Marjaana Koponen

From prescription drug purchases to drug use periods – a second generation method (PRE2DUP)

BackgroundDatabases of prescription drug purchases are now widely used in pharmacoepidemiologic studies. Several methods have been used to generate drug use periods from drug purchases to investigate various aspects; e.g., to study associations between exposure and outcome. Typically, such methods have been fairly simplistic, with fixed assumptions of drug use pattern and or dose (for example, the assumed usage of 1 tablet per day). This paper describes a novel PRE2DUP method that constructs drug use periods from purchase histories, and verified by a validation based on an expert evaluation of the drug use periods generated by the method.MethodsThe PRE2DUP method is a novel approach based on mathematical modelling of personal drug purchasing behaviors. The method uses a decision procedure that includes each person’s purchase history for each ATC code, processed in a chronological order. The method constructs exposure time periods and estimates the dose used during the period by considering the purchased amount in Defined Daily Doses (DDDs), which is recorded in the prescription register database. This method takes account of stockpiling of drugs, personal purchasing pattern; i.e., regularity of the purchases, and periods of hospital or nursing home care where drug use is not recorded in the prescription register. The method can be applied to a variety of drug classes with different doses and use patterns by controlling restriction parameters for each ATC class, or even each drug package. In the presented example, the PRE2DUP method was applied to a register-based MEDALZ-2005 study cohort. All drug purchases (3,793,085) recorded in the Finnish prescription register between 2002 and 2009 for persons with Alzheimer’s disease (28,093) were included.ResultsResults of the expert-opinion based validation indicate that PRE2DUP method creates drug use periods with a relatively high correctness. Drugs with varying patterns of use and drugs used on a short-term basis only require more precise parameters.ConclusionsPRE2DUP method gives highly accurate drug use periods for most drug classes, especially those meant for long-term use.

High prevalence of psychotropic drug use among persons with and without Alzheimer's disease in Finnish nationwide cohort

Psychotropic drugs are used for treatment of behavioral and psychological symptoms of dementia (BPSD) although they are associated with serious adverse drug events. Objective of our study was to investigate prevalence of psychotropic drug use one year after diagnoses of Alzheimers disease (AD), to compare prevalence to persons without AD and to assess changes in prevalence over time. Data from the MEDALZ (Medication use and Alzheimers disease) cohort was utilized in the study including all 69,080 community-dwelling persons with new diagnosis of AD during years 2005-2011 in Finland. Four age-, gender- and region of residence-matched persons without AD were identified for each case. Register-based data included prescription drug purchases and comorbidities from Special Reimbursement Register. Annual prevalence of psychotropic drug use one year after diagnosis was determined for each person. Psychotropic drugs were used by 53% of persons with AD compared with 33% of persons without AD during one year after diagnoses. Persons with AD were six times more likely to use antipsychotics and three times more likely to use antidepressants whereas benzodiazepine and related drug (BZDR) use was comparable between persons with and without AD. According to year of AD diagnoses during 2005-2011, antipsychotic use increased from 18% to 20% (p<0.0001) and BZDR use declined from 31% to 26% (p<0.0001) among persons with AD. Widespread utilization of psychotropic drugs was observed among persons with AD. Despite safety warnings of antipsychotic use for BPSD, antipsychotic use increased from 2005 to 2011 among newly diagnosed persons with AD in Finland.

Impact of high risk drug use on hospitalization and mortality in older people with and without Alzheimer's disease: a national population cohort study.

Background Evidence is lacking about outcomes associated with the cumulative use of anticholinergic and sedative drugs in people with Alzheimer’s disease (AD). This retrospective cohort study investigated the relationship between cumulative exposure to anticholinergic and sedative drugs and hospitalization and mortality in people with and without AD in Finland. Methods Community-dwelling people aged 65 years and over, with AD on December 31st 2005 (n = 16,603) and individually matched (n = 16,603) comparison persons (age, sex, region of residence) were identified by the Social Insurance Institution of Finland. Drug utilization data were extracted from the Finnish National Prescription Register. Exposure to anticholinergic and sedative drugs was defined using the Drug Burden Index (DBI). Hospitalization and mortality data were extracted from national registers. Cox and zero-inflated negative binomial analyses were used to investigate the relationship between DBI and hospitalization and mortality over a one-year follow-up. Results In total, 5.8% of people with AD and 3.7% without AD died during 2006. For every unit increase in DBI, the adjusted hazard ratio for mortality was 1.21 (95% confidence intervals [CI]: 1.09–1.33) among people with AD, and 1.37 (95%CI: 1.20–1.56) among people without AD. Overall, 44.3% of people with AD and 33.4% without AD were hospitalized. When using no DBI exposure as the reference group, the adjusted incidence rate ratio for length of hospital stay among high DBI group (≥1) in people with AD was 1.15 (95%CI: 1.05–1.26) and 1.63 (95%CI: 1.41–1.88) in people without AD. Conclusion There is a dose-response relationship between cumulative anticholinergic and sedative drug use and hospitalization and mortality in people with and without AD.

Use of existing data sources in clinical epidemiology: Finnish health care registers in Alzheimer's disease research - the Medication use among persons with Alzheimer's disease (MEDALZ-2005) study.

Memory diseases are the most important determinant of health care service use and quality of life among older individuals. Adverse effects of medication are common among older people, but this age group is underrepresented in clinical trials. Finnish statutory health care and prescription registers, together with personal identification numbers (PINs) and a tax-supported public health plan covering all citizens provide excellent opportunities for epidemiological research. We used routinely collected data from the Finnish health care system to establish the Medication use among persons with Alzheimer’s disease (MedAlz-2005) cohort. This cohort study will be used to assess medication use and its effects on health status and hospitalization among persons with Alzheimer’s disease (Ad). The cohort includes all community-dwelling persons who had a clinically verified diagnosis of Ad, resided in Finland, and were alive on December 31, 2005 and a matched comparison person for each affected individual. data on purchased prescription medicines (1995–2009), inpatient hospital admissions (1972–2009), outpatient visits (1995–2009), details on diagnosed cancers (1972–2009), and mortality (until October 2010) are available for the whole cohort. This paper describes how this data can be utilized in etiological research and the assessment of health care service use, drug utilization, and associated adverse outcomes in a particularly vulnerable group that is often underrepresented in clinical trials.

Antidementia drug use among community-dwelling individuals with Alzheimer’s disease in Finland: a nationwide register-based study

The objective of this study was to investigate the prevalence of acetylcholinesterase inhibitor (AChEI) and memantine use, duration of treatment, concomitant use of these drugs, and factors associated with the discontinuation of AChEI therapy during 2006–2009. We utilized data from a nationwide sample of community-dwelling individuals with a clinically verified Alzheimer’s disease diagnosed during the year 2005 (n=6858) as a part of the MEDALZ-2005 study. During the 4-year follow-up, 84% used AChEI and 47% used memantine. Altogether, 22% of the sample used both drugs concomitantly. The median duration of the first AChEI use period was 860 (interquartile range 295–1458) days and 1103 (interquartile range 489–1487) days for the total duration of AChEI use. Although 20% of the AChEI users discontinued the use during the first year, over half of them restarted later. The risk of discontinuation was higher for rivastigmine [hazard ratio 1.34 (confidence interval 1.22–1.48)] and galantamine users [hazard ratio 1.23 (confidence interval 1.15–1.37)] compared with donepezil users in the adjusted model. In conclusion, median time for AChEI use was over 3 years and every fifth Alzheimer’s disease patient used AChEI and memantine concomitantly during the follow-up. The low rate of discontinuation is consistent with the Finnish Care Guideline but in contrast to the results reported from many other countries.

Prevalence of Analgesic Use and Pain in People with and without Dementia or Cognitive Impairment in Aged Care Facilities: A Systematic Review and Meta-Analysis

Pain is a frequent cause of discomfort and distress in residents in residential aged care facilities (RACFs). Despite the benefits of adequate pain management, there is inconsistency in the literature regarding analgesic use and pain in residents with dementia. The aim of this systematic review was to determine the prevalence of analgesic drug use among residents with and without dementia or cognitive impairment in RACFs. A systematic search of MEDLINE and EMBASE (inception to January 2014) was conducted using Medical Subject Headings and Emtree terms, respectively. Studies were included if they reported prevalence of analgesic use for residents both with and without dementia within the same study. Data extraction and quality assessment was performed independently by two investigators. Data on the prevalence of analgesic use, pain and painful conditions were extracted. Meta-analyses were performed using random effect models. The 7 included studies were of high quality (≥ 5 out of 7 on the adapted Newcastle-Ottawa Scale). Analgesic use in residents with and without dementia or cognitive impairment ranged from 20.2% to 61.2% and 38.8% to 79.6%, respectively. Paracetamol was the most prevalent analgesic in people with and without dementia. Residents with dementia or cognitive impairment had a significantly lower prevalence of analgesic use (odds ratio [OR] 0.576, 95% confidence interval [CI] = 0.406-0.816) and of self-reported and clinician-observed pain (OR 0.355, 95% CI = 0.278-0.454) than residents without cognitive impairment, despite a comparable prevalence of painful conditions. These findings may indicate under-reporting and under-detection of pain in persons with dementia, and subsequent suboptimal treatment.

Cohort profile: the Finnish Medication and Alzheimer's disease (MEDALZ) study

Purpose The aim of the Medicine use and Alzheimers disease (MEDALZ) study is to investigate the changes in medication and healthcare service use among persons with Alzheimers disease (AD) and to evaluate the safety and effectiveness of medications in this group. This is important, because the number of persons with AD is rapidly growing and even though they are a particularly vulnerable patient group, the number of representative, large-scale studies with adequate follow-up time is limited. Participants MEDALZ contains all residents of Finland who received a clinically verified diagnosis of AD between 2005 and 2011 and were community-dwelling at the time of diagnosis (N=70 719). The diagnosis is based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association (NINCS-ADRDA) and Diagnostic and Statistical Manual Fourth Edition (DSM-IV) criteria for Alzheimers disease. The cohort contains socioeconomic data (education, occupational status and taxable income, 1972–2012) and causes of death (2005–2012), data from the prescription register (1995–2012), the special reimbursement register (1972–2012) and the hospital discharge register (1972–2012). Future updates are planned. The average age was 80.1 years (range 34.5–104.6 years). The majority of cohort (65.2%) was women. Currently, the average length of follow-up after AD diagnosis is 3.1 years and altogether 26 045 (36.8%) persons have died during the follow-up. Findings Altogether 53% of the cohort had used psychotropic drugs within 1 year after AD diagnoses. The initiation rate of for example, benzodiazepines and related drugs and antidepressants began to increase already before AD diagnosis. Future plans We are currently assessing if these, and other commonly used medications are related to adverse events such as death, hip fractures, head injuries and pneumonia.

Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons

Background PRE2DUP is a modeling method that generates drug use periods (ie, when drug use started and ended) from drug purchases recorded in dispensing-based register data. It is based on the evaluation of personal drug purchasing patterns and considers hospital stays, possible stockpiling of drugs, and package information. Objective The objective of this study was to investigate person-level agreement between self-reported drug use in the interview and drug use modeled from dispensing data with PRE2DUP method for various drug classes used by older persons. Methods Self-reported drug use was assessed from the GeMS Study including a random sample of persons aged ≥75 years from the city of Kuopio, Finland, in 2006. Drug purchases recorded in the Prescription register data of these persons were modeled to determine drug use periods with PRE2DUP modeling method. Agreement between self-reported drug use on the interview date and drug use calculated from register-based data was compared in order to find the frequently used drugs and drug classes, which was evaluated by Cohen’s kappa. Kappa values 0.61–0.80 were considered to represent good and 0.81–1.00 as very good agreement. Results Among 569 participants with mean age of 82 years, the agreement between interview and register data was very good for 75% and very good or good for 93% of the studied drugs or drug classes. Good or very good agreement was observed for drugs that are typically used on regular bases, whereas “as needed” drugs represented poorer results. Conclusion PRE2DUP modeling method validly describes regular drug use among older persons. For most of drug classes investigated, PRE2DUP-modeled register data described drug use as well as interview-based data which are more time-consuming to collect. Further studies should be conducted by comparing it with other methods and in different drug user populations.

Systematic Review: Representativeness of Participants in RCTs of Acetylcholinesterase Inhibitors.

Objective To determine whether there are differences in age and sex distribution and presence of comorbidities between participants included in randomized controlled trials of acetylcholinesterase inhibitors and nationwide cohort of persons with Alzheimer’s disease. Methods PubMed, Scopus and Cochrane Library databases were searched for original articles from their inception to January 4, 2015. Double-blind randomized controlled trials with donepezil, rivastigmine or galantamine compared to placebo in participants with Alzheimer’s disease were included. Data from a nationwide cohort of persons with clinically verified diagnoses of Alzheimer’s disease was defined as a reference population. Results 128 full-text articles were assessed for eligibility, 31 of them fulfilled criteria. Mean age of participants in randomized controlled trials (n = 15,032) was 5.8 years lower (95% CI 5.7 to 5.9, P < 0.001), compared to the mean age of 79.7 years in the reference population with Alzheimer’s disease (n = 28,093). Most of the articles did not report age distribution of participants. The proportion of women was 63.2% (9,475/14,991) in randomized controlled trials and 67.8% (19,043/28,093) (P < 0.001) in the reference population. Information on comorbidities and use of concomitant drugs were lacking or poorly reported in most articles. Conclusions There is a discrepancy between participants in randomized controlled trials of acetylcholinesterase inhibitors and real-life population with Alzheimer’s disease. Participants in randomized controlled trials were significantly younger. Further, more detailed reporting of age distribution, comorbidities and concomitant drugs would be important information for clinicians when evaluating conclusions from randomized controlled trials to real-life practice. The existing recommendations of inclusion of older people should be followed to ensure safe pharmacotherapy for older people.

The Incidence of Benzodiazepine and Related Drug Use in Persons with and without Alzheimer's Disease.

BACKGROUND Benzodiazepines and related drugs (BZDR) are occasionally used to treat certain symptoms of Alzheimers disease (AD). However, the risks related to BZDR use are high in older persons. Although frequent BZDR use has been reported in persons with AD, no previous study has focused specifically on the incidence of BZDR use in this population. OBJECTIVE We investigated the incidence of BZDR use in persons with and without AD during a five-year follow-up. METHODS The Finnish nationwide, register-based MEDALZ cohort includes all AD cases who received a clinically verified AD diagnosis in 2005-2011 (n = 70,718) and their matched comparison persons. Incidence of BZDR, including benzodiazepines (lorazepam, oxazepam, temazepam, alprazolam, chlordiazepoxide, diazepam, and nitrazepam) and Z-drugs (zolpidem and zopiclone), use was investigated in the cohort from two years before to three years after the diagnosis of AD. Further, initial BZDRs were investigated. RESULTS The incidence of BZDR use was higher in persons with AD starting from 12 months before the diagnosis and peaked at six months after the diagnosis of AD (incidence rate ratio [IRR] = 2.6, 95% confidence interval [CI] = 2.5-2.8). Benzodiazepines were more frequently initiated by persons with AD, with the incidence peaking at six months after the diagnosis (IRR = 4.5, 95% CI = 4.1-4.9) and remaining over three times higher than in comparison persons until three years after the diagnosis. CONCLUSION Early symptomatic treatment with BZDRs is contrary to AD treatment guidelines. As BZDRs impair cognition, the observed early treatment with BZDRs may complicate the monitoring of AD treatment effectiveness.