Incidence of ADHD medication use among Finnish children and adolescents in 2008-2019: a need for practice changes?

AIMS: This study examined the incidence of attention-deficit/hyperactivity disorder medication among children and adolescents by sex and age group in Finland during 2008-2019. METHODS: The data on children and adolescents aged 6-18 years receiving reimbursement for any attention-deficit/hyperactivity disorder medication was collected from the nationwide register on reimbursed purchases. The incidence was calculated as a ratio of the number of new users and the number of age and sex-matched population at risk. Negative binomial models were used to calculate rate ratios (RRs). RESULTS: In 2019, the incidence of attention-deficit/hyperactivity disorder medication was 13.4 per 1000 boys and 4.8 per 1000 girls. Among boys, the incidence became 3.7 times greater during the observed years (RR 95% confidence interval (CI) 2.0, 6.5, P<0.0001), whereas in girls it was 7.6 times greater (RR 95% CI 2.1, 27.4, P=0.0019). The boys had 2.8 times the incidence rate compared with the girls (RR 95% CI 2.2, 3.6, P<0.0001). The increase was associated with age only among boys (P=0.0001). The highest incidence rate 23.4 per 1000 individuals (95% CI 22.5, 24.4) was found in 2019 among 6-8-year-old boys. CONCLUSIONS: The incidence of attention-deficit/hyperactivity disorder medication use among children and adolescents increased significantly in Finland during the study period. Incidence was higher among boys, but the increase was greater among girls. The most common group to start attention-deficit/hyperactivity disorder medication was 6-8-year-old boys. These findings warrant critical evaluation of the diagnostic and treatment policies currently available in Finland for the treatment of attention-deficit/hyperactivity disorder and related symptoms.

Is There Any Research Evidence Beyond Surveys and Opinion Polls on Automatic Substitution of Biological Medicines? A Systematic Review.

BACKGROUND: Biosimilars are expected to decrease growing health care expenditures. Given that uptake of biosimilars has been modest, automatic substitution has been suggested to increase their use, but the practice is not yet allowed or implemented in many jurisdictions. METHODS: A systematic review was performed by searching databases Scopus, Medline (Ovid), CINAHL, and Web of Science. Peer-reviewed, original studies written in English and published during the period January 1, 2006 to April 24, 2021 reporting any interventions, pilots or any other studies including experiences or perceptions of any relevant stakeholders on automatic substitution of biologics were included without limitation by setting or geography. The quality of the included studies were evaluated by pre-determined criteria. RESULTS: Altogether, 27 studies fulfilled the inclusion criteria, of which 23 were surveys, and four semi-structured interviews reporting mainly stakeholders' perceptions on automatic substitution. Most of the studies (56%, 15/27) were from Europe. Studies were conducted among prescribers (n = 12), pharmacists (n = 5), patients (n = 4), payers (n = 1), and mixed stakeholders (n = 5). The primary objective of the majority (81%, 22/27) of the studies was to investigate some other biosimilar topic than automatic substitution. The reported perceptions of substitution were mainly negative. Studies evaluating risks, safety or effectiveness, or reporting real-life experiences of biologic substitution were lacking except one intervention and two prospective risk management studies. The overall quality of the studies was low to moderate, and the results were not generalizable due to convenience sampling not representing the populations of interest, and low response rates. CONCLUSIONS: The current research evidence on the automatic substitution of biologics is scarce and of low to moderate quality, reflecting low stakeholder knowledge and their cautious attitude towards biosimilars. The safe and efficient implementation of automatic substitution requires well-designed practices, pilot studies, and evolving legislation.

Medication safety risks to be managed in national implementation of automatic substitution of biological medicines: a qualitative study.

OBJECTIVES: To explore relevant Finnish stakeholders' perceptions on the automatic substitution of biological medicines with particular focus on medication safety and issues that need to be considered to create an appropriate model for automatic biological product substitution. DESIGN: Qualitative interview study. METHODS: Data were collected in semistructured individual (n=17), pair (n=7) and group (n=8) interviews (32 interviews, 62 participants) in 2018. Participants represented a wide range of stakeholders involved in the pharmacotherapy process: community pharmacists (n=8 interviews), authorities (n=7), prescribers (n=7), pharmaceutical industry and wholesalers (n=6), patients/customers (n=2), hospital pharmacists (n=1) and nurses (n=1). Inductive content analysis was performed. RESULTS: Benefits of automatic substitution were identified as cost savings, more patients receiving biological treatments and enhanced continuity of treatment. Six major risk categories were identified: (1) the patient's medication is interrupted or complicated temporarily or permanently, (2) the patient uses two products with the same active substance, (3) the traceability of the product is compromised, (4) the patient cannot get into healthcare in case of problems, (5) the patient does not receive substitution-related advice from a pharmacy and (6) the patient is distracted by the support material he/she receives. Several risk mitigation measures were commonly mentioned: medication and device counselling by pharmacists (n=23), infrequent substitution interval (n=15) and better knowledge on biosimilars among healthcare providers (n=13). CONCLUSION: Automatic substitution of biologics is associated with risks that should be prospectively managed before implementing the procedure. The substitution also introduces new tasks and communication needs to those involved in actual medication use process, particularly to community pharmacists who will be responsible for substitution and counselling the patients.

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

PURPOSE: We aimed to quantify for the first time the relationship between statin adherence and ischemic stroke (IS) in patients with diabetes. METHODS: Using Finnish health registers, we assembled a cohort of 52 868 statin initiators with diabetes in 1995-2006. We conducted a nested case-control analysis matching cases with IS with up to four controls for age, sex, date of statin initiation and follow-up duration. Adjusted rate ratios for IS were estimated with conditional logistic regression. Additional potential confounders were considered with inverse probability weighting and the role of unmeasured confounding using external adjustment. Statin adherence was measured as the proportion of days covered (PDC). RESULTS: Among 1703 cases and 6799 controls, good adherence to statins (PDC ≥ 80%) was associated with a 23% decreased incidence of IS (95%CI 14-32%) compared with poor adherence (PDC < 80%). This association remained broadly unchanged when stratified by sex, age, history of atherosclerotic cardiovascular disease or IS. There was a dose-response relationship between adherence level and the risk of IS (RR 0.63 [0.53-0.75] for PDC ≥ 80% versus PDC < 20%, P for trend <0.0001). Among patients with good adherence, those initiating with low intensity statin therapy had a 15% lower incidence (95%CI 2-27%) and those initiating with moderate intensity therapy a 29% lower incidence (16-41%) of IS compared with those with poor adherence who initiated with low intensity therapy. Our sensitivity analyses supported the robustness of the results. CONCLUSIONS: In diabetes, poor statin adherence may considerably increase the risk of IS both in primary and secondary prevention of IS.

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.

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.

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily.

OBJECTIVES: To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC). METHODS: Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson's disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included Cmin, Cmax, Cmax - Cmin, AUC, t(1/2), and tmax. RESULTS: In healthy volunteers and PD patients, mean trough levels (Cmin), Cmax, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to Cmin, Cmax, and AUC, differences between the treatments in variability of levodopa concentrations (Cmax - Cmin) were less consistent. CONCLUSIONS: The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson's disease using similar dosing regimens.

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.

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.

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.

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.