Non-Steroidal Anti-Inflammatory Drug and Antacid Co-Prescription in Taiwan: Analysis of National Insurance Claims

Chi nese Med i cal Jour nal (Taipei) 2002;65:588-593 Orig i nal Non-Steroidal Anti-Inflammatory Drug and Antacid Co-Prescription in Taiwan: Analysis of National Insurance Claims Tzeng-Ji Chen Jui-Yao Liu Shinn-Jang Hwang De part ment of Fam ily Med i cine, Tai pei Vet erans Gen eral Hos pi tal; and Na tional Yang-Ming Uni ver sity School of Med i cine, Tai pei, Tai wan, R.O.C. Key Words ant ac ids; anti-inflammatory agents, non-steroidal; drug ther apy, com bi na tion; na tional health pro grams; pharmacoepidemiology Background. Antacids were usually co-prescribed with non-steroidal anti-inflammatory drugs (NSAIDs), al though no broad ev i dences were available as to the effects of antacids in preventing NSAID-associated gastropathy. We per formed a sur vey of na tional in sur ance claims for out - pa tient ser vices in Tai wan to de ter mine the ex tent of this co-therapy na - tionwide. Methods. The Na tional Health In sur ance Re search Da ta base sup plied the sam pling datasets for anal y sis. They rep re sented 0.2% of the en tire claims for out pa tient med i cal ser vices in 1999. Co-prescribing was as sessed as NSAIDs and ant ac ids on the same pre scrip tion. The se lec tion and group - ing of NSAIDs followed the guidelines of the Anatomical Therapeutic Chem i cal (ATC) Classification System rec om mended by the World Health Or ga ni za tion. Only the oral drugs pre scribed on reg u lar vis its were taken into ac count. Results. In to tally 425,442 pre scrip tions with 1,825,604 items of drugs, non-aspirin NSAIDs were pres ent in 108,818 (25.6%) pre scrip tions and ant ac ids in 235,252 (55.3%) pre scrip tions re spec tively. Fur ther more, ant - ac ids were pres ent in 71.3% of pre scrip tions that con tained NSAIDs and in 49.8% of pre scrip tions that did not con tain NSAIDs (p < 0.001). Sig nif - i cant as so ci a tion of NSAIDs and ant ac ids ex isted in dif fer ent spe cial ties of prescribing physicians, but the co-prescription rate (ant ac ids in NSAIDs pre scrip tions) var ied from the high est of 92.8% in the neu ro sur - gery to the low est of 49.8% in the pe di at rics. Sig nif i cant as so ci a tion of NSAIDs and ant ac ids also ex isted at dif fer ent lev els of health care fa cil i - ties, where the co-prescription rates were 80.9% at med i cal cen ters, 83.5% at re gional hos pi tals, 87.4% at lo cal hos pi tals, and 66.6% at pri mary care units. The sub group of oxicams was more fre quently co-prescribed with ant ac ids than other sub groups (odds ra tio = 1.51, p = 0.001). Conclusions. Con com i tant pre scrip tion of oral non-aspirin NSAIDs and ant ac ids was in deed a pop u lar prac tice in Tai wan. Be side their ef fects in al le vi at ing the NSAID-associated dys pep sia, the role of ant ac ids in pre - vent ing NSAID-associated pep tic ul cers or in mask ing the warn ing symp - toms of these ul cers de mands fur ther eval u a tion. [Chin Med J (Tai pei) 2002;65:588-593] Re ceived: January 3, 2002. Ac cepted: October 22, 2002. Cor re spon dence to: Tzeng-Ji Chen, MD, De part ment of Fam ily Med i cine, Tai pei Vet erans Gen eral Hos pi tal, 201, Sec. 2, Shih-Pai Road, Tai pei 112, Tai wan. Fax: +886-2-2873-7901; E-mail: tjchen@vghtpe.gov.tw

De cem ber 2002 NSAID and Ant acid Co-Prescription 589 The ad verse ef fects of non-steroidal antiinflammatory drugs (NSAIDs), es pe cially in the up per gas tro in tes ti nal tract, al ways con cern both phy - si cians and pa tients. The choice of drugs to pre vent such events re mains con tro ver sial. In a pre vi ous ob - ser va tional study con ducted at the out pa tient poly - clinic of a med i cal cen ter in Tai wan, it was found that ant ac ids were con com i tantly pre scribed in 87.3% of pre scrip tions with NSAIDs. 1 A sim i lar phe nom e non has been also ob served in Sin ga pore. 2 No large-scale ran dom ized con trolled trial has been ever per formed to in ves ti gate the ef fi cacy of ant ac ids for pro phy laxis of NSAID-associated gastropathy. A pro spec tive study even found that asymp tom atic pa tients tak ing ant ac ids with NSAIDs had a higher risk of se ri ous gas tro in tes ti - nal com pli ca tions than those tak ing NSAIDs only. 3 The stud ies on con com i tant pre scrip tion of NSAIDs and ant ac ids are rare be cause ant ac ids are nor mally ap proved as non pre scrip tion (over-thecounter) drugs and not re im bursed by most thirdpayer in sur ance in west ern coun tries. Thanks to the lib eral pol icy of Tai wan s Na tional Health In sur ance in re im burs ing ant ac ids, it turns pos si ble to ac cess the data. In the cur rent study, we per formed a sur vey of na tional in sur ance claims for out pa tient ser vices in Tai wan to de ter mine how the co-prescription of NSAIDs and ant ac ids pre vails across the coun try. The dif fer ences among spe cial ties of pre scrib ing phy si - cians, sta tus of health care fa cil i ties and sub groups of NSAIDs would be also an a lyzed. Methods The Na tional Health In sur ance (NHI) in Tai wan was im ple mented in 1995 to cover nearly all cit i zens of the coun try. The pay ment to health care fa cil i ties oc - curs monthly on the ba sis of claims. The claims data in the out pa tient area are visit-based and in clude a visit file and an or der file among oth ers. While one re cord of the visit file reg is ters the sum mary data of each en coun - ter be side the fa cil ity and pa tient iden ti fi ca tion, the or - der file lists the cor re spond ing or der items (in clud ing lab o ra tory tests and drug pre scrip tions) of ev ery visit. A spe cific se rial num ber for each visit al lows the link - age of the visit and or der files. Since 1999, the Bu reau of NHI has re leased all the claims data to the pub lic for the pur pose of ac a demic re search. The iden ti fi ca tion data of pa tients and fa cil i ties are scram bled to at tain an - o nym ity and thus pro tect pri vacy. In the first year the Na tional Health Re search In sti tutes was in charge of the huge da ta base in size of terabytes un der the pro ject of Na tional Health In sur ance Re search Da ta base (NHIRD) (http://www.nhri.org.tw/nhird/) and of fered doz ens of ex tracted datasets for each year be gin ning from 1996. In the cur rent study, we used the files of the year 1999 (S_CD19990 and S_OO19990 of NHIRD) for the anal y sis. These two files were ex tracted from the en tire da ta base of out pa tient claims (ex clud ing ser - vices of the den tal and tra di tional Chi nese med i cine) with the sys tem atic sam pling method. Ac cord ing to the NHIRD, the size of the sub set from each month is de ter mined by the ra tio of the amount of data in each month to that of the en tire year. Then the sys tem atic sam pling is per formed for each month to ran domly choose a rep re sen ta tive sub set. This sam pling da ta - base is ob tained by com bin ing the sub sets from 12 months. The sam pling da ta base of S_CD19990 was con structed at first then the rel a tive ob ser va tions in S_OO19990 were drawn out ac cord ingly. The sam - pling da ta base of S_CD19990 was 0.2% to the orig i - nal da ta base. We also ob tained a com plete da ta base of ap proved drugs in Tai wan from the web site of the Bu - reau of NHI (http://www.nhi.gov.tw/) (ac cessed 25 May 2001). Each drug of dif fer ent brand, strength and form was of fi cially as signed a unique code that was used in the claims file. An other file about ba sic data of health care fa cil i ties (HOSB1999 of NHIRD) pro - vides the sta tus of ac cred i ta tion: med i cal cen ter, re - gional hos pi tal, lo cal hos pi tal, and pri mary care unit. The visit file of S_CD19990 con tained 539,661 re - cords and the order file of S_OO19990 con tained 2,803,110 re cords. Our study in cluded only the reg u lar vis its with phy si cian con sul ta tion and ex cluded emer - gen cies, out pa tient op er a tions, di al y sis, home care, pre - ven tive ser vices, and so forth. Among the reg u lar vis its we fur ther dif fer en ti ated into vis its with or der of ei ther lab o ra tory test(s) or drug(s), vis its with pre scrip tion of drug(s), and vis its with pre scrip tion of drug(s) for oral

590 Tzeng-Ji Chen, et al. Chi nese Med i cal Jour nal (Tai pei) Vol. 65 No. 12 Table 1. The summary of S_CD19990 and S_OO19990 datasets (0.2% sampling) Claim Regular visit Visit withorder Visitwith drug Visitwith PO drug Record count 539,661 506,639 492,457 470,423 425,442 Patient count a 524,784 493,295 479,734 458,671 415,496 Male 234,658 222,741 217,111 207,956 190,164 Female 287,657 268,286 260,424 248,634 223,432 Unknown 2,482 2,279 2,209 2,090 1,909 Patient s average age 37.0 (SD b 24.4) 36.8 (SD 24.5) 36.9 (SD 24.5) 36.8 (SD 24.7) 36.4 (SD 24.7) Total count (items) of order 2,803,110 2,640,236 2,640,236 Total count (items) of drug 2,126,397 2,064,552 2,064,552 2,064,552 Total count (items) of PO drug 1,868,337 1,825,604 1,825,604 1,825,604 1,825,604 a Slight discrepancy because some patients had more than one record sampled but different values were given in the field of patient s sex. PO = per os; SD = standard deviation. Table 2. The relationship of NSAID and antacid prescriptions Number of prescriptions With NSAIDs Without NSAIDs Total With antacids 77,605 (71.3%) 157,647 (49.8%) 235,252 Without antacids 31,213 (28.7%) 158,977 (50.2%) 190,190 Total 108,818 (100.0%) 316,624 (100.0%) 425,442 p < 0.001 by chi-square test. in take (PO) in a hi er ar chi cal way. Ta ble 1 shows the sum mary of our data source. Sub se quent anal y sis in our study fo cused only on the drugs for oral in take. Ad di tionally, the Bu reau of NHI of fered a list of An a tom i cal Ther a peu tic Chem i cal (ATC) codes for each drug. This ATC clas si fi ca tion sys tem was rec om - mended by the World Health Or ga ni za tion for drug uti - li za tion stud ies 4 and has been in ter na tion ally used. The struc ture of ATC code has five lev els to divide the drugs into dif fer ent groups and sub groups. Two groups of drugs in which our study has in ter est are M01A (anti-inflammatory and anti-rheumatic prod ucts, non-steroids) and A02A (ant ac ids, drugs for treat ment of pep tic ul cer and flat u lence). NSAIDs have 7 chem i - cal sub groups of the 4th level: butylpyrazolidines (M01AA), ace tic acid derivatives and related sub - stances (M01AB), oxicams (M01AC), propionic acid de riv a tives (M01AE), fenamates (M01AG), coxibs (M01AH), and others (M01AX). Because salicylic acid and de riv a tives (N02BA) were usu ally pre scribed in low dos age for the pre ven tive pur pose of cardio- and cerebrovascular dis eases in Tai wan, our study did not in clude them in the anal y sis. The da ta base soft ware of Microsoft SQL Server 2000 was used for data link age and pro cess ing. The as so ci a tion of NSAID and ant acid pre scrip tions was tested by chi-square test. Co-prescribing was as sessed as NSAID(s) and ant acid(s) on the same pre scrip tion. Be side the over all anal y sis of the files, we con ducted sim i lar anal y ses strat i fied by spe cialty of phy si cian, ac cred i ta tion sta tus of health care fa cil ity and chem i - cal sub group of NSAID. A p-value of less than 0.05 (two-tail test) was con sid ered as sig nif i cant sta tis ti - cally. Results Among the 425,442 vis its with pre scrip tion of drug(s) for oral in take, non-aspirin NSAIDs and ant - ac ids were pres ent in 25.6% (108,818) and 55.3% (235,252) of pre scrip tions re spec tively. Ant acids were pres ent in 71.3% of pre scrip tions that con tained NSAIDs and in 49.8% of pre scrip tions that did not con tain NSAIDs (p < 0.001) (Ta ble 2). Sig nif i cant association of ant ac ids pre scrip tion

De cem ber 2002 NSAID and Ant acid Co-Prescription 591 Table 3. The relationship of NSAID and antacid prescriptions, stratified by selected specialties with more than 1000 sampling records Specialty Number of prescriptions Frequency of antacids in prescriptions with NSAIDs Frequency of antacids in prescriptions without NSAIDs p value a Practitioners 111,261 66.8% (20621/30873) 51.8% (41662/80388) < 0.001 Internal Medicine 65,787 77.3% (10633/13755) 58.1% (30214/52032) < 0.001 Otorhinolaryngology 55,387 66.1% (10736/16235) 52.9% (20701/39152) < 0.001 Family Medicine 48,909 67.1% (8399/12513) 52.2% (18998/36396) < 0.001 Pediatrics 39,732 49.8% (3411/6848) 30.2% (9926/32884) < 0.001 Gynecology 22,618 76.6% (4409/5759) 46.6% (7858/16859) < 0.001 Dermatology 12,716 62.3% (839/1346) 42.2% (4802/11370) < 0.001 Surgery 12,703 85.9% (4302/5008) 66.1% (5086/7695) < 0.001 Orthopedics 10,532 90.5% (7563/8360) 67.0% (1455/2172) < 0.001 Neurology 6,539 85.2% (1609/1889) 51.6% (2399/4650) < 0.001 Cardiology 6,191 67.8% (160/236) 39.3% (2340/5955) < 0.001 Gastroenterology 5,639 79.1% (174/220) 61.6% (3338/5419) < 0.001 Psychiatry 4,388 69.5% (130/187) 21.0% (883/4201) < 0.001 Urology 4,034 85.6% (517/604) 52.2% (1790/3430) < 0.001 Ophthalmology 3,534 70.3% (586/833) 41.4% (1119/2701) < 0.001 Endocrinology 3,259 62.5% (105/168) 31.1% (962/3091) < 0.001 Rehabilitation 2,593 84.4% (1378/1632) 45.1% (433/961) < 0.001 Chest Medicine 2,309 80.7% (171/212) 60.0% (1258/2097) < 0.001 Nephrology 1,616 77.5% (155/200) 36.9% (522/1416) < 0.001 Neurosurgery 1,530 92.8% (606/653) 61.5% (539/877) < 0.001 Rheumatology 1,458 89.3% (698/782) 54.1% (366/676) < 0.001 a chi-square test. Table 4. The relationship of NSAID and antacid prescriptions, stratified by accreditation status of health care facilities Kind of facility Number of prescriptions Frequency of antacids in prescriptions with NSAIDs Frequency of antacids in prescriptions without NSAIDs p value a Medical centers 29,353 80.9% (3638/4498) 37.8% (9396/24855) < 0.001 Regional hospitals 33,343 83.5% (4927/5904) 44.0% (12063/27439) < 0.001 Local hospitals 59,663 87.4% (14761/16880) 57.7% (24691/42783) < 0.001 Primary care units 303,083 66.6% (54279/81536) 50.3% (111497/221547) < 0.001 a chi-square test. with NSAIDs ex isted in nearly all spe cial ties. Ta ble 3 lists only the data of those spe cial ties with more than 1,000 sam pling vis its. The co-prescription rate dif fered among spe cial ties (Chi-square test, p < 0.001) and var - ied from the high est of 92.8% in the neu ro sur gery to the lowest of 49.8% in the pe di at rics. Although some subspecialties (e.g. gastroenterology, car di ol ogy, chest med i cine and nephrology) of in ter nal med i cine pre - scribed NSAIDs less fre quently, their co-prescription rate of NSAIDs with ant ac ids re mained high. The association of ant ac ids pre scrip tion with NSAIDs also ex isted in dif fer ent lev els of health care fa cil i ties (Ta ble 4) and the co-prescription rate dif fered among lev els of health care fa cil i ties (Chi-square test, p < 0.001). Nev er the less, the pri mary care units had a lower co-prescription rate of 66.6% than hospitals (odds ra tio = 0.338, p < 0.001). The co-prescription rates with ant ac ids in ma jor sub groups of NSAIDs are listed in Ta ble 5. The sub - group of oxicams (M01AC), which in cluded piroxicam, tenoxicam, droxicam, lornoxicam and meloxicam, was more fre quently co-prescribed with ant ac ids than

592 Tzeng-Ji Chen, et al. Chi nese Med i cal Jour nal (Tai pei) Vol. 65 No. 12 Table 5. The relationship of different subgroups of NSAID prescriptions with antacids Subgroup of NSAID Number of prescriptions With antacids Without antacids M01AA: butylpyrazolidines 32 19 (59.4%) 13 (40.6%) M01AB: acetic acid derivatives 44,555 32,571 (73.1%) 11,984 (26.9%) M01AC: oxicams 5,477 4,346 (79.4%) 1,131 (20.6%) M01AE: propionic acid derivatives 33,455 22,907 (68.5%) 10,548 (31.5%) M01AG: fenamates 26,788 19,020 (71.0%) 7,768 (29.0%) M01AH: coxibs 0 M01AX: others 4,964 3,445 (69.4%) 1,519 (30.6%) other sub groups (odds ra tio = 1.51, p = 0.001). In 1999, the sub group of coxibs (M01AH) was not yet avail able to the NHI in sured. The dis crep ancy be - tween the sum of pre scrip tions with dif fer ent groups of NSAIDs in Ta ble 5 and the to tal count of pre scrip - tions with NSAIDs in Ta ble 2 was caused by the fact that 8000 pre scrip tions con tained mul ti ple (> = 2) NSAIDs. Discussion Our study re-confirmed the fact that con com i tant pre scrip tion of oral non-aspirin NSAIDs and ant ac ids was a pop u lar prac tice in Tai wan. In our study, co-prescribing was as sessed as NSAIDs and ant ac ids on the same pre scrip tion. Be cause the datasets arose from visit-based sam pling, the lon gi tu di nal data of in - di vid ual pa tients were not avail able. We thus could not iden tify the sit u a tion in which a pa tient re ceived NSAIDs and ant ac ids from sep a rate pre scrip tions. If the pa tient re ally took all drugs pre scribed, the con - com i tant use of NSAIDs and ant ac ids would be more prev a lent than that cal cu lated in our study. Our study showed that pri mary care units had a lower co-prescription rate of NSAIDs and ant ac ids than hos pi tals, which might be at trib uted to case mix at dif fer ent lev els of health care fa cil i ties. The out pa - tient de part ments of hos pi tals in Tai wan are open to all the in sured with out any re fer ral lim i ta tion. The NHI has a fee-for-service pay ment in the ma jor ity of cases. The trend was then to ward that the hos pi tals saw more chronic pa tients and the pri mary care units pre scribed more with short du ra tion. Be sides, the pri - mary care units with dis pens ing rights are al lowed to charge the daily drug fee as a lump sum for the pre - scrip tions with up to three days sup ply. This reg u la - tion on pri mary care units im plic itly puts con straints on polypharmacy and helps avoid un nec es sary drug pre scrip tions. On the other hand, the pe di at ric pa tients were less likely to be chronic and thus had the low est co-prescription rate among all spe cial ties. In the lit er a ture, ant ac ids were sel dom pro posed for pre ven tion of NSAID-related gas tro in tes ti nal prob lems. The re search in ter ests fo cused on H 2 -re cep - tor an tag o nists (e.g. ranitidine), pros ta glan din analogs (e.g. misoprostol), and pro ton pump in hib i tors (e.g. omeprazole) in stead. 5-7 In Tai wan, the NHI re im - bursed these ul cer-healing drugs with strict lim i ta - tions. Ex cept for some small groups of high-risk pa - tients, ul cer-healing drugs could be pre scribed only if the di ag no sis of pep tic ul cer or re flux esophagitis is proved by a re cent en dos copy, ra di og ra phy or sur gery. Sim i lar re stric tions were also pres ent in other coun - tries. 8 Al though such re stric tions might lead to more ant ac ids pre scrip tion, they could hardly ex plain the ex tremely high co-prescription rate of NSAIDs with ant ac ids in Tai wan. The rea son for the ex treme frac tion of ant ac ids in the pre scrip tions with NSAIDs might come from both the phy si cian s and pa tient s sides. The phy si cians feared for side ef fects of NSAIDs and the pa tients had con cerns about in tol er ance to NSAIDs and other chem i cal drugs. The ex act cause de manded qual i ta - tive in ves ti ga tions. Sim i larly, it re mained un known whether ant ac ids were pre scribed to treat a pre ex ist ing gas tro in tes ti nal dis ease rather than to pre vent the po - ten tial NSAID-related gas tro in tes ti nal prob lems. Al - though up to three di ag nos tic codes of ICD-9-CM (In - ter na tional Clas si fi ca tion of Dis eases, 9th Re vi sion,

De cem ber 2002 NSAID and Ant acid Co-Prescription 593 Clin i cal Mod i fi ca tion) were pro vided in each NHI claims re cord, we did not in tend to use them for a judg ment about the pur pose of treat ment. The claims di ag no ses in the in sur ance sys tem usu ally serve for the re im burse ment only and are not ver i fied, es pe - cially in the out pa tient area. Be sides, there is no spe - cific code for the gastropathy caused by NSAIDs. It is in con clu sive whether the in sur ance pol icy should limit the co-therapy of NSAIDs with ant ac ids. The acid ity does play a role in NSAID dam age to the gas tric mu cosa through al ter ing the gas tric ab sorp tion of NSAIDs and in ter fer ing in the sec ond ary acid in - jury. 9 Be sides, ant ac ids can al le vi ate the more fre - quent NSAID-associated dys pep sia that dif fers from NSAID-associated ul cer in pathophysiological mech - anism. 10 Al though ant ac ids might not ef fec tively pre - vent ul cers in chronic NSAID us ers, they could lessen the in tol er ance in most pa tients who just oc ca sion ally take NSAIDs. On the con trary, the phy si cian should ex er cise cau tion in high-risk pa tients and adopt more po tent ul cer-healing drugs for pro phy laxis. Al though rou tine pre scrib ing of ant ac ids to gether with NSAIDs might not be a uni ver sal phe nom e non, 11 our study had yet an other par tic u lar mean ing. No phar ma ceu ti cal firms would take in ter est in sup port - ing stud ies re lated to ant ac ids, which have not so many fi nan cial ben e fits. The seem ingly ir ra tio nal or con tro ver sial pre scrib ing pro vides ex cel lent ma te ri als for nat u ral ob ser va tion or sur veil lance. If the di men - sion of co-prescription is sig nif i cant, fol low-up stud - ies can con tinue. Of course, due cau tion should also be needed in such ret ro spec tive ob ser va tional stud - ies. 12 Finally, the meth ods and tech niques we used to an a lyze the large amount of data could be ex tended to any pos si ble com bined pre scrip tion of drugs. In the era of elec tronic pre scrib ing, our ap proach might con - trib ute to the field of pharmacoepidemiology. Acknowledgements This study is based in part on data from the Na - tional Health In sur ance Re search Da ta base pro vided by the Bu reau of Na tional Health In sur ance, De part - ment of Health and man aged by Na tional Health Re - search In sti tutes in Tai wan. The in ter pre ta tion and con clu sions con tained herein do not rep re sent those of Bu reau of Na tional Health In sur ance, De part ment of Health or Na tional Health Re search In sti tutes. References 1. Liu JY, Chen TJ, Hwang SJ. Con com i tant pre scrip tion of non-steroidal anti-inflammatory drugs and ant ac ids in the out pa tient set ting of a med i cal cen ter in Tai wan: a pre scrip - tion da ta base study. Eur J Clin Pharmacol 2001;57:505-8. 2. See Y, Ng SC, Tho KS, Teo SK. Are ant ac ids nec es sary as rou tine prescriptives with non-steroidal anti-inflammatory drugs? Ann Acad Med Sin ga pore 1998;27:219-22. 3. Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gas tro in tes ti nal tract com pli ca tions of nonsteroidal anti-inflammatory drug treat ment in rheu ma toid ar thri tis: a pro spec tive ob ser va tional co hort study. Arch In tern Med 1996;156:1530-6. 4. Guide lines for ATC Clas si fi ca tion and DDD As sign ment. 3 rd edi tion. Oslo: WHO Col lab o rating Cen tre for Drug Sta tis tics Meth od ol ogy, 2000. 5. Ehsanullah RS, Page MC, Tildesley G, Wood JR. Pre ven tion of gastroduodenal dam age in duced by non-steroidal antiinflammatory drugs: con trolled trial of ranitidine. BMJ 1988;297:1017-21. 6. Gra ham DY, Agrawal NM, Roth SH. Pre ven tion of NSAID-induced gas tric ul cer with misoprostol: multicentre, dou ble-blind, pla cebo-controlled trial. Lancet 1988;2:1277-80. 7. Yeomans ND, Tulassay Z, Juhasz L, Racz I, Howard JM, van Rensburg CJ, et al. A com par i son of omeprazole with ranitidine for ul cers as so ci ated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338:719-26. 8. West brook JI, Duggan AE, McIntosh JH. Pre scrip tions for antiulcer drugs in Aus tra lia: vol ume, trends, and costs. BMJ 2001;323:1338-9. 9. Yeomans ND. Ap proaches to heal ing and pro phy laxis of nonsteroidal anti-inflammatory drug-associated ul cers. Am J Med 2001;110(1A):24-8S. 10. Jones J, Raud J. Nonsteroidal anti-inflammatory drug-associated dys pep sia: ba sic mech a nisms and fu ture re search. Am J Med 2001;110(1A):14-8S. 11. Clinard F, Bardou M, Sgro C, Lefevre N, Ra phael F, Paille F, et al. Non-steroidal anti-inflammatory and cytoprotective drug co-prescription in gen eral prac tice: a gen eral prac ti tio - ner-based sur vey in France. Eur J Clin Pharmacol 2001; 57:737-43. 12. McMahon AD. Ob ser va tion and ex per i ment with the ef fi - cacy of drugs: a warn ing ex am ple from a co hort of nonsteroidal anti-inflammatory and ul cer-healing drug us ers. Am J Epidemiol 2001;154:557-62.