Shift of statin use towards the elderly in : a nation-wide register study in Finland

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1 British Journal of Clinical Pharmacology DOI:1.1111/j x Shift of statin use towards the elderly in : a nation-wide register study in Finland Päivi Ruokoniemi, 1,2,3 Arja Helin-Salmivaara, 1,2,4 Timo Klaukka, 5 Pertti J. Neuvonen 4 & Risto Huupponen 2,3 1 Graduate School of Clinical Drug Research, 2 Dept. of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland, 3 Clinical Pharmacology, Tykslab, Health Care District of Southwest Finland, Turku, Finland. 4 Dept. of Clinical Pharmacology, University of Helsinki, Helsinki, Finland, 5 Research Department, Social Insurance Institution, Helsinki, Finland Correspondence Dr Päivi Ruokoniemi MD, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, FI-214 Turku, Finland Tel.: Fax: paivi.ruokoniemi@utu.fi Keywords hydroxymethylglutaryl-coa reductase inhibitors, incidence, prevalence, statins, utilization Received 4 January 28 Accepted 2 June 28 WHAT IS ALREADY KNOWN Statin use has increased in western societies since the 199s. Efficacy of statins in the prevention of coronary heart diseases has been clearly documented in the general population but only recently in elderly persons. WHAT THIS STUDY ADDS Since 1995 the use of statins has clearly shifted towards the elderly in Finland. At the beginning of the 11 year follow-up the prevalence of statin use was higher among males than females but since 22 the prevalence has been higher among females. AIM To describe nation-wide secular trends in statin use. METHODS Reimbursed prescriptions for lipid lowering drugs between 1995 and 25 in Finland were retrieved from the nation-wide Prescription Register. The 1 year prevalence and incidence of statin use stratified by gender and age of users were measured for each calendar year. The relative changes (RR) in the incidence and the prevalence were calculated by using the year 1995 as a reference. RESULTS The 1 year prevalence increased 11-fold (95% confidence interval 11.2, 11.5), i.e. from 7.8 per 1 inhabitants in 1995 to 88.9 in 25. The incidence increased five-fold (95% CI 4.9, 5.1) from 355 per 1 inhabitants to 1772 during the respective years. The prevalence and incidence were the highest among persons aged years. The largest relative increase in incidence was found among those aged 75 years, in both females (RR 14.1, 95% CI 13., 15.3) and males (RR 14., 95% CI 12.5, 15.7). Since 22 the prevalence has been higher among females (P <.5). CONCLUSIONS As statin use has increased particularly among the elderly, further studies on the benefits in real life situation are needed in this age group. 28 The Authors Journal compilation 28 Blackwell Publishing Ltd Br J Clin Pharmacol / 66:3 / / 45

2 P. Ruokoniemi et al. Introduction The use of lipid-lowering drugs (LLDs), mainly 3-hydroxy- 3-methylglutaryl coentzyme A reductase inhibitors (statins) has increased exponentially in western societies [1, 2] since the publication of the Scandinavian Simvastatin Survival Study (4S) in 1994 [3]. Publication of other benchmarking trials in the late 199s [4 6] further stimulated the use. The increase has been seen in pharmacy based registers [7 9], surveys [1, 11] and administrative databases [8, 12 16] including drug consumption statistics [17]. Despite the increase in statin use, data on its prevalence, and especially on new users categorized by the demographic characteristics are scarce in general population [2, 9, 13 15]. Furthermore, the generalizability of previous utilization studies is limited due to the small size or restrictions of the study populations, or the time windows included in the studies: most of them describe statin use during the 199s. As in other western societies, statin use in Finland has also increased exponentially [17]. In 25 the total consumption was 94.9 defined daily doses (DDD) per 1 inhabitants a day [18]. Simvastatin has been the most used statin since 1997; in 25 it accounted for 4% of statin consumption [18]. The use of atorvastatin has steadily increased since its introduction in 1998, and atorvastatin accounted for 34% of statin consumption in 25. Rosuvastatin, pravastatin, fluvastatin and lovastatin are clearly smaller players in the market, each of them accounting for less than 1% of the consumption [18]. The comprehensive nation-wide drug reimbursement registers make Finland suitable for studies on drug utilization patterns.the aim of the present study was to evaluate the use of statin therapy in the Finnish population between the years 1995 and 25. We analyzed trends of prevalence and incidence of statin use separately for both genders in various age categories. Methods Data source The data were based on the national Prescription Register managed by the Social Insurance Institution. All permanent residents living in community are included in the Register. In 23, 94.6% of the consumption for lipid lowering drugs (consisting mainly statins) outside institutions was covered by the Register (Martikainen J, the Social Insurance Institution, personal information). In this study a prescription refers to the amount of reimbursable medicine which consists of one preparation purchased during one transaction from a pharmacy. Reimbursed medicines can be supplied to a patient for no longer than 3 months per purchase. Consequently, a 1 year therapy issued by a physician contributes at least four prescriptions. The reimbursement register covers purchases that meet the minimum deductible limit, i.e euros until 22 and 1 euros thereafter until 26. All statins are available on prescription only. During the study period all statin prescriptions were reimbursable, and with a minor exception their purchases were also registered. After the introduction of generic substitution in 23 a limited number of lowprice simvastatin packages remained below the deductible limit in and were registered only if the patient purchased other reimbursable medicines at the same transaction. The data on the population were collected by the Social Insurance Institution. During the study period the population increased from 5.1 to 5.3 million. Prescriptions The following LLD prescriptions were retrieved using the corresponding Anatomical Therapeutic Chemical code (ATC) presented by the WHO [19]: simvastatin (C1AA1), lovastatin (C1AA2), pravastatin (C1AA3), fluvastatin (C1AA4), atorvastatin (C1AA5), cerivastatin (C1AA6), rosuvastatin (C1AA7), clofibrate (C1AB1), bezafibrate (C1AB2), gemfibrozil (C1AB4), fenofibrate (C1AB5), cholestyramine (C1AC1), colestipol (C1AC2) and ezetimibe (C1AX9). These ATC codes were applied for the years between 1996 and 25 [19].For the years 1994 and 1995 respective ATC codes valid for that time were used [2]. The LLD users were identified by a unique social security number linked to each prescription in the register. Reimbursed LLD prescriptions were further linked with the date of the purchase, the gender and the age of the patient in years at the end of each calendar year. Definitions The 1 year period prevalence of statin use was calculated from the number of persons who redeemed at least one reimbursed statin prescription during a calendar year divided by the number of inhabitants in Finland at the end of the respective year. The 1 year incidence of statin use was defined as the number of initiators, new users in the respective year divided by the number of inhabitants excluding those who had redeemed at least one statin prescription during the previous year. The prescription data in 1994 were used to ensure that new users of statins in 1995 had not redeemed any statins during the previous year. The genders were analyzed separately. Both the prevalence and the incidence were calculated for patients aged 44 years or less, for those aged 45-54, 55-64, and 75 years or more.the age and gender specific population was used in the denominator where appropriate. Statistical analysis To analyze the relative changes in statin use, the rate ratios (RR) of the 1 year prevalence in each year in relation to the reference year 1995 and the respective RRs of incidences and their 95% confidence intervals were calculated using 46 / 66:3 / Br J Clin Pharmacol

3 Statin use Table 1 1 year prevalence of statin use (at least one reimbursed statin prescription per year); users per 1 inhabitants in Finland and the median age of all users in respective years Both genders Males* Females* Median age, year (interquartile range) (54 68) (55 69) (56 7) (56 7) (56 71) (56 72) (56 72) (57 73) (57 73) (57 73) (57 74) *The difference between males and females P <.5 in all other years but in 2 and 21. Users/1 male inhabitants Users/1 female inhabitants 4 A B the Poisson regression. A two-tailed P value <.5 was regarded as statistically significant. The crude prevalence and incidence in each year were standardized according to the age and gender specific population in 2.The statistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC). Results After the exclusion of persons with incomplete data (n = 16) a total of persons who had received at least one prescription for a LLD were identified. Among these, persons received at least one prescription for a statin. The number of statin users increased from 4 89 (.8% of the population) in 1995 to (8.9%) in 25. The number of users of other LLDs than statins decreased slightly from 846 to 7314 during the respective years. In the following only data on statins are presented. The median age of the users increased from 62 to 66 years during the 11 year observation period (Table 1). Among the users in 25 ( persons) the largest group was males younger than 65 years who accounted for 33.3% of the users, and the second largest group was females 65 years of age with the 26.5% share. Prevalence The 1 year prevalence of statin use increased from 7.8 per 1 inhabitants in 1995 to 88.9 in 25 (RR 11.3, 95% CI 11.2, 11.5). Among females, the prevalence increased from 6.9 per 1 female inhabitants to 89.3, and among males from 8.8 to 88.5 per 1 male inhabitants during the respective years (Table 1). From 1995 to 1999 the prevalence of statin use was significantly higher among males Figure 1 1 year prevalence of statin use stratified by age among males (A) and females (B) in Finland. >75 years ( ); years ( ); years ( ); years ( ); <44 years ( ) than among females (P <.5) but since 22 the situation has reversed: the prevalence was higher among females (P <.5). The direct standardization procedure according to the population in 2 did not affect the results and hence the crude period prevalence is presented (Table 1, Figure 1). Among both genders the prevalence increased in all age categories during the 11 year follow-up (Figure 1).The relative increase was most prominent among those aged at least 75 years (RR 4.6, 95% CI 37.5, 43.9 for males and RR 4.2, 95% CI 38.1, 42.4 for females). The gender specific 1 year prevalence in this age category increased from 7. per 1 male inhabitants in 1995 to in 25 and from 6.7 per 1 female inhabitants to 264.4, respectively. Incidence The overall incidence of statin use increased from 355 per 1 inhabitants in 1995 to 1772 in 25 (RR 5., 95% CI 4.9, 5.1). Among females, the incidence increased from 312 per 1 female inhabitants to 1732, and among males from 399 to 1815 per 1 male inhabitants. In 1995 the 1 year incidence was higher among males than females (RR 1.3, 95% CI 1.2, 1.3) but since 1996 no significant difference was observed. Persons aged between 65 and 74 years showed the highest incidence in both genders over the whole observation period (Figure 2). Direct standardization to the year 2 population did not significantly affect the incidence figures either. Br J Clin Pharmacol / 66:3 / 47

4 P. Ruokoniemi et al. New users/1 male inhabitants New users/1 female inhabitants Figure 2 A In concordance with prevalence, the relative increase in the number of new users was the highest among persons aged at least 75 years (RR 14., 95% CI 12.5, 15.7 for male users and RR 14.1, 95% CI 13., 15.3 for female users). The increase in the incidence among the oldest persons was from 353 per 1 male inhabitants in 1995 to 4948 in 25, and from 31 per 1 female inhabitants to 4 252, respectively. All values for prevalence and incidence for both genders in various age categories are presented in the electronic supplementary data online. Discussion B year incidence of statin use stratified by age among males (A) and females (B) in Finland. >75 years ( ); years ( ); years ( ); years ( ); <44 years ( ) Among the whole population of Finland the relative increase of the prevalence of statin use was 11-fold between 1995 and 25. The most evident, 4-fold, increase was observed among persons aged at least 75 years. The relative increase of the incidence was five-fold among the whole population. In accordance with the highest relative change of the prevalence, the largest (14- fold) increase of the incidence was observed among the oldest persons. In absolute terms, both the highest prevalence and incidence of statin use were found among persons aged between 65 and 74 years; 31% of the persons in this age category had used statins in 25. Only small differences in the statin use between the genders were found. The Prescription Register covers every permanent resident of Finland receiving statin treatment in open care. The further strength of our study was the low turnover of the population. However, persons staying permanently in public institutional care are not entitled to drug reimbursement, and were thus not included in our study. Therefore, we may have underestimated statin use especially among the elderly.furthermore, the Prescription Register does not cover non-reimbursed medicines of low-price packages. During all statin prescriptions were registered, but after the introduction of generic substitution in 23 prices of a limited number of simvastatin packages fell below the reimbursement level in Thus, the plateau observed in the incidence level in 25 may be more of a reflection of the decreased coverage of statins in the Register than a real decrease in the number of new users. The observed increase in prevalence among those aged at least 75 years partly reflects a continuum of statin therapy initiated at earlier ages. However, the relative increase in the number of new users among the oldest population, already observed during the 199s, is concordant with the transition of coronary heart disease (CHD) prevalence towards the oldest group. In Finland the prevalence of CHD has decreased among persons younger than 65 years, and increased during the past 2 years among those aged more than 75 years [21]. Consequently, in 2 the most dominant group of patients with CHD was females aged 75 years [21]. The increase in the prevalence of statin use also reflects the increase in the morbidity of CHD. The ageing of the Finnish population has promoted the increase in the total estimated number of persons with established CHD by 18% during the past 2 years [21] although the incidence of first myocardial infarction (MI) decreased between 1991 and 21 [22]. The reduction in MI incidence and the shift of CHD morbidity towards those aged over 75 years suggests successful primary prevention among the younger population. Large statin trials conducted during the 199s showed clear evidence on statin efficacy in the prevention of CHD events [3 6]. These trials were not specifically conducted among the elderly though data from sub-analyses revealed efficacy of statin treatment also among those aged up to 75 years [3, 5]. The first trials showing efficacy among persons aged over 75 years were not published until 22 [23, 24] and the respective recommendations were incorporated into the Finnish evidence-based clinical guidelines on dyslipidaemia 2 years later [25]. Thus, the clinical trial evidence on the younger population present in the 199s may have already been extrapolated to elderly patients by physicians before 22. A cross-sectional survey conducted among Finns in 2 showed that the percentage of males with CHD or with low density lipoprotein values higher than 3. mmol l 1 (116 mg dl 1 ) was significantly higher than 48 / 66:3 / Br J Clin Pharmacol

5 Statin use that for females [26]. Hence, we assumed that males would use statins more frequently than females, but after 1999 no remarkable gender differences in prevalence existed (Table 1). The slopes of the incidence curves were steepest in 1998/1999 and 23/24 (Figure 2). These coincide with, and may be explained by, the launching of atorvastatin in 1998 onto the Finnish market and the introduction of generic substitution in 23. The intensive marketing of atorvastatin may have targeted therapy to persons not previously considered eligible for statins. On the other hand, the substantial price reductions of generic simvastatin and other generic statin preparations may have boosted their use. The direct comparison of our results with other studies is difficult since only a few studies have used similar methodology to describe the demographics of statin users. In Norway, the 1 year prevalence of statin use among males was 7.5% and among females 6.3% in 24/25 [27]. Furthermore, national statistics on drug use in other Nordic countries offer relevant comparison data [28, 29]. In Sweden the intensity of statin use among females counted by DDDs was 27% lower than among males, and in Denmark 46% of the users were females. The use was the most intensive among persons aged years in Sweden. In Denmark the median age of the users was 2 years lower than in Finland, 64 years (interquartile range 57-72) in 25 [29]. The prevalence and incidence figures on statin use in our study corresponded to the highest prevalence and incidence of the use of all lipid lowering drugs among populations aged 6-69 years in some previous studies [14, 15]. A previous report from Finland [8], as well as reports from Sweden [12], Denmark [2, 13, 15] and the Netherlands [14] have shown increasing LLD use in the 199s to be dominated by males. In conclusion, in Finland the use of statins had already shifted to elderly persons some years before rigorous evidence from clinical trials was available. The shift was in accordance with the change in the age-specific prevalence of CHD. However, current targeting of statin therapy may be partly suboptimal as reflected by the missing difference in the utilization pattern between the genders. Considering the large number of the elderly, a fragile population, continuously on statins studies on benefits and harms in a real-life setting among elderly are needed. Disclosures: Päivi Ruokoniemi: No conflict of interests. Arja Helin-Salmivaara: No conflict of interests. Timo Klaukka: No conflict of interests. Pertti J. Neuvonen: No conflict of interests. Risto Huupponen: No conflict of interests. We thank Hilkka Ruuska and Kristiina Tyrkkö, from the Social Insurance Institution, for their data management skills and biostatistician Tero Vahlberg, Department of Biostatistics, University of Turku, for his valuable instructions and comments on statistical analysis. This study was partly funded by the research grant from the Social Insurance Institution (1/26/27). The sponsor had no role in the design, conduct, analysis, interpretation of the data, or in the preparation, review, or approval of the manuscript. REFERENCES 1 Baxter C, Jones R, Corr L. Time trend analysis and variations in prescribing lipid lowering drugs in general practice. BMJ 1998; 317: Larsen J, Andersen M, Kragstrup J, Gram LF. Changes in the utilisation of lipid-lowering drugs over a 6-year period ( ) in a Danish population. Eur J Clin Pharmacol 21; 57: Scandinavian Simvastatin Survival Study Group. 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