Päivi Ruokoniemi

Long-Term Persistence with Statin Therapy: A Nationwide Register Study in Finland

BACKGROUND Preventive statin therapy is often recommended as lifelong treatment. OBJECTIVE The aim of this study was to analyze persistence with statin therapy over a decade of use and to identify factors associated with its discontinuation. METHODS Persistence with therapy among new users of statins in 1995 was followed up until December 31, 2005, in Finland using the nationwide drug reimbursement register. Cumulative persistence was analyzed using Kaplan-Meier analysis. A Cox regression model was applied to analyze associations of various baseline covariates with discontinuation. We further modeled the association of time-specific covariates by stratifying the duration of therapy in years and using a logistic regression in which those continuing therapy until the end of follow-up (persistent users) formed the reference group. Adherence, defined as the proportion of days covered by statins, stratified by the timing of discontinuation, was computed for the respective groups. RESULTS Of the 18,072 new statin users, 73.3% (n =13,254) were aged >54 years and 54.8% (n =9908) were men. Of this cohort, 43.9% (n = 7926) were using statins throughout and at the end of the tenth year. Sex was not associated with persistence at any point. In the Cox model, persons aged 45 to 74 years at initiation were more likely to continue statin use than younger or older age groups. Among those who still used statins after the fifth year of observation, the age difference was not observed in the logistic regression model. The use of 1, 2, 3, or > or =4 cardiovascular drugs before the initiation predicted continuation relative to no cardiovascular drug use (hazard ratio for discontinuation significantly <1.00 in all comparisons). Adherence was best (median 93.9%) among the persistent users. CONCLUSIONS The 10-year persistence with statin use in this general population was approximately 44%. Persons aged 45 to 74 years at initiation and those with at least 1 prescription for another cardiovascular medication were the most likely to continue statin therapy up to the fifth year.

Shift of statin use towards the elderly in 1995−2005: a nation-wide register study in Finland

AIM To describe nation-wide secular trends in statin use. METHODS Reimbursed prescriptions for lipid lowering drugs between 1995 and 2005 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 1000 inhabitants in 1995 to 88.9 in 2005. The incidence increased five-fold (95% CI 4.9, 5.1) from 355 per 100 000 inhabitants to 1772 during the respective years. The prevalence and incidence were the highest among persons aged 65-74 years. The largest relative increase in incidence was found among those aged >/= 75 years, in both females (RR 14.1, 95% CI 13.0, 15.3) and males (RR 14.0, 95% CI 12.5, 15.7). Since 2002 the prevalence has been higher among females (P < 0.05). 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.

Statin adherence and the risk of major coronary events in patients with diabetes: a nested case-control study.

AIMS To evaluate whether good statin adherence is associated with a reduced incidence of major coronary events (MCEs) among diabetic patients with and without coronary heart disease (CHD). METHODS Using data derived by linkage of nationwide health databases in Finland, we conducted a nested case-control analysis of 3513 cases with an MCE, a composite of acute myocardial infarction and/or coronary revascularization, and 20,090 matched controls identified from a cohort of 60,677 statin initiators with diabetes. Cases and controls were matched according to gender, time of cohort entry and duration of follow-up and further classified to two risk groups according to the presence of CHD at statin initiation. The incidence of MCEs was compared between patients with good statin adherence (the proportion of days covered ≥80%) and patients with poor statin adherence (<80%). Odds ratios (OR) for MCEs were estimated by conditional logistic regression adjusting for several covariables. RESULTS Good statin adherence was associated with a reduced incidence of MCEs in those with prior CHD [OR 0.84 (95% CI 0.74-0.95)] and in those without it [OR 0.86 (95% CI 0.78-0.95)]. The association persisted among those followed up for 5 years or longer [OR 0.77 (95% CI 0.58-1.02) and OR 0.79 (95% CI 0.66-0.94) respectively]. In sensitivity analyses, a reduced MCE incidence was observed also in those without any documented cardiovascular disease (CVD) at statin initiation [OR 0.87 (95% CI 0.78-0.96) overall and OR 0.80 (95% CI 0.66-0.97) for those followed up 5 years or longer]. CONCLUSIONS In patients with diabetes, good adherence to statins predicts reduced incidence of MCEs irrespective of the presence of CHD at statin initiation.

Statins and Hip Fracture Prevention – A Population Based Cohort Study in Women

Objective To study the association of long-term statin use and the risk of low-energy hip fractures in middle-aged and elderly women. Design A register-based cohort study. Setting Finland. Participants Women aged 45–75 years initiating statin therapy between 1996 and 2001 with adherence to statins ≥80% during the subsequent five years (n = 40 254), a respective cohort initiating hypertension drugs (n = 41 610), and women randomly selected from the population (n = 62 585). Main Outcome Measures Incidence rate of and hazard ratio (HR) for low-energy hip fracture during the follow-up extending up to 7 years after the 5-year exposure period. Results Altogether 199 low-energy hip fractures occurred during the 135 330 person-years (py) of follow-up in the statin cohort, giving an incidence rate of 1.5 hip fractures per 1000 py. In the hypertension and the population cohorts, the rates were 2.0 per 1000 py (312 fractures per 157 090 py) and 1.0 per 1000 py (212 fractures per 216 329 py), respectively. Adjusting for a propensity score and individual variables strongly predicting the outcome, good adherence to statins for five years was associated with a 29% decreased risk (HR 0.71; 95% CI 0.58–0.86) of a low-energy hip fracture in comparison with adherent use of hypertension drugs. The association was of the same magnitude when comparing the statin users with the population cohort, the HR being 0.69 (0.55–0.87). When women with poor (<40%), moderate (40 to 80%), and good adherence (≥80%) to statins were compared to those with good adherence to hypertension drugs (≥80%) or to the population cohort, the protective effect associated with statin use attenuated with the decreasing level of adherence. Conclusions 5-year exposure to statins is associated with a reduced risk of low-energy hip fracture in women aged 50–80 years without prior hospitalizations for fractures.

Statin adherence and the risk of major coronary events in patients with diabetes: a nested case-control study

AIMS To evaluate whether good statin adherence is associated with a reduced incidence of major coronary events (MCEs) among diabetic patients with and without coronary heart disease (CHD). METHODS Using data derived by linkage of nationwide health databases in Finland, we conducted a nested case-control analysis of 3513 cases with an MCE, a composite of acute myocardial infarction and/or coronary revascularization, and 20,090 matched controls identified from a cohort of 60,677 statin initiators with diabetes. Cases and controls were matched according to gender, time of cohort entry and duration of follow-up and further classified to two risk groups according to the presence of CHD at statin initiation. The incidence of MCEs was compared between patients with good statin adherence (the proportion of days covered ≥80%) and patients with poor statin adherence (<80%). Odds ratios (OR) for MCEs were estimated by conditional logistic regression adjusting for several covariables. RESULTS Good statin adherence was associated with a reduced incidence of MCEs in those with prior CHD [OR 0.84 (95% CI 0.74-0.95)] and in those without it [OR 0.86 (95% CI 0.78-0.95)]. The association persisted among those followed up for 5 years or longer [OR 0.77 (95% CI 0.58-1.02) and OR 0.79 (95% CI 0.66-0.94) respectively]. In sensitivity analyses, a reduced MCE incidence was observed also in those without any documented cardiovascular disease (CVD) at statin initiation [OR 0.87 (95% CI 0.78-0.96) overall and OR 0.80 (95% CI 0.66-0.97) for those followed up 5 years or longer]. CONCLUSIONS In patients with diabetes, good adherence to statins predicts reduced incidence of MCEs irrespective of the presence of CHD at statin initiation.

Are statin trials in diabetes representative of real-world diabetes care: a population-based study on statin initiators in Finland

Objective To assess the representativeness of the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS) for incident statin users. Design A population-based analysis with linked register data. Setting Finland. Population 56 963 patients with diabetes initiating statin use from 2005 to 2008. Main outcome measures We determined the proportions of real-world patients who fulfilled the eligibility criteria for HPS and CARDS trials and assessed the cardiovascular disease (CVD) event rates, assumed to reflect the background CVD risk, for those eligible and ineligible. We used descriptive statistics to identify the patient characteristics, lipid-lowering interventions and adherence to statin therapy. Results Of the real-world patients, 57% (N=32 582) fulfilled the eligibility criteria for HPS (DM) and 49% (N=20 499) of those without CVD for CARDS. The patients ineligible for HPS (DM) had a higher cumulative risk for CVD events than those eligible, whereas regarding CARDS the cumulative risks were of similar magnitude. The overall CVD event rates seemed to be comparable to those in the reviewed trials. Both trials were under-representative of women and users of antihypertensive agents and metformin. 27% and 29% of real-world patients had an initial statin dose corresponding to <20 mg of simvastatin. The proportions of patients who were deemed adherent were 57% in the real world and 85% in both trials. Conclusions Only half of the real-world patients would have qualified for the HPS (DM) and CARDS, limiting their representativeness for clinical practice. Women and users of antihypertensive agents and metformin were under-represented in both trials. These deviations reflect the changes in diabetes treatment over the years and are not expected to modify the average treatment effects of statins on CVD. Prescribing of lower statin doses in clinical practice than used in the trials and lower adherence may, however, attenuate the benefits in the real world.

Adherence to statin therapy and the incidence of ischemic stroke in patients with diabetes

We aimed to quantify for the first time the relationship between statin adherence and ischemic stroke (IS) in patients with diabetes.

Persistence with statin therapy in diabetic and non-diabetic persons: a nation-wide register study in 1995-2005 in Finland

Persistence with statin therapy was studied among 562 598 new statin users in 1995-2005 in Finland. Discontinuation was most likely during the first year. Persons with diabetes (15.0% of initiators) were significantly more likely to continue statin therapy compared with person not having diabetes.

Protopathic bias in observational studies on statin effectiveness.

A meta-analysis of 14 randomized controlled trials (RCT) of statins in prevention of major vascular events suggests that almost all diabetic patients benefit from statin therapy, with a 10% relative reduction in event rates for every millimole per litre reduction in low-density lipoprotein cholesterol seen in 1 year [1]. The results of the RCTs including only patients with diabetes are, however, inconclusive. For ethical reasons, long-term placebo-controlled RCTs of statins in diabetic populations are no longer possible. Therefore observational studies are an essential tool for future research [2], but they are prone to various biases. Protopathic bias occurring when the drug is preferentially prescribed to persons with early symptoms of the outcome under study is one of them [3]. We evaluated the potential for protopathic bias in an observational study on cardiovascular benefits of statins in diabetes by examining the rates of major cardiac events (MCE) among statin initiators with diabetes, with a focus on the first year of therapy. Using a nationwide prescription-claims database maintained by the Social Insurance Institution of Finland [4], we identified 53,943 statin initiators (mean age, 62.0 years; 44.2% female) among community-dwelling patients with diabetes, aged 45–75, between January 1, 1995, and December 31, 2006. Initiators had no statin purchases in the year before the start of follow-up. MCEs included acute myocardial infarctions, subendocardial infarctions, and coronary revascularization procedures captured through the national hospital discharge register. The follow-up ended with the occurrence of an MCE, death, permanent institutionalization, or December 31, 2007, whichever came first. During a mean of 4.0 years of follow-up, there were 6,270 hospitalizations for MCEs (2,370 for infarctions, 3,580 for revascularization procedures, 320 with both diagnoses) among patients with diabetes, corresponding to an incidence rate of 2.9 per 100 person-years. Almost half (46.4%) of the events, however, occurred within 365 days of statin initiation, resulting in an incidence rate of 5.9 per 100 person-years during the first year. Of these early MCEs, 67.1% were coronary revascularization procedures. Monthly MCE rates, especially revascularization procedure rates, declined steeply, stabilizing by the ninth month of therapy (Fig. 1). The MCE rates during the first months of therapy were higher among statin initiators in 1995–1998 (n=9,971) than among initiators in 2004–2006 (n=17,668). This probably reflects the shift in statin initiators’ baseline risk, as the proportion of initiators with coronary artery disease (CAD) decreased to 10.7 from 36.3% during the same period. M. J. Korhonen :R. Huupponen : P. Ruokoniemi : A. Helin-Salmivaara Pharmacology, Drug Development and Therapeutics, University of Turku, 20014 Turku, Finland

Acetazolamide may provoke cyclosporine toxicity—a case report

We describe a 58-year-old female renal transplantant recipient with standard cyclosporine-based immunosuppression who developed a potentially toxic cyclosporine concentration of 265 ng/ml after having started acetazolamide for severe glaucoma. The mechanism explaining the interaction between acetazolamide and cyclosporine remains unknown, but the concomitant use of these agents is not uncommon. The follow-up of cyclosporine concentrations is necessary, and the reduction of the cyclosporine dose is likely to be needed when patients taking cyclosporine are started with acetazolamide.