Co-prescription of gastroprotective agents in patients taking non-selective NSAIDs or COX-2 selective inhibitors: analysis of prescriptions

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1 In ter na tional Jour nal of Clin i cal Phar ma col ogy and Ther a peu tics, Vol. 48 No. 11/2010 ( ) Original 2010 Dustri-Verlag Dr. K. Feistle ISSN Co-prescription of gastroprotective agents in patients taking non-selective NSAIDs or COX-2 selective inhibitors: analysis of prescriptions L. Pasina 1, A. Nobili 1, M. Tettamanti 1, E. Riva 1, U. Lucca 1, R. Piccinelli 2, L. Defendi 2, L. Perego 2, S. Lucifora 2 and C. Bulla 2 1 Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, and 2 Local Health Authority, Bergamo, Italy Non-selective NSAIDs or COX-2 se lec tive in hib i tors and gastroprotective agents Key words drug uti li za tion study non-steroidal antiinflammatory drugs gastroprotective agents Re ceived March 5, 2010; ac cepted June 13, 2010 Cor re spon dence to L. Pasina, PharmD Lab o ra tory for Qual ity As sess ment of Ge ri at ric Ther a pies and Ser vices, Drug Information Service for the El derly, Istituto di Ricerche Farma co - logiche Mario Negri, Via Giuseppe La Masa, 19, Milano, It aly pasina@marionegri.it Ab stract. Objective: To eval u ate the prev a lence of co-pre scrip tion of GPAs (pro - ton pump in hib i tors PPIs and H2-re cep tor an tag o nists) and non-se lec tive NSAIDs or COXIBs in pa tients reg is tered un der the lo cal health au thor ity (LHA) of Bergamo, a city in the north of It aly. Meth ods: A drug uti li za tion anal y sis was done us ing the Bergamo pre - scrip tion Health Ser vices Elec tronic Da ta - base. All pa tients aged 35 years or older who had re ceived at least one pre scrip tion dur ing 2004 for non-se lec tive NSAIDs and/or COXIBs were di vided into three groups: oc - ca sional, chronic and new us ers. Results: Among chronic us ers, 44.8% were treated with non-selective NSAIDs, 11.6% with COXIBs, and 43.6% with both (mixed NSAIDs). For new users, non-selective NSAIDs were pre - scribed to 82.7%, COXIBs and mixed NSAIDs to 10.8% and 6.5%. PPIs were co-pre scribed to 7.1% of COXIB us ers and 5.8% of non-se lec tive NSAID occasional us - ers. Among chronic us ers, the fig ures were 15.6% and 14%. For new us ers, pre scrip tions for COXIBs were as so ci ated with less use of GPA for pa tients who re ceived the first and last prescription for NSAIDs and GPAs on the same day, while for pa tients who be came chronic us ers COXIBs did not re duce the prob a bil ity of co-pre scrip tion of a GPA: the number of co-prescribed medications and antithrombotics or corticosteroids were in de - pend ent pre dic tors of GPA use. Conclusions: COXIBs seem to be used in pa tients at high risk of GI tox ic ity. How ever, the fear of GI ad - verse re ac tions and the un cer tain safety pro file of COXIBs leads many phy si cians to boost the gastroprotection by pre scrib ing a PPI. Background and objectives In It aly, pro ton pump in hib i tors (PPIs) are among the most com monly pre scribed drugs in pri mary care and ac count for 8% of gross phar ma ceu ti cal ex pen di ture [1]. Stud ies have sug gested that be tween 25% and 70% of pa - tients tak ing these drugs had no ap pro pri ate in di ca tion [2, 4, 5, 14, 27, 32]. Al though ef - fective and less expensive H2-receptor antag - o nists could still be an al ter na tive for many pa tients, their use has in ex o ra bly de clined since the commercialization of PPIs and the pat ent ex piry of the most com monly pre - scribed H2-re cep tor antagonists [1, 14, 27]. PPIs are ef fec tive in the treat ment of acid pep tic dis or ders and are used for the treat ment of many gas tro in tes ti nal pa thol o gies. One com mon in di ca tion is the pre ven tion of NSAID- induced gastrointestinal (GI) toxic - ity. An Ital ian sur vey re ported that 38% of pa - tients chron i cally treated with non-steroidal anti-in flam ma tory drugs (NSAIDs) re ceived at least one prescription of PPIs [15]. Strat e gies to re duce the risk of NSAID-in - duced GI tox ic ity in clude us ing the low est ef - fec tive dose, the use of non-se lec tive NSAIDs with co-ad min is tra tion of a gastro pro tective agent (GPA) or a cyclooxygenase (COX-2) selective inhibitor (COX-2 inhibitor). Gastro - protective ther apy con sists of gas tric acid sup - pres sive agents (PPIs or H2-re cep tor an tag o - nists) or pros ta glan din ana logues such as misoprostol [11, 26]. COX-2 in hib i tors are a sub class of NSAIDs that spe cif i cally in hibit the pro duc - tion of inflammatory prostaglandins, with out af fect ing the pro duc tion of gastroprotective prostaglandins, syn the sized through the ac - tion of COX-1. The in tro duc tion of this new class of anti-in flam ma tory drugs was claimed

2 Pasina, Nobili, Tettamanti et al. 736 Ta ble 1. Dis tri bu tion of NSAID us ers by level of ex po sure and du ra tion of treat - ment: oc ca sional and chronic us ers of NSAIDs. as a new way to re duce the GI tox ic ity of NSAIDs and the need for co-pre scrib ing GPAs, par tic u larly in high-risk pa tients, as some cost-effectiveness analyses and pharma ceu ti cal com pa nies stated [12, 13, 21, 28]. Un for tu nately, the over all safety pro file of COX-2 in hib i tors has re cently come un der fire be cause they have been as so ci ated with severe cardiovascular complications, includ - ing myocardial infarction and stroke [9, 10, 16, 17, 19, 20, 24, 31]. In It aly, the pre scrip tion of NSAIDs and the co-pre scrip tion of GPAs paid by the Na - tional Health Ser vice must fol low the rules set by the Agenzia Italiana del Farmaco (AIFA, the Ital ian Drug Agency); at the last up date (Feb ru ary 2007) these did not al low co-pre scrip tion of GPAs and COX-2 in hib i - tors, and es tab lished spe cific cri te ria for the ap pro pri ate use of NSAIDs and GPAs, such as the use of GPAs in pa tients chron i cally treated with NSAIDs and in pres ence of pep - tic ul cer or con com i tant ther apy with oral corticosteroids or antithrombotic therapy [2, 5]. In this study we an a lyzed the prev a lence of co-prescription of GPAs (PPIs and H2-re - ceptor antagonists) and non-selective NSAIDs or COX-2 in hib i tors in pa tients reg is tered un - der the Lo cal Health Au thor ity (LHA) of Bergamo, a city in the North of It aly, dur ing the year Methods Du ra tion of treat ment (days) Level of ex po sure (DDD) < ,913 1,429 2, ,137 6,244 17, ,928 21,742 DDD = de fined daily doses; NSAIDs = non-steroidal anti-in flam ma tory drugs (non-se lec tive NSAIDs and COX-2 in hib i tors). Bold dig its iden tify oc ca sional and chronic us ers. We per formed drug uti li za tion anal y ses us ing the Health Ser vices Elec tronic Da ta base of out pa tient pre scrip tions of the Bergamo LHA, which counts about a mil lion in hab it - ants. The database includes longitudinal data on prescriptions and information on patient demo graphics. To pre serve pa tients and phy si - cian confidentiality all records were coded anonymously. We se lected all pa tients who had re ceived at least one pre scrip tion of non-se lec tive NSAIDs and/or COX-2 inhibitors dur ing Then we di vided pa tients given NSAIDs into three groups: oc ca sional, chronic and new us ers. The chronic and oc ca - sional users were established according to two in di ca tors: the level and the du ra tion of ex po sure to NSAIDs. The level of ex po sure was cal cu lated on the ba sis of the num ber of de fined daily doses (DDD) of non-se lec tive NSAIDs and/or COX-2 in hib i tors pre scribed dur ing 2004; the du ra tion of the treat ment was the in ter val be tween the first and last pre - scrip tions [29]. Oc ca sional us ers were de - fined as pa tients who re ceived less than 20 DDD of any NSAID in a pe riod of less than 30 days dur ing 2004, and chronic us ers were those who re ceived more than 60 DDD of any NSAID in more than 90 days. For our anal y - ses we did n t con sider the sub group of pa - tients with an in ter me di ate level of ex po sure, who re ceived more than 20 DDD and less than 60 DDD [15, 30] (Ta ble 1). New us ers were pa tients who had had no pre scrip tion for non-se lec tive NSAIDs or COX-2 in hib i tors dur ing the pre vi ous year (2003). We con sid - ered only pa tients aged 35 years or older, be - cause in our anal y sis they are the pop u la tion with the high est rate of NSAID pre scrip tions. Among new and chronic us ers we found a sub group, mixed NSAID us ers, who re ceived non-se lec tive NSAIDs plus COX-2 in hib i - tors. In this group non-se lec tive NSAIDs or COX-2 in hib i tors could be pre scribed at dif - fer ent times, for ex am ple when a pa tient switched from non-se lec tive NSAIDs to COX-2 in hib i tors or vice versa, or were taken at the same time. In the group of chronic us ers we con sid ered pa tients who re ceived non-se - lective NSAIDs and COX-2 in hib i tors to - gether, and se lected pa tients who re ceived at least two pre scrip tions of both non-se lec tive NSAIDs and COX-2 in hib i tors for lon ger than 30 days, es tab lished from dates of pre - scription. Then we an a lyzed the prev a lence of pre - scrip tions for GPAs (PPIs and H2-re cep tor an tag o nists) in all groups, de fin ing chronic GPA us ers with the same cri te ria as for

3 Non-se lec tive NSAIDs or COX-2 se lec tive in hib i tors and gastroprotective agents 737 Ta ble 2. Dis tri bu tion of NSAID us ers. Vari ables No (%) NSAID us ers (%) To tal pop u la tion 1,016,027 (100) Women (%) 511,323 (50.3%) Pop u la tion 35 years 601,830 (59.2) Women (%) 311,050 (51.7%) NSAID 1 us ers 137,032 (13.4) 100 NSAID 1 us ers 35 years 125,821 (12.4) 91.8 Oc ca sional us ers 2 63,913 (6.3) Oc ca sional us ers 35 years 55,619 (5.5) 40.6 Chronic us ers 3 21,742 (2.1) Chronic us ers 35 years 21,533 (2.1) 15.7 New us ers 4 35 years 50,359 (5.0) Non-steroidal anti-in flam ma tory drug (non-se lec tive NSAIDs and COX-2 in hib - i tors); 2 DDD < 20 days of treat ment and < 30 days be tween last and first pre - scrip tion; 3 DDD > 60 days of treat ment and > 90 days be tween last and first pre - scrip tion; 4 No pre scrip tion of NSAIDs and GPAs dur ing Bold dig its iden tify to tal us ers of NSAIDs and the groups of us ers (oc ca sional, chronic and new) aged 35 years or older, con sid ered in the study. The anal y sis did not con sider misoprostol be cause global pre scrip tions of this drug were significantly lower than PPIs or H2-re cep tor an tag o nists (10,000 pre scrip tions vs. 30,000 anti-h2 and 250,000 PPI). Age and sex were de rived from the LHA reg is try. Drugs pre scribed were pro vided free of charge by the Ital ian Na tional Health Sys - tem (NHS). Con sump tion of NSAIDs in LHA of Bergamo and in re gional or na tional con text should be in ter preted as the num ber of DDD of NSAIDs pre scribed per 1,000 res i dents in 1 day. The re la tion be tween pres ence of GPA and type of NSAID was first eval u ated by cal - culating a univariate odds ra tio (OR). Sub se - quently multivariate logistic regression was done to con trol for the fol low ing fac tors that could in flu ence or af fect GPA pre scrip tions: sex, age, num ber of other ac tive sub stances and use of low-dose acetylsalicylic acid (ASA) (ATC code B01AC06), antithrombotic agents (ATC code B01) or cortico - steroids (ATC code H02). Age and num ber of drugs were en tered as ei ther con tin u ous or categorical, with similar results on the OR mea sur ing the association between NSAID type and GPA. Results Dur ing 2004, NSAIDs were pre scribed to 13.4% of the pop u la tion stud ied; 40.6% of all pa tients treated with NSAIDs were oc ca - sional us ers. Small groups (15.7%) were chronic us ers, and 36.7% were new us ers (Ta - ble 2). Fig ure 1. Age dis tri bu tion of NSAID pre scrip tions. NSAIDs. In the group of new us ers we se - lected pa tients who re ceived the first and last pre scrip tions for NSAIDs and GPAs on the same day in or der to in ves ti gate the prob a bil - ity of a pre scrip tion of GPAs re lated to treat - ment with NSAIDs and pos si bly aimed at gastro-protection. We also selected patients with out any pre scrip tion for GPA dur ing the pre vi ous year, in or der to cal cu late the odds ra tio for the prob a bil ity of re ceiv ing a GPA pre scrip tion with a non-se lec tive NSAID or COX-2 in hib i tor pre scrip tion. Occasional users About 91% of oc ca sional us ers re ceived a pre scrip tion for a non-se lec tive NSAIDs and only 9% for COX-2 in hib i tors. Women were gen er ally more ex posed to NSAIDs than men (Ta ble 3). The NSAID pre scrip tions in - creased with age, and COX-2 in hib i tors were pre scribed more to the old est pa tients: COX-2 in hib i tor pre scrip tions rose in pa tients over 55, while pre scrip tions of non-se lec tive NSAIDs de creased (Figure 1). We also found that chronic pre scrip tions of GPAs were higher

4 Pasina, Nobili, Tettamanti et al. 738 Ta ble 3. Char ac ter is tics of NSAID us ers. Vari ables Oc ca sional us ers Non-se lec tive NSAIDs COXIBs No. (%) 50,291 (90.6) 5,328 (9.4) Non-se lec tive NSAIDs and COXIBs Age, mean (± SD) 59.5 (14.0) 63.1 (13.5) < Fe male (%) < Ac tive sub stances, mean (± SD) 1.6 (2.1) 1.8 (2.2) < Chronic us ers No. (%) 9,639 (44.8) 2,492 (11.6) 9,402 (43.6) Age, mean (± SD) 69.8 (11.9) 71.3 (11.0) 70.9 (10.8) < Fe male (%) < Ac tive sub stances, mean (± SD) 3.0 (2.7) 2.9 (2.4) 3.1 (2.6) < New us ers New us ers (co-pre scrip tion of NSAIDs and GPAs) No. (%) Age, mean (± SD) 58.0 (13.8) 61.6 (12.3) < Fe male (%) < Ac tive sub stances, mean (± SD) 2.6 (2.6) 3.8 (2.7) < New us ers (chronic NSAIDs) No. (%) Age, mean (± SD) 66.2 (12.9) 68.0 (12.3) 67.6 (11.6) 0.03 Fe male (%) Ac tive sub stances, mean (± SD) 4.3 (3.3) 3.8 (2.8) 4.4 (4.4) 0.02 p COXIBs = COX-2 in hib i tors; GPAs = gastroprotective agents (PPIs and H2-re cep tor an tag o nists); NSAIDs = non-steroidal anti-in flam ma tory drugs. for occasional users of COX-2 inhibitors than non-selective NSAIDs; 7.1% and 0.8% of oc - ca sional COX-2 in hib i tor us ers were also chronic us ers of PPI and H2-blockers, while 5.8% and 0.6% of pa tients re ceiv ing non-se - lective NSAIDs had co-pre scrip tions of GPA (Fig ure 2). Pa tients re ceiv ing COX-2 in hib i - tors were older and re ceived more pre scrip - tions and ac tive sub stances than pa tients treated with non-se lec tive NSAIDs. Chronic users Fig ure 2. Co-pre scrip tion of GPAs in oc ca sional" and chronic us ers of dif fer ent classes of NSAIDs. In this group 44.8% were treated with non-se lec tive NSAIDs, 11.6% with COX-2 in hib i tors, and 43.6% with both non-se lec tive NSAIDs and COX-2 in hib i tors (mixed NSAIDs).

5 Non-se lec tive NSAIDs or COX-2 se lec tive in hib i tors and gastroprotective agents 739 and mean number of ac tive substances were similar. New users Fig ure 3. Co-pre scrip tion of GPAs in new us ers of NSAIDs and in pa tients who be came chronic us - ers dur ing Women were more ex posed to NSAIDs in all groups. Among the mixed NSAID us ers (n = 9,402), 2,686 (29%) were tak ing COX-2 in hib i tors and non-se lec tive NSAIDs at the same time, while 20% switched from non-se - lective NSAIDs to COX-2 in hib i tors and 31% from COX-2 in hib i tors to non-se lec tive NSAIDs. 20% of the chronic us ers could not be clas si fied be cause they had mul ti ple switches. COX-2 in hib i tors and mixed NSAIDs were most fre quently used in the groups aged and years. Nei ther COX-2 in hib i tors nor non-se lec - tive NSAIDs did in flu ence the pre scrip tion of a GPA: in fact 17.4%, 17.2% and 18.7% of pa tients re ceiv ing COX-2 in hib i tors, non-se - lective NSAIDs or mixed NSAIDs also had a co-pre scrip tion of a GPA. PPIs were pre - scribed more than H2-re cep tor an tag o nists and were com bined in 15.6% of the chronic us ers of COX-2 in hib i tors, 14% of non-se lec - tive NSAIDs us ers and 16.2% of the chronic us ers of mixed NSAIDs. H2-re cep tor an tag o - nists were pre scribed to only 1.3%, 2.3% and 1.8%. A sub group of pa tients (0.5%) re ceived both GPAs. Patients receiving COX-2 inhibi - tors were older but re ceived fewer pre scrip - tions and ac tive sub stances than pa tients treated with non-se lec tive NSAIDs. Com par - ing pa tients in the mixed NSAIDs group with those tak ing non-se lec tive NSAIDs, age, sex In this group, non-se lec tive NSAIDs were the most pre scribed drugs (82.7%); COX-2 in hib i tors and mixed NSAIDs were pre - scribed re spec tively to 10.8% and 6.5%. Women were more ex posed to NSAIDs in all groups. Again, ex po sure in creased with age, es pe cially for COX-2 in hib i tors and the mixed NSAIDs (Figure 1). To in ves ti gate the prob a bil ity of a pre - scrip tion of GPAs, re lated to treat ment with NSAIDs and pos si bly aimed at gas tro-pro tec - tion, we con sid ered only pa tients who had the first and last pre scrip tion for NSAIDs and GPAs on the same day. In this group the mean du ra tion of treat ment, ac cord ing to the DDD, was 15 days for NSAIDs and 14 for GPAs, cor re spond ing to 1 pre scrip tion of each drug. This sug gests that the use of GPAs was closely linked to NSAID pre scrip tion. Pa - tients receiving non-selective NSAIDs had a higher prob a bil ity of co-pre scrip tion of GPA than those re ceiv ing COX-2 in hib i tors (Figure 3). Women/men ra tio of the pop u la tion study was 1.07 and women were more ex posed to NSAIDs in both groups. Us ers of COX-2 in - hib i tors were slightly older and re ceived about the same num ber of ac tive sub stances as pa tients given non-se lec tive NSAIDs (Ta ble 3). Af ter ad just ment for age, sex, pre scrip tion of low-dose as pi rin, antithrombotic agents or corticosteroids and num ber of drugs, the pre - scription of COX-2 inhibitors was associated with a lower prob a bil ity of co- prescription of a GPA (OR = 0.66) (Ta ble 4). Pre scrip tions for corticosteroids were closely re lated to GPA use (OR = 2.05). Con sid er ing the new us ers of NSAIDs who be came chronic us ers dur ing 2004 and who had the first pre scrip tion of a GPA on the same day or at most within the next 30 days, co-pre scrip tion of GPAs was higher in the group of mixed NSAIDs than in the other two (22.2% vs. 18.8% of non-se lec tive NSAIDs and 12.2% of COX-2 in hib i tors) (Fig ure 3). Women were more ex posed to NSAIDs in all groups and pa tients treated with COX-2 in - hib i tors were slightly older and re ceived

6 Pasina, Nobili, Tettamanti et al. 740 Ta ble 4. Pre dic tors of GPA co-pre scrip tion with NSAIDs in new us ers. New us ers (co-pre scrip tion of NSAIDs and GPAs; n = 42,122) Ad justed OR** (95% CI) p Age 1.00 ( ) 0.70 Fe males 0.91 ( ) 0.16 Num ber of drugs* (ex cept NSAID and GPA) 0.99 ( ) 0.46 COX-2 in hib i tors vs. non-se lec tive NSAIDs 0.66 ( ) ASA, low-dose 1.18 ( ) 0.17 Antithrombotic drugs (ATC code: B01) 1.35 ( ) 0.01 Corticosteroids (ATC code: H02) 2.05 ( ) < New us ers (chronic NSAIDs; n = 2,189) Ad justed OR** (95% CI) p Age 1.00 ( ) 0.66 Fe males 0.88 ( ) 0.28 Num ber of drugs* (ex cept NSAID and GPA) 1.09 ( ) < COX-2 in hib i tors vs. non-se lec tive NSAIDs 0.71 ( ) 0.09 Non-se lec tive NSAIDs and COX-2 in hib i tors 1.14 ( ) 0.29 ASA, low-dose 1.38 ( ) 0.04 Antithrombotic drugs (ATC code: B01) 1.88 ( ) < Corticosteroids (ATC code: H02) 4.48 ( ) < NSAIDs = non-steroidal anti-in flam ma tory drugs; COXIBs = COX-2 in hib i tors; GPAs = gastroprotective agents (PPIs and H2-re cep tor an tag o nists); OR = odds ra tio; ATC = an a tom i cal ther a peu tic chem i cal clas - si fi ca tion sys tem ( *ac tive sub stances; **ad justed for sex, age, num ber of other ac tive sub stances, and the pre scrip tion of low-dose acetylsalicylic acid (ASA) (ATC code B01AC06), antithrombotic agents (ATC code B01) or corticosteroids (ATC code H02). fewer ac tive sub stances than pa tients given non-se lec tive NSAIDs or mixed NSAIDs (Ta ble 3). The ad justed odds ra tio (Ta ble 4) showed that antithrombotic agents, num ber of drugs and es pe cially corticosteroids were strong pre dic tors of the prob a bil ity of be ing given a GPA, while no dif fer ence was found be tween COX-2 inhibitors and non-selective NSAIDs. Discussion Even with the in trin sic lim i ta tion of an a - lyz ing only pre scrip tions, with out any spe - cific in for ma tion on di ag no ses and ther a peu - tic in di ca tions, and fo cus ing anal y sis in a lo cal con text, we found that, in the year be - fore with drawal of rofecoxib, COX-2 in hib i - tors had a higher rate of co-pre scrip tion with GPAs (especially PPIs) in oc ca sional and chronic us ers, while new us ers treated with non-se lec tive NSAIDs were more likely also to re ceive a GPA. The re sults in the chronic us ers seem to con trast with the claimed better GI tolerability of COX-2 in hib i tors, that should re duce the need for co-pre scrip tion of GPAs. Al though COX-2 in hib i tors were pre - scribed less fre quently than non-se lec tive NSAIDs, pa tients ex posed prob a bly had a higher risk of GI tox ic ity than those treated with non-selective NSAIDs, so the fear of GI adverse events could have induced phy si - cians to give a GPA too. Among new us ers, the pre scrip tion of COX-2 inhibitors was associated with less use of GPA for pa tients who had the first and last prescription of NSAIDs and GPAs on the same day, while in pa tients who be came chronic us ers this was not the case. In this sub group the num ber of co-pre scribed med i - ca tions and the pre scrip tion of antithrombotic drugs or corticosteroids were in de pend ent predictors of GPA use.

7 Non-se lec tive NSAIDs or COX-2 se lec tive in hib i tors and gastroprotective agents 741 Why do phy si cians need to co-pre scribe GPAs when they use NSAIDs with better GI tolerability and, in new us ers, why should they be gin us ing COX-2 in hib i tors to gether with a GPA? Prob a bly, the avail abil ity of COX-2 in - hib i tors could have ex tended the use of NSAIDs to pa tients who oth er wise could not be treated with non-se lec tive NSAIDs [3, 8, 22, 24]. Fur ther more, phy si cians are well aware that the better GI tolerability of COX-2 in hib i tors has not been fully proved, and pre - fer to pro tect pa tients with a GPA, con sid er - ing this safer, al though at the time of our anal - ysis in Italy this association amounted to in ap pro pri ate use [2, 9, 11, 21]. No spe cific ran dom ized con trolled trial has eval u ated which of these strat e gies is safer, or whether it is better to use COX-2 in hib i tors alone, or to com bine non-se lec tive NSAIDs and GPAs. Cur rent guide lines sug gest us ing non-se - lective NSAIDs plus a PPI only in pa tients at risk of NSAID-in duced tox ic ity, and ad dress the choice of NSAIDs ac cord ing to their ef fi - cacy, GI tolerability and car dio vas cu lar risk pro file [3, 7, 11]. The co-pre scrip tion of COX-2 in hib i tors plus GPAs is not sup ported by firm sci en tific ev i dence and is ex pen sive, even though some pharmacoeconomic anal y - ses have re ported economic advantages [8, 15]. An other crit i cal as pect was the num ber of pa tients tak ing COX-2 in hib i tors and non-se - lective NSAIDs at the same time, a prac tice not sup ported by any ev i dence-based guide - line, and that ex poses pa tients to a higher risk of se ri ous ad verse drug re ac tions. Nearly 30% of the mixed NSAIDs chronic us ers were ex posed to this as so ci a tion, and there was a high rate of co-prescription of GPAs. Al though ob tained in a lo cal con text, these re sults should be taken into par tic u lar ac count be cause they re fer to a LHA that rep - re sents an area of good pre scrib ing prac tice both at re gional and na tional level [1]. The con sump tion of NSAIDs, calculated as DDD/1000 res i dents/day, was sig nif i cantly lower in Bergamo city (17.9 DDD/1000 in - hab it ants/day) than in the re gional (21.5) and na tional con text (30.8), where it was nearly dou ble. Sim i larly, the con sump tion of GPAs was lower (about 21.2 DDD/1000 res i - dents/day for PPI and 2.0 for H2-blockers in Bergamo city), in com par i son to re gional and na tional fig ures of 23.0 and 24.6 for PPI and 2.1 and 2.7 for H2-blockers. Thus, the pic ture might in fact be more trou bling in other con - texts where the rate of COX-2 in hib i tor pre - scrib ing is higher and less attention is paid to appropriate drug prescribing. Conclusion Al though new, more se lec tive and claimed safer NSAIDs are now avail able, the prac tice of co-pre scrib ing non-se lec tive NSAIDs or COXIB plus GPAs is rais ing [15]. The not dem on strated ab sence of sup posed gastrointestinal toxicity of COX-2 inhibitors [18] has prob a bly con trib uted to this. Be hav - ior more closely fol low ing ev i dence-based guide lines and na tional rec om men da tion on ap pro pri ate drug pre scrib ing is es sen tial for a ra tio nal, cost-ef fec tive ap proach [6, 18, 23, 25, 33]. COX-2 in hib i tors are much more ex - pen sive than non-se lec tive NSAIDs and their pre scrip tion is jus ti fied only in se lected pa - tients, and their com bi na tion with GPAs should be re stricted to pa tients at particularly high risk of NSAID-induced GI toxicity [11, 28, 33]. Ac cord ing to our find ings we sup pose that in clinical practice COX-2 inhibitors are used in pa tients at high risk of GI tox ic ity. How ever, the fear of GI ad verse re ac tions and the con tro ver sial safety pro file of these drugs lead phy si cians to add gastroprotection, and to pre scribe a GPA that is rec om mended only for pa tients with a prior com pli cated up per GI event or mul ti ple GI risk fac tors [7]. In fact the find ings in new us ers sug gest that the main in de pend ent pre dic tors of con com i tant use of GPA were the num ber of co-pre scribed med i ca tions and the use of antithrombotic drugs or corticosteroids. In these pa tients, the de ci sion to pre scribe a COX-2 in hib i tor did not re duce the prob a bil ity of co-pre scrib ing a GPA and adds un nec es sary cost for the NHS, because of the higher cost of COX-2 in - hibitors. According to scientific evidence, the as - so ci a tion of non-se lec tive NSAIDs plus GPAs should be pre ferred, in the ab sence of spe cific con tra in di ca tions or in pa tients at par tic u larly high risk of NSAID-in duced se ri - ous GI ad verse ef fects. The dif fi culty in choos ing non-se lec tive NSAID plus GPAs or

8 Pasina, Nobili, Tettamanti et al. 742 COXIB monotherapy is that, for equiv a lent pain con trol, it is still hard to quan tify the bal - ance be tween car dio vas cu lar risk and GI ben - efit. COXIBs, in fact, seem to cause un known in crease in the risk of car dio vas cu lar events, be sides their higher cost, with out a full dem - on stra tion of the ab sence of GI tox ic ity [18]. Dur ing 2005, af ter the with drawal of rofeco - xib, global pre scrip tions of COX-2 in hib i tors felt steeply from about 66,000 to nearly 22,000, show ing that concern about the car - dio vascular risk had risen among physicians. From July 2008 the Ital ian NHS has al - lowed the co-pre scrip tion of COX-2 in hib i - tors and PPIs on the ba sis of a sin gle, small clin i cal trial [8].This could fur ther in crease the use of COX-2 in hib i tors plus PPIs es pe - cially in el derly pa tients who, al though at higher risk of GI tox ic ity, are also at higher risk of car dio vas cu lar events. Un for tu nately, GPAs have no ef fect on the pre ven tion of se ri - ous cardiovascular adverse events. Financial disclosure This study was sup ported by grants from the Direzione Generale Sanità of Lom bardy Re gion. Acknowledgment The au thors thank Mrs Ju dith Baggott (Mario Negri In sti tute, Mi lan) for the English re vi sion of the manu script and for ed i to rial assistance. Sponsor role The spon sors of the study had no role in the con cep tion and de sign of the study; col - lection, management, analysis and interpretation of data as well as in the prep a ra tion and writ ing of the re port or in the de ci sion to sub - mit the manu script for publication. Author contribution Study con cept and de sign: Nobili, Pasina, Tettamanti, Riva, Lucca, Piccinelli, Defendi, Perego, Lucifora, Bulla. Ac qui si tion of data: Perego, Piccinelli, Defendi, Tettamanti. Anal y sis and in ter pre ta tion of data: Nobili, Pasina, Tettamanti, Riva, Lucca, Piccinelli, Defendi. Draft ing the manu script: Nobili, Pasina, Tettamanti. Crit i cal re view of the manu script: Nobili, Pasina, Tettamanti, Riva, Lucca, Piccinelli, Defendi, Perego, Lucifora, Bulla. References [1] AIFA. L uso dei farmaci in Italia. Rapporto nazio nale anno /sites/de - fault/files/rapporto_osmed_primi_9_mesi_2009. pdf. [2] AIFA. Le Note AIFA per l uso appropriato dei farmaci wscs_ ren der_at tach ment_by_id/ e.pdf?id = [3] Antman EM, Bennet JS, Daugherty A. Use of non - steroidal antiinflammatory drugs. Cir cu la tion. 2007; 115: 19. [4] Batuwitage BT, Kingham JGC, Mor gan NE, Bart - lett RL. In ap pro pri ate pre scrib ing of pro ton pump in hib i tors in pri mary care. Postgrad Med J. 2007; 83: [5] BIF. Le note in ag gior na men to: Bollettino d Informazione sui Farmaci 2008; XV n.1: note1_66.pdf. [6] Can tor SB. Pharmacoeconomics of coxib ther apy. J Pain Symp tom Man age. 2002; 24: [7] Chan FKL, Abra ham NS, Scheiman JM. Man age - ment of pa tients on nonsteroidal anti-in flam ma - tory drugs: a clin i cal prac tice rec om men da tion from the First In ter na tional Work ing Party on Gas - tro in tes ti nal and Car dio vas cu lar Ef fects of Nonsteroidal Anti-in flam ma tory Drugs and Antiplatelet Agents. Am J Gastroenterol. 2008; 103: [8] Chan FKL, Wong VWS, Suen BY, Wu JCY, Ching JYL, Tsui Hung LC et al. Com bi na tion of a cyclooxygenase-2 in hib i tor and a pro ton-pump in - hib i tor for pre ven tion of re cur rent ul cer bleed ing in pa tients at very high risk: a dou ble blind, ran - dom ized trial. Lan cet. 2007; 369: [9] Dieppe P, Bart lett C, Davey P, Doyal L, Ebrahim S. Bal anc ing ben e fits and harms: the ex am ple of non-steroidal anti-in flam ma tory drugs. BMJ. 2004; 329: [10] Drazen MJ. COX-2 inhibitors: a les son in un ex - pected prob lems. N Engl J Med. 2005; 352: 11. [11] Dubois RW, Melmed GY, Henning JM, Laine L. Guide lines for the ap pro pri ate use of non-steroidal anti-in flam ma tory drugs, cyclo-oxygenase-2-spe - cific in hib i tors and pro ton pump in hib i tors in pa - tients re quir ing chronic anti-in flam ma tory ther - apy. Al i ment Pharmacol Ther. 2004; 19: [12] Fendrick AM. Cost-ef fec tive use of NSAIDs: is - sues per ti nent to coxib use in man aged care. Am J Manag Care. 2002; 8:

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