Gut 1994; 35: 891-895 891 Predicting NSAID related ulcers - assessment of clinical and pathological risk factors and importance of differences in NSAID A S Taha, S Dahill, R D Sturrock, F D Lee, R I Russell Abstract posed to improve the yield of endoscopy. Although ulcers are often associated with These included simple age restrictionsl 2 and non-steroidal anti-inflammatory drugs strategies to characterise patients at risk of (NSAIDs) little is known about the benign or malignant ulcer disease.3-5 More feasibility of predicting their development recently it has been suggested that the detec- in patients taking NSAIDs. In addition, tion ofHelicobacterpylori by serology be used to the ulcerogenic potentials of the newer diagnose peptic ulcers in dyspeptic patients NSAIDs, taken on long term basis, have without the need for endoscopy.67 Despite not been compared with those of more the increased frequency of ulcers in patients established preparations. The aim of this taking non-steroidal anti-inflammatory drugs study was to identify the clinical and patho- (NSAIDs), very little is known about the risk logical characteristics of patients at a factors for their development. Nor is it clear higher risk of NSAID induced ulcers, whether the above observations would apply to measure the ulcerogenic potential of a NSAID patients. This is because: (1) NSAID- variety of NSAIDs, and test the effect induced ulcers can be completely asympto- of these potentials on the predictability matic8 9; (2) the precise contribution of of ulceration. Altogether 190 long term H pylori to NSAID related peptic damage is NSAID users were studied. The presence not fully defined; (3) the specificity of some of abdominal complaints, previous history serological tests for H pylori may be low in of ulcers, arthritis related physical dis- chronic NSAID users10; (4) there is a growing ability, anaemia, gastritis, and Helico- belief that the various NSAIDs may differ in bacter pylon status were all assessed as their ulcerogenic potentials.I 1-13 possible risk factors. NSAIDs were classi- This study aimed, therefore, to assess a fied into established drugs (group I), and group of clinical and pathological characteris- newer agents (group II). Group I included tics that might identify patients at a higher risk naproxen, indomethacin, diclofenac, of having NSAID related ulcers and to test the ketoprofen, piroxicam, and flurbiprofen. possibility that such risk might vary according Group II included fenbufen, nabumetone, to the type ofNSAID used. ibuprofen, etodolac, azapropazone, and tiaprofenic acid. Of 63 ulcers identified in the study group, 51 (81%) were seen in Patients and methods group I NSAID patients (51 of 132, 39%) Patients aged 18 years or over were recruited compared with 12 ulcers in group II (12 of from the rheumatology clinic provided they had 58, 21%), p<0.02; estimated relative risk osteoarthritis or adult rheumatoid arthritis. (ERR): 2.41). In group I, 25 ulcers were NSAIDs had to have been taken in therapeutic found in 38 patients with abdominal pain doses for at least four weeks. Patients were (25 of38, 66%, p<0-01, ERR: 5.03); 18 in 25 excluded if they had had gastric surgery, malig- (72%) patients with a previous history of nancy, or if they had taken anti-ulcer drugs or ulcers (p<0001, ERR: 5.77), 26 in 44 (59%/o) antibiotics within a week of endoscopy. patients with debilitating arthritis Blood was taken to measure the haemoglo- (p<0-001, ERR 3-64), and 35 in 73 (48%) bin concentration, erythrocyte sedimentation patients with H pylori associated gastritis rate (ESR), and C reactive protein (CRP). (p<001, ERR: 2.48). The presence ofthese Physical disability related to arthritis was factors in group II patients did not in- measured using the Health Assessment fluence the risk of ulceration. Group I Questionnaire.'4 Patients who scored 2 1 or NSAIDs were more likely to be associated more were considered to have debilitating Departments of with chemical gastritis and to intensify arthritis (finding much difficulty in performing Gastroenterology, Pathology, and H pylon related damage. Although silent their daily activities and needing to use several Rheumatology, ulcers are not uncommon in patients aids and devices). Informed consent was Glasgow Royal taking NSAIDs, recognition of the risk obtained and endoscopy was performed using Infirmary, Glasgow A S Taha factors might help predict a significant midazolam for sedation. Gastric antral biopsy S Dahill number (up to 81%), especially in those specimens were taken to test for H pyloni by R D Sturrock receiving group I NSAIDs. both histology (two specimens) and culture F D Lee (Gut 1994; 35: 89 1-895) (one specimen), as previously described.'5 R I Russell Gastritis was classified according to the Sydney Correspondence to: Dr A S Taha, GI Centre, system,'6 which also encompasses chemical Southern General Hospital, Over the years, several attempts have been and lymphocytic gastritis.17-20 Glasgow G5 1 4TF. made to the presence of peptic ulcers The following characteristics were assessed Accepted for publication predict 28 October 1993 and various screening policies have been pro- as possible risk factors: (1) upper abdominal 892 Taha, Dahill, Sturrock, Lee, Russell TABLE I Characteristcs ofpatients taking established (group I) or newer (group II) pathologists were not aware ofpatients' clinical NSAIDs details, and the study was approved by the All NSAID local ethics committee. Group I Group II patients (n = 132) (n = 58) (n = 190) Men 32 23 55 Results Women 100 35 135 Age (y) (median (IQ range)) 56 (46-60) 54 (46-66) 55 (46-62) A total of 190 patients was studied. Their Smokers 54 21 75 demographic characteristics are shown in Drinkers 61 24 85 Rheumatoid arthritis 107 39 146 Table I. Patients in both NSAID groups were Osteoarthritis 25 13 38 similar in terms of sex distribution, age, smok- Duration of NSAID (y) (median 2 (1-4) 1 (1-3) 2 (1-4) (IQ range)) ing and drinking habits, type of arthritis, and the duration of NSAID intake. In addition, there were no significant differences between TABLE II Duration ofarthritis, its activity, and details ofsecond line drugs the two groups with regard to the duration of arthritis, its activity (as judged by the erythro- All NSAID Group I Group II patients cyte sedimentation rate and C reactive (n= 132) (n= 58) (n= 190) protein), and the types of second line drugs as Duration of arthritis (y) (median 8 (4-14) 6 (2-18) 7 (3-14) shown in Table II. (IQ range)) The numbers of patients and ulcers in ESR (mm/h) (median (IQ range)) 24 (9-47) 22 (10-42) 23 (9-44) CRP (mg/i) (median (IQ range)) 13 (8-30) 11 (9-29) 12 (8-29) association with the various risk factors are Second line drugs: illustrated in Figures 1 and 2. Patients taking Gold 31 5 36 Sulphasalazine 31 15 46 group I NSAIDs had more ulcers than those Penicillamine 10 1 11 receiving group II drugs. The presence ofupper Hydroxychloroquine 13 4 17 abdominal complaints, a previous history of ulcers, debilitating arthritis, or H pylori signifi- ESR= sedimentation rate, CRP = C reactive protein. erythrocyte cantly increased the risk of having ulcers in group I NSAID patients. These factors did not symptoms, (2) previous history of ulcers, influence the risk of ulcers in group II patients, (3) debilitating arthritis, (4) anaemia (haemo- although more H pylon positive patients than globin less than 11 00 g/dl with iron deficiency Hpylori negative patients had ulcers. It is worth picture), (5) gastritis, and (6) H pylori status. noting that the ulcers described in this study NSAIDs were divided into two groups: group I were more common in the stomach (n=36) (older or established agents) including than in the duodenum (n=27). However, this naproxen, indomethacin, diclofenac, ketopro- pattern was reversed in smokers: 15 of23 ulcers fen, piroxicam, and flurbiprofen and group II (65%) in smokers were seen in the duodenum (newer agents) including fenbufen, nabume- compared with eight (35%) in the stomach tone, ibuprofen, etodolac, azapropazone, and (p<0 05), and this did not differ in the two tiaprofenic acid. The ulcerogenecity of most of NSAID groups. Also, group I patients included the newer preparations had been assessed 33 cases of anaemia (33 of 132, 25%) and 15 previously in short term trials only.12 13 ulcers (15 of 33, 45%) compared with seven of Statistical analyses included the x2 test, anaemia cases (seven of 58, 12%, p<0.05) and logistic regression, and the 95% confidence one ulcer (one of seven, 14%, p<0 05) in intervals for the estimated relative risk (odds group II patients. In addition, 18 ulcers were ratio) where appropriate. The endoscopist and found in 65 patients aged 60 years or over (28%), regardless of the type of NSAID, and men and women were equally effected. The estimated relative risk values and the All patients 950/o confidence intervals for the factors 140 included in Figure 1 are presented in Table III. ~~~~~~~~~~~Ulcers Patients with abdominal pain or a previous 100 .: Risk factor present history of ulcers had the highest values, while factor absent 80 ~ ~~~Risk those with anaemia had the lowest estimated 60. relative risk. Using logistic regression, it was found that only the type of NSAID (group I versus group II), the presence of abdominal pain, and a previous history of ulcers were 40 Al independent predictors of ulceration in the %0- 140 All patients Abdominal pain Past history of ulcers 140 study group as a whole. 120 z 100 TABLE iII The estimated relative risk (odds ratio (OR)) and 95% confidence intervals (95% CI) for the individual 80 riskfactorsfor ulcer development in patients taking group I 60 NSAIDs Riskfactors (OR) (95% CI) Previous history of ulcers 5-77 (2-2,15) 20 Abdominal pain 5 03 (2-27,11-2) Debilitating arthritis H pylori Anaemia Debilitating arthritis 3-64 (1-7, 7-9) Helicobacterpylori 2-48 (1-2,5- 12) Figure 1: The numbers ofulcers in the presence or absence ofthe various risk factors in Group I NSAID as a whole 2-41 (1-17,4-98) group I NSAID patients.