... Methods. Roberto Gnavi 1, Alessandro Migliardi 1, Moreno Demaria 2, Alessio Petrelli 1, Adele Caprioglio 1, Giuseppe Costa 1,3.

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1 European Journal of Public Health, Vol. 17, No. 5, ß The Author Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved. doi: /eurpub/ckm005 Advance Access published on February 15, Statins prescribing for the secondary prevention of ischaemic heart disease in Torino, Italy. A case of ageism and social inequalities Roberto Gnavi 1, Alessandro Migliardi 1, Moreno Demaria 2, Alessio Petrelli 1, Adele Caprioglio 1, Giuseppe Costa 1,3 Background: Socio-demographic and clinical characteristics can influence statins prescribing for the secondary prevention of ischaemic heart disease (IHD). We studied the determinants of the prescription of statins in people with IHD in a population in Italy, the country with the lowest prescribing rate in Europe. Methods: All 2001/2002 residents in Torino, aged years, with a hospital discharge diagnosis of IHD were linked to the regional Database of Drug Prescriptions to identify those persons who, within 3 months after discharge, had been prescribed statins. Log-binomial models were used to test statins prescription associations with clinical and socio-demographic characteristics. Results: Statins were prescribed to 31.0% of 7446 patients. Among persons >74 years of age, the prescription rate was 40% lower than that found for younger persons. A positive association was also found for: female gender, being married, a main discharge diagnosis of acute myocardial infarction, revascularization, diabetes and discharge from a cardiology ward. Age was an important effect modifier of the relationship between the prescribing rate and social, but not clinical, determinants. Conclusions: The prevention of IHD with statins is influenced by age, clinical and social factors. The prescribing rate is higher among population groups for whom statins are of proven efficacy. Among patients for whom the efficacy is uncertain, the decision to prescribe is influenced by non-clinical factors, suggesting that there exist both age-based and social-based mechanisims of rationing. Age and social determinants act in concert to further reduce the propensity of physicians to prescribe statins. Keywords: coronary heart disease, drug, Italy, prescriptions, socioeconomic factors, statins... Statins constitute one of the most commonly prescribed drug classes worldwide, and their use continues to increase. 1 The success of these drugs is largely due to their efficacy in reducing blood cholesterol concentration, the low-density lipoprotein fraction, the progression of atheromasic plaque, and, above all, total mortality, cardiac mortality and recourse to revascularization in persons with ischaemic heart disease (IHD). 2 4 Moreover, the spectrum of statins continues to widen, well beyond the initial indications for treating hypercholerestolaemia. 5 7 It is thus reasonable to expect that the indications for the use of statins will be expanded and that the prescribing rate will increase further. In Europe, the prescribing rate for statins greatly varies among individual countries, yet these differences cannot be completely ascribed to differences in morbidity. 1 Italy, the country with the highest public coverage of medicines in Europe, has the lowest prescribing rate, yet this low rate does not seem to correspond to the prevalence of IHD, and in countries such as France, whose IHD prevalence is similar to that of Italy, the prescribing rate is three times higher. It is uncertain if France is overusing or Italy underusing statins and how appropriate is their use in the two countries, but these reports suggest that there exist other factors beyond the frequency of IHD that influence the prescribing rate. Numerous studies have shown that the use of statins in the secondary prevention of IHD is lower than the 1 Epidemiology Unit, ASL 5 Regione Piemonte, Italy 2 Environmental Epidemiolgy Unit, Regional Enviromental Protection Agency of Piedmont, Italy 3 Department of Public Health, University of Turin, Italy Correspondence: Dr Roberto Gnavi, Epidemiology Unit, ASL 5, Via Sabaudia 164, Grugliasco (TO), Italy, tel: þ , fax: þ , roberto.gnavi@epi.piemonte.it recommended levels and that social and demographic characteristics, particularly age, influence the prescribing rate The objective of the present study was to investigate which of a wide range of social and clinical factors influences the start of statins treatment in persons with IHD in the city of Torino, a population with one of the lowest prescribing rates in Europe. Methods Study population The study was conducted in Torino (capital city of the Piemonte Region, northwest Italy, population of ). From the Piemonte Database of Hospitalizations, we extracted records for Torino residents aged 30 to 85 years, who were discharged alive in the period from 1 January 2001 to 31 December 2002 with a diagnosis of IHD (ICD-9-CM codes ) as one of the discharge diagnosis. If the same individual had been hospitalized more than once for IHD, we considered the hospitalization closest to the beginning of the observation period (i.e. closest to 1 January 2001). From the Piemonte Database of Drug Prescriptions, we extracted statin prescriptions (code ATC C10AA) for for persons residing in Torino in the same period. This database contains data on all drug prescriptions made by general practitioners (GP) and public specialists; in Italy, only drugs obtained with a prescription from a GP (or from specialists of the Public Health Service), and not from private physicians, are free of charge. The data from the two registries were linked using an anonymous individual identification key, which allowed us to identify those persons who, after discharge, had been prescribed statins at least once. As use of statin prior to hospital admission is a strong predictor of prescription after hospital discharge, we excluded all patients with a statin

2 Statins for ischaemic heart disease 493 prescription 1-year prior to admission. Patients were defined as statins users if at least one statin was picked from a pharmacy within 3 months after discharge. Patients who died or emigrated from Torino within 3 months from hospital discharge were excluded. The database created by linking the IHD hospitalizations and the statins prescriptions was further linked to the Torino Population Register (TPR), which collects data on all residents of Torino. The TPR data are linked every 10 years to the database of the national census to assign individual socioeconomic variables. was assigned using the data from the 1991 census, or, for people who moved to Torino after this census, using the self-reported information collected by the TPR. 14 These linkage procedures led us to define two groups of persons with IHD: one with at least one prescription of statins (first users) and one without any prescription. For each individual, the following information was available: variables predictive of disease severity, taken from the hospital discharge record (type of diagnosis, associated diseases and performance of revascularization during the observed hospitalization); socio-demographic variables, taken from the TPR (gender, age, educational level and marital status) and a variable that may predict the speciality of the physician most responsible for the care of the patient during the hospital stay, taken from the hospital discharge record (the ward of discharge). Statistical analysis The relation between the prescribing of statins and clinical and socio-demographic variables was investigated by a logbinomial regression model and presented as Prevalence Rate Ratio (PRR), which is a better estimate of the relative risk when the prevalence of the outcome is high. 15 Of the sociodemographic variables taken from the TPR, we used: gender; age class (30 64, 65 74, and years); educational level (elementary school or lower, middle school, high school or college) and marital status (married, unmarried, widowed and divorced/separated). From the Hospital Discharge Database, we used: ward of discharge, aggregated into two classes (either cardiology þ intensive coronary care unit þ heart surgery or other); the performance of revascularization (either PTCA or CABG); the presence of diabetes; and the discharge diagnosis, classified into three classes: main diagnosis of acute myocardial infarction or other acute forms of IHD (AMI) (ICD-9-CM: 410, 411), main diagnosis of chronic IHD ( ), and main diagnosis other than IHD. The models were fitted using PROC GENMODE by SAS System, version 8, and 95% confidence intervals (95% CI) were estimated. Results In the period , of the 7446 Torino residents aged years, who were alive 3 months after discharge from a hospital with a diagnosis of IHD, and with no statins prescription in the 12 months before hospital admission, 2305 (31.0%) had been prescribed statins at least once within 3 months from hospital discharge. The percentage of persons who had received a prescription was highest for the following categories: the youngest age class, men, persons with high educational level, married and divorced persons, persons with a main diagnosis of AMI, persons who had undergone revascularization and persons discharged from a cardiology ward (including intensive coronary care unit and heart surgery). After having adjusted for age, the differences by gender disappeared and the other social differences (education and marital status) decreased, whereas clinical differences were not affected (table 1). Table 2 shows the results of the multivariate model, which includes, in addition to age, all of the other variables listed in table 1. Table 1 Prescribing rate of statins among persons with ischaemic heart disease and prevalence rate ratios (PRR), by social and clinical characteristics; Turin, Italy; Variable Persons with IHD Persons with statin prescription % PRR 95% CI PRR a 95% CI Total Age class (in years) ( ) ( ) Men Women ( ) 0.96 ( ) Elementary or lower Middle school ( ) 1.14 ( ) High school/college ( ) 1.04 ( ) Married Unmarried ( ) 0.64 ( ) Widowed ( ) 0.84 ( ) Separated/divorced ( ) 0.88 ( ) AMI (main diagnosis at discharge) IHD (chronic main diagnosis) ( ) 0.75 ( ) IHD (not main diagnosis) ( ) 0.37 ( ) No Yes ( ) 2.03 ( ) No Yes ( ) 1.02 ( ) Cardiology Other ( ) 0.38 ( ) a: Adjusted for age.

3 494 European Journal of Public Health Among persons greater than 74 years of age, the prescription rate was 40% lower than that found for younger persons, and was slightly lower among men, unmarried and widowed persons; it was slightly higher among persons with intermediate educational level. Regarding the clinical variables, Table 2 Prevalence rate ratios (PRR) for the prescribing of statins among persons with ischaemic heart disease, by social and clinical characteristics; Turin, Italy; Variables PRR 95% CI Age class (in years) ( ) ( ) Men 1 Women 1.09 ( ) Elementary or lower 1 Middle school 1.11 ( ) High school/college 0.99 ( ) Married 1 Unmarried 0.71 ( ) Widowed 0.87 ( ) Separated/divorced 0.89 ( ) AMI (main diagnosis at discharge) 1 IHD (chronic main diagnosis) 0.86 ( ) IHD (not main diagnosis) 0.62 ( ) No 1 Yes 1.39 ( ) No 1 Yes 1.09 ( ) Cardiology 1 other 0.60 ( ) All of the variables have been reciprocally adjusted. the prevalence was highest among persons who had undergone revascularization, persons with diabetes and persons with a main diagnosis at discharge of AMI. Prevalence was highest among persons discharged from a cardiology ward. We thus tested the interaction among age, prescribing rate, and all of the other variables; these were statistically significant for educational level (P < ) and marital status (P ¼ ) and nearly significant for gender (P ¼ ), but for none of the clinical variables. Consequently, the analysis was repeated separately for the three age classes (table 3). In the youngest age class (30 64 years), there were no significant social differences, except for a lower prescribing rate among unmarried and separated/divorced persons, whereas prescribing rate was associated to clinical determinants, as a main diagnosis at discharge of AMI or revascularization, and was highest in persons discharged from cardiology wards. In the intermediate age class (65 74 years), these differences were confirmed, and there was also greater prescribing rate among persons with diabetes and for women (although not statistically significant). Finally, in the oldest age class (75 85 years), there was an association with both clinical determinants and social determinants. Of the clinical determinants, the prescribing rate was highest among persons who had undergone revascularization and lower among persons with a main discharge diagnosis other than IHD. Of the social determinants, the prescribing rate was significantly lower among men, unmarried and widowed persons, and it was higher among persons with the highest educational levels. Among persons discharged from a cardiology ward, the prescription rate was almost double that found for other wards. Discussion The results of this study show that in a large city in Italy, the country with the lowest statins prescribing rate in Europe, fewer than one third of persons discharged from the hospital Table 3 Prevalence rate ratios (PRR) for the prescribing of statins among persons with ischaemic heart disease, by age class; Turin, Italy; Age class (in years) Variable PRR 95% CI PRR 95% CI PRR 95% CI Men Women 0.95 ( ) 1.11 ( ) 1.54 ( ) Elementary or lower Middle school 1.05 ( ) 1.11 ( ) 1.29 ( ) High school/college 0.92 ( ) 1.00 ( ) 1.38 ( ) Married 1 ( ) 1 1 Unmarried 0.68 ( ) 0.80 ( ) 0.52 ( ) Widowed 0.82 ( ) 1.00 ( ) 0.65 ( ) Separated/divorced ( ) 0.75 ( ) AMI (main diagnosis at discharge) IHD (chronic main diagnosis) 0.85 ( ) 0.88 ( ) 0.92 ( ) IHD (not main diagnosis) 0.63 ( ) 0.66 ( ) 0.57 ( ) No Yes 1.36 ( ) 1.38 ( ) 1.49 ( ) No Yes 1.00 ( ) 1.21 ( ) 1.04 ( ) Cardiology Other 0.60 ( ) 0.62 ( ) 0.56 ( ) All of the variables have been reciprocally adjusted.

4 Statins for ischaemic heart disease 495 with a diagnosis of IHD, and without statin prescription within one year before admission, were prescribed statins. As expected, the prescribing rate was correlated with clinical determinants, but also social characteristics of the patients played a role, and this role differed by age. Given that the study was conducted by linking records from different databases, the quality of these databases must be taken into account. The diagnosis of IHD reported on the hospital discharge form is generally considered to be reliable and is commonly used in epidemiological studies. 16 The ATC code for statins reported on GP prescriptions is also considered reliable and used in epidemiological studies. 1 Moreover, the Database on Drug Prescriptions is used to determine reimbursements for drugs, prescription profiles and the medical expenses of GPs for the Piemonte Region: it can thus be reasonably assumed that the existing procedures for controlling this information ensure its accuracy. Another consideration is that this database only contains data on prescriptions made by GPs and not on drugs acquired by patients who obtain a prescription from a private physician, which are not provided free of charge. However, given the high cost of statins, this is probably a rare occurrence and would be more common among the most advantaged social classes; in our study, it would result in an underestimate of the prescribing rate mainly among persons with the highest educational level. An additional limitation in the use of this database is that it is not possible to identify prescriptions that are not picked up at the pharmacy, which is probably more common among persons who have less of a social network on which to rely (e.g. unmarried or widowed persons). In interpreting the results of this study, the quality of the linkage itself must also be considered. The data from the databases were linked using deterministic record linkage, adopting the procedures used in the Torino Longitudinal Study. 14 If the linkage key were of poor quality, errors in linkage could have occurred, such as attributing the prescription to an individual who did not receive it or not attributing the prescription to an individual who did. In either case, the mislinkage would have been caused by errors in recording the variables that constitute the key, and these errors would not be correlated with either the determinants or outcome considered in this study. The prescribing rate of statins for secondary prevention in Torino is lower than the rates reported in other areas of Europe in the same period, but some of these studies included fibrates besides statins, or used slightly different case definitions. 8,17 20 Moreover, in these studies, there was an almost linear inverse association with age 9,10,12,21 whereas in our study age differences were observed only for persons >74 years of age. This is consistent with the results of the large clinical trials, 2,3 which, at the time of our study, did not recommend statins prescription to persons 75 years of age or older. We also found modest gender inequalities, with men being disadvantaged, whereas differences between low and high educational levels were practically nonexistent. The role of gender as a determinant of the prescribing rate is different in different populations, 10,12,22 whereas most studies have shown social differences that disadvantage the less privileged groups. 9,12,13 The higher prescribing rate among married individuals, which has been reported in another study (although the difference was not significant), 12 can be explained by a greater general tendency for this population group to adopt healthy behavioural practices. 23 With regard to the variables directly correlated with disease severity, our results are similar to those reported in other European countries. In particular, the prescribing rate has been reported to be higher among persons with more severe disease, such as those who have undergone revascularization and persons with diabetes. 8,17 Higher prescribing rates have also been reported for patients with a main discharge diagnosis of IHD, compared with those for whom IHD is not the main diagnosis; 12 a secondary diagnosis of IHD is probably indicative of less severe disease (at least as perceived by the treating physician) or of a diagnosis made much earlier, which is negatively correlated both with prescribing 9,12 and with adherence to statins. 24 Another finding of this study is the association between the prescribing rate of statins and the discharge ward, in particular, a strong positive association between the prescribing of statins and having been discharged from the cardiology ward, independently of disease severity, gender, age and educational level. One of the most plausible explanations is that medical specialists tend to treat their patients more aggressively than non-specialists, 25 yet, it is also possible that cardiologists follow the literature on cardiology more attentively, attend scientific speciality meeting where late-breaking results of clinical trial are first presented, and are often the first to be targeted for marketing of new drugs by pharmaceutical companies. 26 Another possible explanation is that, for IHD patients, GPs are more reluctant to make changes in the therapy prescribed by the hospital cardiologist, as opposed to that prescribed by other types of specialists. Another original finding is that the association between the start of statins treatment and the social characteristics of the patients, but not the clinical characteristics, differed by age class. We observed a significant interaction effect between age and social characteristics of patients in the prescription of statins. Age and social determinants acted in concert to further reduce the propensity of physicians to prescribe statins in secondary prevention. The lower use of statins in older age classes could reflect physicians doubts as to the efficacy of statins in persons beyond a certain age and a tendency to be more prudent in treating elderly patients. 27 This phenomenon may be accompanied by a social mechanism; in particular, among the elderly, more disadvantaged persons (low educational level, unmarried or widowed persons) may be even less likely to receive statins. Physicians may be less inclined to prescribe therapies to patients thought unlikely to adhere to treatment. 28 It is not clear why men also fall into this category, yet as stated previously, the role of gender as a determinant is controversial, and men (at least in Italy) may be less likely than women to take care of themselves. In conclusion, although the results of this study cannot be generalized to Italy s entire population they do suggest that the low prescribing rates are associated with factors beyond the low prevalence of IHD. Many patients are not prescribed adequate therapy by either the treating hospital physician or their own GP. Moreover, it is possible that, in light of decreases in the resources available to the National Health System, physicians tend to prescribe statins only to those population groups for whom statins are of proven efficacy. Among patients for whom the efficacy is uncertain, implicit mechanisms of rationing come into play, leading to the exclusion of elderly persons and, among the elderly, those who are socially disadvantaged. To understand to what extent these results can explain the low prescriptions rate of statins in Italy, more studies in different areas of the country are required. From this point of view, this study, limited to the residents of the city of Torino can only be considered as a partial contribution to an intriguing issue of European Public Health. However, it is clear that, in Torino, to improve the prevention of recurrent AMI and death, the transfer of evidence from clinical trials to prescribers must be improved, and areas of uncertainty should be reduced.

5 496 European Journal of Public Health Acknowledgements This study was supported by the 2001 Research Program of the Regione Piemonte Finanaziamento di progetti per iniziative di farmacovigilanza, di informazione degli educatori sanitari, nonchè per le campagne di educazione sanitaria nella stessa materia. Key points Italy is the country with the lowest prescription rate of statins in Europe, but factors influencing prescription rate are poorly known. In , use of statins for secondary prevention of ischaemic heart disease in Torino, Italy, is low and is influenced by age, clinical and social factors. Age and social determinants act in concert to reduce the propensity of physicians to prescribe statins: among the elderly, more disadvantaged persons are less likely to receive statins. There is a need to improve the transfer of evidence from clinical trials to prescribers and to reduce uncertainty. References 1 Walley T, Folino-Gallo P, Schwabe U, et al. 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