intern Med 1987; 14 7: 1054-9.

24. Duggan JM, Dohwn AJ, Johnson 11, rt al. Pcpuc ulccr and non,tcn ,,dal ,111u-111flammmnry agents. Gui I 988;27:929-3 3.

25. Kuraca JH. Ulcer c:p1dcm1\>ll>gy: An llVCrview and pmpo,cd re,carch trnmcwnrk . G,1stmentcmll>gy J 989;96:569-80.

26. Kurara JI I, Hade !3M, Ela,hoff JD. Sex difference:, 111 pcptll ulcer dt,ca,c. Gastrocmerology I 985;88:96- 100.

27. Kurarn JH, Elashoff JD, Nllgawa AN. I lade RM. Sex and smllkmg differcn-ces 111 duodenal ulcer m,>nal,ty. Am J Public I lealth 1986;76:700-2.

28. Henry DA, Johmmn A, Dobson A, Duggan J. Fatal pcplll ulcer rnmpltca-110m aficr the u,l' of nomtcrrndal ,mu-inflammatory drugs, aspirin and cnmcosrcro,ds. Br Med J 1987; 295:1227-9.

CAN J GA~"TROENTERl )L VOL 4 No 3 MAY l 990

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