Arja Helin-Salmivaara

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.

Risk of serious upper gastrointestinal events with concurrent use of NSAIDs and SSRIs: a case-control study in the general population

ObjectivesTo study the risk of serious upper gastrointestinal (GI) events associated with the concurrent use of selective serotonin re-uptake inhibitors (SSRIs) and different types of non-steroidal anti-inflammatory drugs (NSAIDs).MethodsThis was a nationwide, register-based matched case-control study on non-institutionalized residents of Finland during the period 2000–2004. Patient-cases with serious upper GI events (n = 9191) were drawn from the Hospital Discharge Register, and individually matched controls (n = 41,780) were drawn from the Population Register. Logistic regression was applied in the data analysis, and adjustments were made for various co-morbidities and the use of other drugs associated with the risk of serious upper GI event.ResultsThe adjusted odds ratio (AOR) of serious upper GI events for SSRI use compared to non-use of SSRIs or NSAIDs was 1.30 [95% confidence interval (95%CI: 1.13–1.50)], and the AOR for concurrent SSRI and NSAID use compared to the non-use of either drug was 4.19 (95%CI: 3.30–5.31). The AOR of upper GI events for the concurrent use of SSRIs with NSAIDs compared to patients using NSAIDs only was 1.57 (95%CI: 1.24–1.99). The respective AOR for traditional, non-selective NSAIDs was 1.77 (95%CI: 1.31–2.38), for semi-selective NSAIDs (nimesulide, nabumetone, meloxicam, and etodolac) 1.30 (95%CI: 0.76–2.24) and for COX-2 selective NSAIDs 1.33 (95%CI: 0.70–2.50).ConclusionsThe concurrent use of SSRIs and NSAIDs is associated with a moderate excess relative risk of a serious upper GI event when compared with NSAID use alone.

Impact of restricted reimbursement on the use of statins in Finland: a register-based study.

Objectives:New and expensive medicines are a driving force behind growth in medicine costs, and policies promoting use of less expensive products have been widely introduced. This study investigated the short-term consequences of the restricted reimbursement of expensive statins (atorvastatin and rosuvastatin) on the use of statins in Finland. Methods:Data on patients purchasing atorvastatin, rosuvastatin, or simvastatin in 2002–2007 were retrieved from the nationwide Prescription Register. Outcome measures included the time trend in the numbers of purchasers and initiators of different statins, the morbidities of new users before and after the new policy, and the proportion of users of expensive statins switching to other statins. Results:After the restriction, the numbers of purchasers of atorvastatin and rosuvastatin dropped, and atorvastatin and rosuvastatin were seldom prescribed as first-line therapy. Before the restriction, 20.9% of new users of atorvastatin and 18.4% of those of rosuvastatin had either coronary artery disease or familial hyperlipidemia. After the restriction the corresponding figures were 28.7% and 26.8%. After the restriction new users of atorvastatin and rosuvastatin were also more likely to use other cardiovascular medicines or antidiabetics or to have previous statin purchases. A total of 57.6% of those using atorvastatin and 49.2% of those using rosuvastatin before the restriction switched to a less expensive statin. Conclusions:Restricted reimbursement of expensive statins decreased their use. It seems that after the policy new statin treatments have channeled appropriately. Although it is likely that the cost-containment aim of the policy was reached, health and long-term effects are not known.

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.

Risk of upper gastrointestinal events with the use of various NSAIDs: A case-control study in a general population

Objective. The gastrointestinal (GI) safety of different non-steroidal anti-inflammatory drugs (NSAIDs) in a real-life setting remains ill defined. The aim of this study was to examine the risk of upper GI events associated with various NSAIDs in a general population. Material and methods. A nationwide, register-based, matched case-control study was carried out in outpatient residents of Finland in 2000–04. Cases with upper GI events (n=9191) were drawn from the Hospital Discharge Register and individually matched to controls (n=41,780) from the Population Register. Results. The semi-selective NSAIDs (nimesulide, nabumetone, meloxicam, etodolac) had the highest odds ratio for upper GI events even after adjusting for various potential confounders (adjusted odds ratio (AOR) 3.63; 95% CI 3.08–4.28), followed by non-selective (2.98; 2.70–3.29) and COX-2 selective NSAIDs (2.53; 2.09–3.07). When the current use of semi-selective NSAIDs was compared with that of non-selective and COX-2 selective NSAIDs, the AORs were 1.54 (1.13–2.09) and 1.67 (1.10–2.53), respectively. The AORs for the use of COX-2 selective NSAIDs did not differ statistically from the non-selective NSAIDs (AOR 0.92; 0.65–1.31). The AORs for individual NSAIDs varied across and within categories. Conclusions. As a group, the GI safety of the COX-2 selective NSAIDs was not demonstrated as definitively superior to non-selective NSAIDs. Semi-selective NSAIDs do not seem to offer any GI advantage over other NSAIDs.

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.

Impact of Statin Adherence on Cardiovascular Morbidity and All-Cause Mortality in the Primary Prevention of Cardiovascular Disease: A Population-Based Cohort Study in Finland.

OBJECTIVES To assess the extent to which adherence to statins is associated with the incidence of cardiovascular (CV) events and all-cause mortality in the primary prevention of CV diseases and whether different analytical approaches influence the observed associations. METHODS This population-based cohort study used data from Finnish registers. The cohort included 97,575 new statin users aged 45 to 75 years in 2001 to 2004 with no CV diseases at baseline. Exposure was defined as adherence to statins (proportion of days covered [PDC]). The primary outcome was any CV event or death during a 3-year follow-up. Different analytical approaches, including multivariable-adjusted Cox regression, inverse probability weighting with time-varying adherence, and propensity score calibration, were used. RESULTS During the first year of follow-up, 53% displayed good (PDC ≥80%), 26% had intermediate (PDC 40%-79%), and 21% exhibited poor (PDC <40%) adherence. After adjustment for sociodemographic and clinical covariates, a 25% relative risk reduction (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.71-0.79) was observed in the rate of any CV event or death among good versus poor adherers. Good adherers also had a lower incidence than poor adherers of acute coronary syndrome (HR 0.56; 95% CI 0.49-0.65) and acute cerebrovascular disease events (HR 0.67; 95% CI 0.60-0.76). The different analytical approaches achieved comparable results for all the outcomes. CONCLUSIONS The incidence of CV events and mortality was higher in poor versus good adherers. Different analytical methods that took into account changes in adherence and confounding at baseline did not appreciably affect the results.

Frequent prescribing of drugs with potential gastrointestinal toxicity among continuous users of non-steroidal anti-inflammatory drugs

ObjectiveA number of drugs used concurrently with non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of gastrointestinal (GI) haemorrhage. We studied the prescribing of NSAIDs with corticosteroids, oral anticoagulants or selective serotonin re-uptake inhibitors (SSRIs), as well as the use of gastroprotection among continuous and non-continuous users of NSAIDs in Finland.MethodsConcurrent use of various drugs was analysed in a nested case-control study in a population-based cohort of NSAID users in 2000 using data in the National Prescription Database.ResultsPrescribing of any other drug with the potential to increase the risk of GI bleeding with NSAIDs was five times [5.2; 95% confidence interval (CI) 4.7–5.9] more common among continuous than non-continuous NSAID users, and the odds ratio for oral corticosteroids was 8.0 (95% CI 6.6–9.6). Of patients using continuous NSAIDs with oral corticosteroids, 73.3% had rheumatoid arthritis (RA). After excluding RA patients, the odds ratio remained high (4.5; 95% CI 3.3–6.1) and at the same level as for SSRIs (3.7; 3.1–4.4). Gastroprotective drugs were prescribed for 6.8% of the continuous users of NSAIDs alone, and for 20.4% of patients taking any of the studied drug combinations with NSAIDs. The continuous users of NSAIDs alone had gastroprotection 2.9 (2.5–3.3) times more often than other users of NSAIDs. With drug combinations (NSAID+corticosteroid, NSAID+SSRI, NSAID+anticoagulants), the use of gastroprotection did not differ from patients using lower amounts of NSAIDs.ConclusionsWhen prescribing NSAIDs, situations leading to habitual use should be avoided, potential complications due to clustering of risk factors recognised, and gastroprotection prescribed for patients with increased risk of GI haemorrhage.

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.