Lack of adherence to lipid-lowering drug treatment. A comparison of utilization patterns in de ned populations in Funen, Denmark and Bologna, Italy

Lack of adherence to lipid-lowering drug treatment. A comparison of utilization patterns in de ned populations in Funen, Denmark and Bologna, Italy John Larsen, 1,2 Alberto Vaccheri, 3 Morten Andersen, 1 Nicola Montanaro 3 & Ulf Bergman 1,4 1 Department of Clinical Pharmacology and 2 Research Unit of General Practice, University of Southern Denmark, Odense University, Odense, Denmark, 3 Interuniversity Research Centre for Pharmacoepidemiology, Department of Pharmacology, University of Bologna, Bologna, Italy and 4 Department of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden. Aims The objective was to explore differences in lipid-lowering drug (LLD) prescribing in Italy and Denmark. Methods We used two geographical areas with computerized drug prescription records in de ned populations, one in Funen, Denmark with 5 inhabitants, the other in Bologna, Italy with 4 inhabitants. Prescriptions for patients who had purchased a LLD from 1994 until 1996 were retrieved as well as coprescriptions of antidiabetic and cardiovascular drugs as markers for diabetes and cardiovascular disease. Only patients surviving and remaining in the area were included. Compliance was de ned as percentage of DDDs purchased divided by the number of days within the time window. The limit between good and poor compliance was set at 82%. Results In Bologna, LLD consumption measured in DDD increased by 41% and in Funen by 129%. Annual prevalence increased from 36.9 to 46.3 users/1 inhabitants from 1994 to 1996 and from 3.2 to 6.6 users/1 inhabitants in Bologna and Funen, respectively. From 1995 to 1996, the incidence of use decreased slightly in Bologna from 19.3 to 18.8/1 inhabitants/year, whereas in Funen the incidence increased from 1.8 to 2.3/1 inhabitants/year. In Bologna 48% and in Funen 91% of users persisted with treatment for 2 years or longer. In Bologna, 7% and in Funen 45% were good compliers. In Bologna, 61% and in Funen, 72% received other drugs indicating cardiovascular or diabetic comorbidity. Conclusions Patterns of use differed substantially between the two areas. In contrast with Funen, where long-term use was common, Bologna LLD use was sporadic. Based on a higher rate of coprescription, LLDs seemed to be used for secondary prevention to a higher extent in Funen than in Bologna. In Funen it appeared that the correct patients, but an insuf cient number of them, were being treated adequately according to guidelines. The higher discontinuation rate of lipid lowering drugs in the Bologna area indicates that a large proportion of patients use these drugs for too short a period of time to bene t from treatment. Since society's health care resources are limited it is dif cult to justify public funding of these medications without at the same time giving appropriate attention to these problems. Keywords: individualized prescription databases, international comparison, lipidlowering drug utilization, persistence Correspondence: John Larsen, Department of Clinical Pharmacology and Research Unit of General Practice, Winslùwparken 19, DK-5 Odense C, Denmark. Tel.:+45 65 5 3 28. Fax:+45 65 91 82 96. E-mail: j-larsen@cekfo.sdu.dk Received 24 June 1999, accepted 7 February 2. Introduction The rising costs of pharmaceuticals is of great concern and different methods have been used to combat this development. With a limited health budget, priority decisions have to be made by politicians. The aim of health f 2 Blackwell Science Ltd Br J Clin Pharmacol, 49, 463±471 463

J. Larsen et al. care professionals is to make sure that the resources provided are used in the most effective way. Medications are no exception in this regard. New lipid lowering drugs (LLD) ± HMG CoA reductase inhibitors, also referred to as statins ± were introduced in the late 198s and constituted a breakthrough in the management of hypercholesterolaemia. In a previous comparison of the use of LLDs in ve countries in 199±94, it was found that usage was double in Australia and Italy compared with three of the Nordic countries [1]. Additionally, it was found that a restriction in the reimbursement status in Italy in 1994 almost halved the use in that year. The pattern of use in Italy and Sweden was very different, with much higher use in Italian women than in men, with a reverse pattern in Sweden. At that time key studies such as 4S (secondary prevention of myocardial infarction) [2] and West of Scotland (primary prevention) [3] had not yet in uenced the prescribing of LLDs. Several studies outside Europe have demonstrated failure to continue long-term treatment with LLDs [4±6]. In one study a high 1 year discontinuation rate was found, and in the other, about half of the surviving cohort of patients older than 65 years had stopped using LLDs after 5 years [5, 6]. The primary purpose of the present study was to explore differences in the prescribing of LLDs demonstrated in the previous paper [1] by analysing on an individual level the prescribing patterns in two population-based prescription databases, one in Funen, Denmark representing a Nordic country (with an age and sex pattern of use similar to the Swedish as such data were not available in Sweden), the other one in Bologna, Italy. We were speci cally interested in how LLDs were prescribed in the two de ned populations with regard to prevalence and incidence, in different age and sex strata, according to different risk pro les (comorbidity with diabetes and cardiovascular diseases), and if there were any differences with regard to persistence and continuity of treatment with these medications. Methods Setting Drug prescription data were retrieved from the Odense Pharmacoepidemiologic Database (Denmark) [7] and the Emilia Romagna Health Authority Database (Italy) [8]. Both databases provide the following information for each reimbursed prescription: identi cation of the dispensed product according to the ATC-classi cation [9], number of packages and number of De ned Daily Doses (DDD) dispensed, code of the prescriber, anonymous code of the patient and date of prescription. In both databases, the patient code allows the reconstruction of each individual's drug history without identi cation of the individual. In the present study, we retrieved the 1994±96 data on lled prescriptions from the County of Funen, Denmark (467 695 inhabitants in 1995 [1]), and from the town of Bologna, Italy (386 935 inhabitants in 1995 [11]). The study population was restricted to individuals permanently living in the areas; those who had moved or died during the study period were excluded from the analyses. The study cohort comprised 42 731 persons in Funen and 334 935 persons in Bologna. In the following sections, gures from Funen and Bologna refer to these selected cohorts. Data on overall LLD utilization in previous years and in other countries were retrieved from the previous study [1], from other sources [12±14] and from our prescription databases. Ethics Information from both regions consisted exclusively of anonymised data. Therefore, the project needed no approval by the regional scienti c ethical committees. For the Danish part, the Danish Registry Board approved the project and the regional scienti c ethics committee was noti ed. Reimbursement In Italy, several restrictions in reimbursement rules have been made since the early nineties; in 1993 this lead to a decrease in LLD consumption [1]. In 1994, a reimbursement list was issued where almost all drugs (including LLDs) were without any copayment by the patient apart from a xed fee of Euro 1.55 per prescription. Owing to this, the average copayment fell from 2 to 25% to 1% of the gross drug bill of the Italian National Health Service (NHS). LLDs were, however, free-of-charge only for patients with familial hyperlipidaemias with high blood levels of cholesterol or triglycerides, and fully paid for by the others. Only by the end of 1997, full reimbursement of simvastatin and pravastatin was extended to the secondary prevention of myocardial infarction in patients with a total cholesterol of greater than 5.4 mmol l x1. In Denmark the reimbursement rules remained unchanged throughout the study period. LLDs were reimbursed to the extent of 75% of the cost after individual application from the patient's physician to the Danish National Board of Health under the following conditions: (1) known ischaemic heart disease, e.g. former myocardial infarction, angina pectoris and serum cholesterol above 5.4 mmol l x1 in spite of diet; (2) inherited hyperlipidaemia; and (3) high serum cholesterol and concurrent important risk factors for developing ischaemic heart disease (family disposition or diabetes mellitus). Furthermore, following publication of the 4S study [2] it was 464 f 2 Blackwell Science Ltd Br J Clin Pharmacol, 49, 463±471

Lack of adherence to lipid-lowering drug treatment pointed out by the Danish National Board of Health in a letter to all physicians in January 1995 that reimbursement could not be obtained for the purpose of primary prevention. Age and sex breakdown of drug use The extent of LLD use (ATC code C1, formerly B4) was analysed as the number of DDD/1 inhabitants/ day, according to the ATC/DDD methodology [9], and as the annual prevalence of use (number of individuals receiving at least one prescription in 1 year per 1 inhabitants). Data were broken down by sex and age classes in ways that ensured comparability with previous studies. Waiting-time distribution and incidence The waiting time distribution as described by Hallas et al. [15] charts for drug users their rst prescription presented within a speci ed time window. For drugs used for chronic treatment, most current users will be captured at the beginning of the window. After some months (the run-in period), incident users will dominate the graph. In the present study, the waiting-time distributions were generated for LLD users according to sex and age below or above 65 years of age on the basis of both Italian and Danish data. It was used mainly for determining the length of the run-in period. Incidence was calculated as the number of new users per 1 inhabitants per year after having determined the runin period. Data from Bologna from July 1995 concerning new users were missing. Therefore, the sex-and age speci c incidence was for this month estimated as the average incidence for the rest of 1995. Co-prescription of other drugs as indicator of risk factors The presence of cardiovascular disease or risk factors was assessed by identifying the LLD-treated individuals who also received in the same year at least one prescription of one or more drugs belonging to the following ATC groups: A1 (insulins and oral antidiabetics) as a marker for diabetes and B1 (antithrombotics), C1 (cardiac glycosides, antiarrhythmics, nitrates), C2 (antihypertensives), C3 (diuretics), C7 (beta-blockers), C8 (calcium antagonists) and C9 (ACE inhibitors) as markers for cardiovascular disease. Persistence and continuity of lipid-lowering drugs Persistence of LLD use during 1994±95±1996 was assessed by identifying all individuals treated in 1994 who were still on a lipid-lowering drug in 1996. In a more detailed analysis, the total number of DDDs received by each individual in 1 year was evaluated. This number re ects both persistence of treatment and within-treatment adherence to the recommended regimen (continuity). Continuity was further investigated under the assumption that 1 DDD represents an average day of treatment. A fully compliant long-term user should grossly receive 365 DDDs in 1 year. The limit between good and poor compliance has previously been de ned as 8% [5]. For practical purposes, we put the limit at 3 DDD/year (i.e. 82%). This analysis was performed in the subgroups of individuals who received one or more prescriptions of LLDs in the rst month (January) of each year. This was done in order to capture prevalent users in three complete 1 year periods. Statistical methods Univariate analyses were used to estimate the percentage and 95% con dence intervals of LLD users in 1994 still under treatment in 1996 according to sex, age group and comedication. The Chi-square test was used to evaluate differences between categories. A multivariate model was used to describe the relative in uence of the variables on each other. STATA version 6. was used for all of the analyses mentioned. Results Overall use In the Emilia Romagna Region (Italy), consumption increased by 37% from 6.7 DDD per 1 inhabitants per day (TID) in 1994 to 9.2 DDD/TID in 1996. Statins made up 72% of the use, an increase of 5% since 1994. In Bologna (part of the Emilia Romagna Region), use was generally about 3% higher than in Italy as a whole. In Funen, Denmark, consumption increased from 2.1 to 4.8 DDD/TID. The share of statin use increased from 81.8% to 91.3%. In 1996, use was slightly higher in Funen compared with the Danish average [13]. In Bologna and in Funen use of LLDs increased during the study period by 41% and 129%, respectively. Bologna LLD prescribing exceeded Funen by a factor of 3±4 in all 3 years. This difference was found to be more pronounced in patients over the age of 65 years and in females. Table 1 shows the number and percentage of users for each region speci ed by LLD group as average of the 3 years and the dose of cially recommended in Denmark [16]. Annual prevalence In Bologna, the annual prevalence of LLD treatment was f 2 Blackwell Science Ltd Br J Clin Pharmacol, 49, 463±471 465

J. Larsen et al. Table 1 Average number and percentage of users over the years 1994±96 speci ed by LLD group in Bologna, Italy and Funen, Denmark. Doses recommended in of cial drug catalogues and corresponding number of DDD as of 1998 in Denmark [9, 16]. Bologna n % Funen n % Recommended dose mg DDD C1AA1 Simvastatin 6721 43.4 915 42.8 1 1±4*.67.67±2.67* C1AA2 Lovastatin 517 24.2 3 1. C1AA3 Pravastatin 2383 15.4 314 14.7 15±2.75±1. C1AA4 Fluvastatin 593 3.7 57 2.7 4 1. C1AA STATINS 9696 62.5 183 84.4 C1AB1 Clo brate 7.3 2 1. C1AB2 Beza brate 1696 1.9 95 4.4 6 1. C1AB4 Gem brozil 322 19.6 96 4.5 12 1. C1AB5 Feno brate 388 2.5 3* 1.** C1AB6 Sim brate 1. 75±15*.75±1.5** C1AB FIBRATES 517 33. 198 9.3 C1AC1 Colestyramin 488 3.2 99 4.6 16 1.14 C1AC2 Colestipol 22 1. 2 1. C1AC3 Detaxtran 181 1.2 2±3*.8±1.2** C1AC RESINS 669 4.4 121 5.6 C1AD5 Nicotinyl alcohol 4.2 9.96 C1AD6 Acipimox 1.5 5 1. C1AD OTHERS 14.7 C1 15473 1. 2136 1. *Italian recommendations. **DDD created by DURG-Italia, as no information was available from the WHO. on average about eight times higher than in Funen (36.9 vs 3.2 users/1 inhabitants/year in 1994, 38.7 vs 4.7 in 1995 and 46.3 vs 6.6 in 1996). Figure 1 shows the development in age speci c 1 year prevalence for the two regions. Trends were similar for females and males in both countries (data not shown). In Funen, for all 3 years analysed, prevalence turned out to be highest in the 65-74 year age group for both males and females, with the exception of 1994 where prevalence for males was marginally higher in the 45-64 year age group. The prevalence in those below 65 years of age increased from 5.6 to 13.2 users per 1 inhabitants. The overall female:male ratio was.7±.8. In Bologna, the 1 year prevalence was also higher in the 65+ age group (78.7±14.3 users per 1 inhabitants) in all 3 years, being highest in the 65-74 year age group. In contrast to Funen, Bologna had a higher female:male ratio of 1.4±1.5. In Bologna, a considerable percentage of people treated were 75 years or older and some were even over 85 years old, whereas in Funen, the number of people treated over the age of 75 years was very low, while no patients were over 85 years old. Incidence The waiting time distribution, showing similar patterns for the sex and age groups described, justi es the use of a runin period of 12 months before a steady level of new users per month is reached (Figure 2). In Bologna the incidence decreased slightly from 19.3 new users/1 inhabitants/ year in 1995 to 18.3 in 1996, the gure being higher for females (21.5±19.9) than for males (16.8±16.5), and higher for the age group above 65 (33.8±29.4) than for the lower age group (14.7±14.8). In Funen, the overall incidence increased from 1.8 new users/1 inhabitants/year in 1995 to 2.3 in 1996, the gure being higher for males (2.2±2.6) than for females (1.4±2.). For the age group below 65 years, incidence increased from 1.4 to 1.7, and for the age group above 65 years incidence increased from 4. to 5. new users/1 inhabitants/year. Co-prescription In Bologna, the number of persons who were cotreated with medications indicating cardiovascular or diabetic comorbidity increased from 57.5% to 62.4% during the study period. Of these, about 62% were females and 74% were greater than 65 years old. In Funen, the number of cotreated persons increased from 68.5% to 76.4% during the period and of these 46% were females and 85% were equal to or greater than 65 years of age. 466 f 2 Blackwell Science Ltd Br J Clin Pharmacol, 49, 463±471

log number of users per 1 inhabitants Number of users per 1 inhabitants Lack of adherence to lipid-lowering drug treatment 12 Bologna 1 8 6 4 2 Funen 24 25 44 45 64 65 74 75 84 85+ Age (years) Figure 1 Age speci c 1 year prevalence of LLD use in Bologna (closed symbols) and Funen (open symbols) 1994±1996.N, % 1994; &, % 1995; n, m, 1996. Persistence and continuity of LLD use In Bologna, only 47.5% of those who obtained a LLD in 1994 were still receiving this medication in 1996. In Funen, 9.8% of people receiving LLDs in 1994 still had at least one prescription in 1996. When stratifying by age, sex 1 1 1.1.1 3 6 9 12 15 18 21 24 27 3 33 36 Time (months) Figure 2 Waiting time distribution for LLD users, Funen (m) and Bologna (&) 1994±1996. Users were counted the rst time they appeared in the time window. In the rst 6 months, the curve represents prevalent users, and after 12 months, it represents incident users. Note that the scale for Funen gures is lower than that for Bologna gures by a factor of 1. f 2 Blackwell Science Ltd Br J Clin Pharmacol, 49, 463±471 467

% of users J. Larsen et al. and comedications as predictors of cardiovascular risk factors, none of the subgroups were below 88% in Funen, but all subgroups were below 53% in Bologna (data not shown). In both areas there was a signi cantly higher degree of persistence of LLD usage in people receiving coprescription of antidiabetic and/or cardiovascular drugs (chi-square P<.1 in Bologna, P<.5 in Funen) compared with those without such comedications. In Bologna, but not in Funen, a signi cantly (chi-square P<.1) higher degree of persistence of LLD usage was observed in women compared with men and in the over 65 year old vs younger patients. After strati cation of the Danish data into narrower age groups, age was also shown to have an effect on persistent usage: in age groups between 45 and 75 years, persistence was high (92%) whereas only 81% of patients below 45 years and above 75 years of age were persistent users. A subgroup consisting of males over the age of 75 years had the lowest persistence (6%). In a multivariate analysis of the Danish data, the effect of comedication and age (the narrower age groups) remained statistically signi cant even after adjusting each variable for each other and for sex. In a similar analysis of the Italian data, the youngest (11.4%) and the oldest females (43.%) turned out to be least persistent and in males, the lowest percentage of persistent users (21.8%) was found in the youngest age group. Multivariate analysis of the Italian data showed that sex as well as age (below or above 65 years or narrower age groups) and comedication remained signi cant, and that neither of these factors could alone account for the pattern seen. The average number of DDD per treated person in Bologna was 87 in 1994, 14 in 1995 and 15 in 1996, whereas in Funen the corresponding gures were 254, 261 and 29, respectively, indicating that continuity of treatment was better in Funen compared with Bologna. Figure 3 shows the proportion of users for both areas according to their use in DDD/year. In all 3 years the number of users peaked at 2±3 (average 25) and 4+DDD/year in Funen. In Bologna the number of users peaked at 5 or less DDD in 1994 and at 151±2 DDD in 1995 and 1996. According to our de nition only 7.3% of users in Bologna in the 3 years considered could be categorized as being good compliers (i.e. 82% continuity or better), while in Funen, 45.2% of users were good compliers. For patients aged 65 years or more, the gures were 7.6% and 38.8%, respectively. Discussion Use of LLDs in Denmark according to the age and sex pro le corresponded to the pattern seen earlier in Sweden [1], while the pattern in Bologna remained the same with a higher usage in women, particularly in those above 65 years of age when compared with Denmark/Sweden. 4 35 3 25 2 15 1 5 5 4+ 351 4 31 35 251 3 21 25 151 2 11 15 51 1 5 4+ 351 4 31 35 251 3 21 25 151 2 11 15 51 1 5 4+ 351 4 31 35 251 3 21 25 151 2 11 15 51 1 4 35 3 25 2 15 1 5 4 35 3 25 2 15 1 5 1994 1995 1996 DDD Figure 3 Distribution of annual LLD use (DDD/user/year) for selected populations prescribed a LLD in January for each of the years 1994±95±1996 in Bologna (&) (n=355±3434±428) and Funen (%) (n=517±635±124). In Bologna, consumption and prevalence increased, while incidence (using a 1 year run-in period) decreased during the study period, indicating that an increasing proportion of LLDs is consumed by prevalent users. This suggests better compliance over time, or that only the most motivated patients remain on therapy. In Funen, consumption and prevalence as well as incidence of use increased threefold from a very low level compared with other countries. Despite this, the number of patients being treated was still only about 1% of the expected. In 1996, Danish cardiologists estimated that the prevalence of patients who needed LLD treatment was 5% of the total 468 f 2 Blackwell Science Ltd Br J Clin Pharmacol, 49, 463±471

Lack of adherence to lipid-lowering drug treatment population [17]. In the present study, we found that only.5% were actually being treated, in spite of the fact that the 4S study had a notable effect on overall use in Denmark [18]. Future research should explore why so few patients actually start LLD use in Denmark and why knowledge from the controlled trials is not implemented. The distribution of users according to individual use in DDD/year (Figure 3) and the results concerning persistent usage (Table 2) indicate that there is a higher degree of sporadic use in Bologna compared with Funen. According to our de nition, very few LLD users in Bologna were good compliers (7.3%), while in Funen 45.2% were good compliers. In a study from Australia (top LLD using country [1]), 6% of the patients failed to collect prescription re lls over 12 months [4]. The predominant reasons for discontinuation were: a) patient unconvinced about need for treatment, b) poor ef cacy and c) adverse events. The reason for the apparent worse compliance in Italy is presently unknown, but it is possible that more patients were prescribed a LLD without proper justi cation and in many of those the drug was stopped fairly soon. As a speculative explanation, we could invoke an effect of the verbal promotional messages given by pharmaceutical representatives in the recent past to doctors according to which the best regimen was as represented by 3 month courses of treatment in patients with a cholesterol level just above 5.2 mmol l x1. The use of individualized prescription databases as opposed to wholesale statistics enabled us to describe LLD utilization in large populations in a natural setting. We were able to describe duration of treatments as well as the amount of drug collected by each individual. In both these databases the amount of drugs purchased by the patients was expressed as the number of De ned Daily Doses (DDD), a useful technical unit for comparative drug utilization studies [1, 19]. A disadvantage of our prescription databases is that they do not hold information on prescribed daily dose (PDD), which measure together with a count of the number of doses ingested by patients within a particular time frame would be the ideal for compliance studies. Since such data are not available, we have to rely on approximations. A weakness of using DDD as a measure in compliance calculations is that one DDD may be a poor re ection of the actual daily use of a certain drug [2]. In Bologna as well as in Funen, 43% of LLD users used a statin assigned.67 DDD as the lowest suggested daily dose (Table 1). Thus, having used one DDD in calculations of continuity, we have clearly underestimated compliance in both regions. The variations in DDD for the various drugs cannot, however, completely account for the six-fold higher compliance in Funen. If serum cholesterol was generally lower in Bologna this would probably lead to prescribing of lower than recommended doses. However, as the mortality rate from cardiovascular diseases is slightly higher in Bologna than in Funen (5.51 vs 4.82/1 inhabitants/year) this is unlikely to be the reason. A more relevant measure of daily use for statins may be one tablet, as tablets come in different strengths. For example, the recommended daily dose of simvastatin in Denmark is 1 mg [16], which corresponds to.67 DDD. According to this, 1% compliance would imply an annual use of 245 DDD. Using this method, 27.7% (CI95%: 21.5±35.9) of Italians and 81.% (CI95%: 75.2±84.9) of Danes would be good compliers. While these gures may better re ect the compliance in these regions, it does not change the fact that there are marked differences between the regions. Not surprisingly, the status of reimbursement regimens tends to in uence consumption of LLDs to a considerable extent. In Italy after changing full reimbursement (up until 1993) to copayment for prescriptions exceeding 16 per year, consumption decreased from 11.5 to 1.4 DDD/ 1 inhabitants/day [1]. Again, after restricting the fully Table 2 Persistence with lipid lowering drugs 1994±96 in Funen and Bologna in total and in selected strata. Co-prescription with antidiabetic or cardiovascular drugs. Variable Persistent n Funen Total n % Persistent (95% CI) Persistent n Bologna Total n % Persistent (95% CI) Total 124 1326 9,8 (89,1±92,3) 587 1236 47,5 (46,6±48,4) Females 552 64 91,4 (88,9±93,5) 3861 7844 49,2 (48,1±5,3) Males 652 722 9,3 (87,9±92,4) 29 4616 43,5 (42,1±45,) ±44 years 122 151 8,8 (73,6±86,7) 2 1162 17,2 (15,1±19,5) 45±64 years 75 89 92,7 (9,7±94,4) 2356 4848 48,6 (47,2±5,) 65±74 years 298 324 92, (88,5±94,7) 2618 468 55,9 (54,5±57,4) 75+ years 34 42 81, (65,9±91,4) 696 167 41,7 (39,3±44,1) xco-prescription 462 524 88,2 (85,1±9,8) 22 5259 41,8 (4,5±43,2) +Co-prescription 742 82 92,5 (9,5±94,2) 367 711 51,7 (5,5±52,9) f 2 Blackwell Science Ltd Br J Clin Pharmacol, 49, 463±471 469

J. Larsen et al. reimbursed part of LLDs to the indication of familial hyperlipidemia with high levels of cholesterol or triglycerides and full patient's payment for other indications, consumption further decreased to 6.7 DDD/1 inhabitants/day. The in uence of the restrictions was, however, rather transient, as consumption increased again to reach 9.2 (12.5 in Bologna) DDD/1 inhabitants/day in 1996 without any change in the reimbursement rules. In Denmark, consumption has been low compared with other countries. Reimbursement (75%) ± remaining unchanged until December 1998 ± has been restricted to secondary prevention of ischaemic heart disease, failure of dietary intervention and only after individual application from the patient's physician. In Italy, restrictions with reimbursement rules showed only temporary impact on consumption, a pattern also seen in other countries [21]. It is possible that the low Danish consumption is due to the rather restrictive reimbursement rules, and also that consumption could increase if the restrictions were eased. As of mid December 1998, reimbursement rules have been eased in Denmark, so that no individual application is needed for the use of LLDs for secondary prevention, although it is still needed for primary prevention. In the years, to come consumption of LLDs will be followed in order to monitor the effect of this change. As to persistence of usage, our follow-up period was 2 years, i.e. 3 years shorter than in the North American study [6]. In that study approximately 5% of patients aged over 65 years were still on the drugs after 5 years. The Italian cohort of similar age had already reached this level after 2 years with 52.2% persistent users, whereas from the Danish cohort, 9.7% were still on the drugs. Compared with the North American study, the percentage of continuous users in Italy was extremely low (7.6% vs 34.1% in New Jersey and 38.9% in Quebec), while the Danish gures were similar (38.8%). According to our de nition of the study cohort, only patients staying alive during the whole study period were included. This selection may have biased our results leading to overestimation of compliance and underestimation of prevalence as patients treated with LLDs are supposed to live longer. Considering this fact, the Italian results may differ even more from the North American results. In the previously published international comparison of LLD use, Sweden was one of the participating countries [1]. The level of LLD use in Sweden (12.6 DDD/TID) was almost three times the use in Funen, Denmark (4.8 DDD/TID), and corresponds to the use in Bologna, Italy (12.7 DDD/TID). Whether the adherence among Swedish patients is as low as in Bologna, or similar to that reported from Australia [4] is, however, not known as corresponding individual prescription data are lacking. In conclusion, the present study found the same differences in age-and sex-speci c prescription patterns between the Emilia Romagna Region and Funen as previously published for another Nordic country [1]. The Danish LLD utilization pattern was comparable to the previously described Swedish pattern, although Danish consumption in DDD/TID was just about 1/3 of the Swedish consumption. Contrary to the use in Denmark, Italian use was characterized by high consumption, prevalence and incidence (although decreasing). Female use dominated in Italy. Two-year persistence with LLD use was only about half the Danish level, lowest in the youngest age groups. Causes for the rather sporadic use in Italy are unclear. Compared with North American results, persistence and continuity of LLD use in Funen was similar, while in Bologna, gures showed considerably lower values. The higher discontinuation rate of lipid lowering drugs in the Bologna area indicates that a large proportion of patients use these drugs for too short a period of time to bene t from the treatment, a pattern also seen in Australia [4]. Additionally, patients may have been prescribed a lipid-lowering drug without proper justi cation. Since society's health care resources are limited, it is dif cult to justify public funding of these medications without at the same time giving appropriate attention to these problems. The authors wish to thank Cristina Castelvetri and Rosa Rizzo for the computer analysis of Italian data and Penelope North-Lewis for proof-reading of the manuscript. 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