Effect of antipsychotics on mortality risk in patients with dementia with and without comorbidities.

BACKGROUND: We investigated the mortality risk associated with the initiation of antipsychotic treatment among patients with dementia and whether comorbidities related to the cardiovascular system and diabetes interact with antipsychotic treatment to increase the mortality risk beyond the risk of death independently associated with antipsychotics and comorbidity alone. METHODS: We designed a matched cohort study using nationwide registry data. All Danish residents aged 65-95 years diagnosed with dementia between 2009 and 2014 were included. Dementia was assessed as a first-time registered dementia diagnosis in the Danish National Patient Register or the Danish Psychiatric Central Research Register and/or a first-time prescription for antidementia medication. Patients exposed to antipsychotics were matched with up to three unexposed patients. Cox proportional hazards models were used to compare rates of death within 180 days after the initiation of antipsychotic treatment. The models were adjusted for potential confounders. Analyses were stratified for diabetes, heart disease, and cerebrovascular disease, and we calculated the relative excess risk due to interaction (RERI). RESULTS: The study cohort included 8244 exposed patients and 24,730 unexposed patients. A total of 5938 patients died during the first 180 days of follow-up. Patients exposed to antipsychotics had a significantly higher adjusted risk of death (hazard ratio: 1.35, 95% confidence interval: 1.27-1.43) than unexposed patients. Crude mortality rates were higher among patients with heart disease and diabetes when antipsychotic treatment was initiated compared with patients without comorbidities. Relative risk estimates did not differ between patients with and without heart disease, cerebrovascular disease, and diabetes, and RERI suggested no positive additive interaction. Risk analysis suggested higher mortality in patients without cerebrovascular disease who initiated antipsychotics. CONCLUSION: This nationwide study adds to the evidence that antipsychotic treatment is associated with increased mortality and suggests that attention should be paid to all initiators of antipsychotics irrespective of cardiovascular disease and diabetes.

Causes of Death in People with Dementia from 2002 to 2015: A Nationwide Study.

BACKGROUND: Dementia is associated with increased mortality. However, it is not clear whether causes of death in people with dementia have changed over time. OBJECTIVE: To investigate if causes of death changed over time in people with dementia compared to the general elderly population. METHODS: We included longitudinal data from nationwide registries on all Danish residents aged≥65 years to 110 years who died between 2002 to 2015. We assessed the annual frequency of dementia-related deaths (defined as a dementia diagnosis registered as a cause of death) and of underlying causes of death in people registered with dementia compared to the general elderly population. RESULTS: From 2002 to 2015, 621,826 people died, of whom 103,785 were diagnosed with dementia. During this period, the percentage of dementia-related deaths increased from 10.1% to 15.2% in women, and from 6.3% to 9.5% in men in the general elderly population. From 2002 to 2015, dementia became the leading, registered underlying cause of death in people diagnosed with dementia. Simultaneously, a marked decline in cardiovascular and cerebrovascular deaths was observed in people with and without dementia. CONCLUSION: This is the first study to investigate if the causes of death change over time in people diagnosed with dementia compared with the general elderly population. The increase in the registration of dementia as an underlying cause of death could reflect increasing awareness that dementia is fatal.

Risk of hospitalization and hip fracture associated with psychotropic polypharmacy in patients with dementia: A nationwide register-based study.

OBJECTIVE: To investigate the association of benzodiazepines and antidepressants on the risk of hospitalization and hip fracture in patients with dementia initiating antipsychotic drug treatment. METHODS: A register-based retrospective cohort study using data on all incident dementia cases (≥65 years) initiating antipsychotic treatment as monotherapy or in combination with benzodiazepines and/or antidepressants in Denmark from 2000 to 2015. The outcomes of interest were all-cause hospitalization and hip fracture. Cox proportional hazards models with adjustment for multiple variables were used to investigate risk of hospitalization and hip fracture within 180 days. RESULTS: The risk of all-cause hospitalization during 180-days follow-up was significantly increased by 55% (adjusted HR: 1.55, 95% CI: 1.29-1.86, p < 0.0001), when antipsychotic use was combined with benzodiazepines, when compared to antipsychotic monotherapy. The association between the combination of antipsychotics and benzodiazepines with the risk of hip fracture did not reach statistical significance (adjusted HR: 1.50, 95% CI: 0.99-2.26, p = 0.0534). CONCLUSIONS: The observed increased risk of all-cause hospitalization and hip fracture may indicate increased drug-related adverse events. Thus, careful and regular monitoring is needed to assess response to treatment and decrease the risk of adverse events, when antipsychotics are combined with BZDs, albeit confounding cannot be fully excluded within the current design.

Dementia increases mortality beyond effects of comorbid conditions: A national registry-based cohort study.

BACKGROUND AND PURPOSE: Mortality is known to be markedly increased in people with dementia. However, the association between multiple chronic conditions and mortality in dementia is not well clarified. The aim of this study was to investigate the impact of somatic and psychiatric diseases on mortality in dementia compared with the general elderly population. METHODS: Using a cohort study design, nationwide registry data from 2006 to 2015 on dementia and psychiatric and somatic comorbidities defined by the Charlson Comorbidity Index (CCI) were linked. Impact of chronic conditions was assessed according to mortality rate ratios (MRRs) in all Danish residents aged ≥65 years with and without dementia. RESULTS: Our population comprised 1,518,917 people, of whom 114,109 people were registered with dementia. The MRRs was 2.70 (95% confidence interval 2.68, 2.72) in people with dementia after adjusting for sex, age, calendar year, and comorbidities. MRRs increased with higher CCI score, and when comparing people with a similar comorbidity load, MRRs were significantly higher for people with dementia. CONCLUSIONS: The comorbidity load was associated with increased mortality in both people with and without dementia. Mortality in dementia remained increased, even after adjusting for psychiatric and chronic somatic comorbidities. Our findings suggest that dementia disorders alone contribute to excess mortality, which may be further increased by comorbidities.

Mortality in Dementia from 1996 to 2015: A National Registry-Based Cohort Study.

BACKGROUND: It remains unclear whether the increased focus on improving healthcare and providing appropriate care for people with dementia has affected mortality. OBJECTIVE: To assess survival and to conduct a time trend analysis of annual mortality rate ratios (MRR) of dementia based on healthcare data from an entire national population. METHODS: We assessed survival and annual MRR in all residents of Denmark ≥65 years from 1996-2015 using longitudinal registry data on dementia status and demographics. For comparison, mortality and survival were calculated for acute ischemic heart disease (IHD) and cancer. RESULTS: The population comprised 1,999,366 people (17,541,315 person years). There were 165,716 people (529,629 person years) registered with dementia, 131,321 of whom died. From 1996-2015, the age-adjusted MRR for dementia declined (women: 2.76 to 2.05; men: 3.10 to 1.99) at a similar rate to elderly people without dementia. The sex-, age-, and calendar-year-adjusted MRR was 2.91 (95%CI: 2.90-2.93) for people with dementia. MRR declined significantly more for acute IHD and cancer. In people with dementia, the five-year survival for most age-groups was at a similar level or lower as that for acute IHD and cancer. CONCLUSION: Although mortality rates declined over the 20-year period, MRR stayed higher for people with dementia, while the MRR gap, compared with elderly people without dementia, remained unchanged. For the comparison, during the same period, the MRR gap narrowed between people with and without acute IHD and cancer. Consequently, initiatives for improving health and decreasing mortality in dementia are still highly relevant.

Association of Benzodiazepines and Antidepressants With 180-Day Mortality Among Patients With Dementia Receiving Antipsychotic Pharmacotherapy: A Nationwide Registry-Based Study.

OBJECTIVE: Antipsychotic drugs are known to increase mortality among patients with dementia. Many patients receive concomitant treatment with other psychotropic agents. The aim of this retrospective cohort study was to investigate the impact of benzodiazepines and antidepressants on the risk of death in patients with dementia initiating antipsychotic drug treatment. METHODS: Nationwide registry data on all incident dementia cases among individuals aged 65 years and older in Denmark between 2009 and 2013 for which antipsychotic treatment was initiated were used. The 180-day mortality was evaluated by crude and adjusted hazard ratios (HRs, including adjustment for somatic and psychiatric comorbidity, other prescription drugs, nursing home residency, and time since diagnosis), comparing periods of antipsychotic treatment with periods of concomitant treatment with benzodiazepines or antidepressants. RESULTS: Among 41,494 incident dementia cases, antipsychotic treatment was initiated for 10,291 (24.8%). After 3,140 people were excluded due to recent antipsychotic drug use or hospitalization, 7,151 people were included in the analysis. The total follow-up time during current antipsychotic treatment was 1,146 person-years, and 831 died during antipsychotic treatment. Compared with antipsychotic treatment alone, the risk of death increased during antipsychotic treatment in combination with benzodiazepines (adjusted HR = 2.19; 95% CI, 1.83-2.63), while there was a decreased risk of death during antipsychotic treatment in combination with antidepressants (adjusted HR = 0.61; 95% CI, 0.50-0.74). CONCLUSIONS: The diverse impact of concomitant use of benzodiazepines and antidepressants on mortality may be due to a direct drug-related effect. Alternatively, the findings could reflect differential mortality associated with different indications for therapy. Although the results cannot prove causality, and there may be residual confounding, clinicians should be cautious when considering the combination of antipsychotics and benzodiazepines in patients with dementia.

Declining incidence of dementia: A national registry-based study over 20 years.

INTRODUCTION: The aim of this study was to investigate the registry-based national time trends in incidence and prevalence rates of dementia from 1996 to 2015. METHODS: We assessed annual incidence and prevalence using longitudinal data from nationwide registries on dementia status and demographics on all residents ≥ 65 years old in Denmark. RESULTS: Our population comprised 2 million people, of whom 152,761 were diagnosed with dementia. The age- and sex-adjusted incidence rate increased, on average, by 9% annually from 1996 to 2003, followed by a 2% annual decline, while total prevalence increased during the whole period. DISCUSSION: This is the first study to report continuous time trends of incidence and prevalence in an entire national population. The incidence rate has declined steadily since 2003, while the total prevalence is still increasing. Future health care planning on prevention and treatment of dementia should take these findings into account.

Geographical Variation in the Diagnostic Rate and Quality of Dementia Diagnoses.

BACKGROUND: Early and accurate diagnosis of dementia opens the door to appropriate treatment, support, and counseling. Despite availability of evidence-based guidelines for diagnostic evaluation of dementia, the diagnostic rate in people with dementia is low and the quality of dementia diagnoses is unknown. OBJECTIVE: The overall aim of this register-based study was to analyze the quality of diagnostic evaluation of dementia by assessing nationwide geographical variations in a range of indicators. METHODS: A register-based cross-sectional study of the entire Danish population aged 65 years or older in 2015 was conducted. The surrogate indicators for diagnostic quality included 1) prevalence rates of dementia diagnoses, 2) incidence rates of dementia diagnoses, 3) age at first diagnosis of dementia, 4) medical specialty responsible for diagnosis, 5) diagnostic rate of dementia subtypes, and 6) use of anti-dementia medication. The indicators were compared across the five Danish regions. RESULTS: The national prevalence and incidence of registered dementia diagnoses was 3.0% and 0.5%, respectively. The proportion of patients diagnosed at a dementia specialist department ranged from 60.9% to 90.5% across the five regions, subtype specific diagnosis ranged from 45.3% to 75.5%, and use of anti-dementia medication ranged from 29.2% to 58.3%. CONCLUSION: The observed geographical variations in dementia diagnoses and treatment indicate inequality in the access to appropriate diagnostic evaluation and care for patients with dementia. Our findings call for more awareness of the benefits of timely diagnosis and for improvement in the quality of diagnostic evaluation of dementia.

Changes in the Prevalence of Polypharmacy in People with and without Dementia from 2000 to 2014: A Nationwide Study.

BACKGROUND: Polypharmacy, the use of multiple medications, has become increasingly widespread. Information on time trends in polypharmacy in people with dementia is limited, although they may be more susceptible to risks associated with polypharmacy. OBJECTIVE: To examine changes in the prevalence of polypharmacy and excessive polypharmacy in people with dementia compared to changes in people without dementia. METHODS: Repeated cross-sectional study of the entire Danish population aged≥65 from 2000 (n = 790,717) to 2014 (n = 1,028,377) using linked register data on diagnoses, filled prescriptions, and demographic data. Multivariate analyses were performed to explore changes in the prevalence of polypharmacy and excessive polypharmacy (≥5 and≥10 different prescription drugs). This was done before and after 2011 to examine whether increasing awareness of potential problems associated with polypharmacy has altered the trend. Estimates for people with and without dementia were compared. RESULTS: In people with dementia, the prevalence of polypharmacy increased from 47.3% to 69.4% from 2000 to 2011 and excessive polypharmacy from 7.4% to 20.9%. In people without dementia, polypharmacy increased from 22.7% to 36.1% and excessive polypharmacy from 3.5% to 7.7%. The increase was significantly more marked in people with dementia across all age groups. From 2011 to 2014, the prevalence of polypharmacy and excessive polypharmacy remained relatively stable: Polypharmacy decreased negligibly from 69.4% to 68.1% in people with dementia and from 36.1% to 35.2% in people without dementia. CONCLUSION: Although the increasing trend has halted, polypharmacy remains widespread in people with dementia. Further research is needed to explore possible implications.

Prolonged or serious conflicts at work and incident dementia: a 23-year follow-up of the Copenhagen City Heart Study.

PURPOSE: Only a few studies have investigated the impact of negative aspects of social relations on cognitive function, and they have shown mixed results. Conflicts at work are part of the negative aspects of social relations, but the impact of experiencing conflicts at work has not yet been investigated as a risk factor for dementia. Therefore, we investigated whether experiencing prolonged or serious conflicts with a supervisor or colleagues at work was associated with incident dementia in old age. METHODS: We analyzed data of 6,436 men and women from the third survey of the Copenhagen City Heart Study. At baseline in 1991-1994, the participants reported whether they had ever had a prolonged or serious conflict at work. The participants were followed until 2014. We used Poisson regression to estimate incidence rate ratios (IRR) and their 95% confidence intervals (CI). RESULTS: After adjusting for potential confounders, the IRR for dementia was 1.53 (95% CI 0.77-3.03) among participants who had reported having prolonged or serious conflicts both with a supervisor and colleagues compared with participants who had never had such conflicts. In separate analyses stratified by sex, the IRRs were 2.14 (95% Cl 0.97-4.71) for men and 0.98 (95% Cl 0.29-3.32) for women. CONCLUSIONS: Our findings did not support an overall association between experiencing prolonged or serious conflicts at work and incident dementia. However, because of the large differences in the point estimates for men and women, future research could aim at investigating potential sex differences regarding the association between conflicts at work and dementia.

Polypharmacy and Potentially Inappropriate Medication in People with Dementia: A Nationwide Study.

BACKGROUND: Polypharmacy (use of ≥5 different medications) and potentially inappropriate medication (PIM) are well-known risk factors for numerous negative health outcomes. However, the use of polypharmacy and PIM in people with dementia is not well-described. OBJECTIVE: To examine the prevalence of polypharmacy and PIM in older people with and without dementia in a nationwide population. METHODS: Cross-sectional study of the Danish population aged ≥65 in 2014 (n = 1,032,120) based on register data, including information on diagnoses and dispensed prescriptions. Polypharmacy and PIM use among people with (n = 35,476) and without dementia (n = 994,231) were compared, stratified by living situation and adjusted for age, sex, and comorbidity. The red-yellow-green list from the Danish Institute for Rational Pharmacotherapy and the German PRISCUS list were used to define PIM. RESULTS: People with dementia were more frequently exposed to polypharmacy (dementia: 62.6% versus no-dementia: 35.1%, p < 0.001) and likewise PIM (red-yellow-green: 45.0% versus 29.7%, p < 0.001; PRISCUS: 24.4% versus 13.2%, p < 0.001). After adjustments for age, sex, and comorbidity, the likelihood of polypharmacy and PIM was higher for community-dwelling people with dementia than without dementia (odds ratio (OR); [95% confidence interval (CI)] polypharmacy: 1.50 [1.45-1.55]; red-yellow-green: 1.27 [1.23-1.31]; PRISCUS: 1.25 [1.20-1.30]). In contrast, dementia slightly decreased the odds of polypharmacy and PIM in nursing home residents. CONCLUSION: Use of polypharmacy and PIM were widespread in the older population and more so in people with dementia. This could have negative implications for patient-safety and demonstrates the need for interventions to improve drug therapy in people with dementia.

Psychotropic Polypharmacy in Patients with Dementia: Prevalence and Predictors.

BACKGROUND: Antipsychotics and other psychotropics are frequently used to treat neuropsychiatric symptoms in patients with dementia, even though the evidence for effect is limited. Concerns have been raised about the safety of antipsychotics, but concomitant use of multiple psychotropic drug classes (psychotropic polypharmacy) may also pose a risk for patients. OBJECTIVE: To investigate the prevalence and predictors associated with use of psychotropic polypharmacy in patients with dementia. METHODS: A population-based study using nationwide registers. Patients with dementia were identified among all Danish residents ≥65 years on January 1, 2012. Data on prescriptions and comorbidity was included in the analysis. Overlapping prescriptions for different psychotropic drug classes were used to determine psychotropic polypharmacy. A multivariable logistic regression analysis was conducted to evaluate factors independently associated with the prescription of other psychotropic drug classes among patients already using antipsychotics. RESULTS: Among all patients registered with dementia (34,553), 25.3% (8,728) used ≥2 psychotropic drugs. Among patients treated with antipsychotics 75.8% (5,403) used at least one other psychotropic drug during the antipsychotic treatment period. Nursing home residency, number of non-psychotropic medications used in 2011, and prior psychiatric diagnosis were associated with psychotropic polypharmacy among antipsychotic drug users. The most frequent combination of psychotropic drugs was antipsychotics and antidepressants. CONCLUSION: Concomitant use of psychotropic drugs was frequent in dementia patients. Patients living in nursing homes had the highest risk of receiving a combination of antipsychotics and other psychotropic drugs. Concomitant use of psychotropics may cause adverse events, and potential consequences for patients' safety call for further investigation.

Geographical Variation in Antipsychotic Drug Use in Elderly Patients with Dementia: A Nationwide Study.

BACKGROUND: Use of antipsychotics in elderly patients with dementia has decreased in the past decade due to safety regulations; however use is still high. Geographical variation may indicate discrepancies in clinical practice and lack of adherence to evidence-based guidelines for the management of behavioral symptoms. OBJECTIVE: To investigate potential geographical variances in use of antipsychotic drugs in dementia care. METHODS: A registry-based cross-sectional study in the entire elderly population of Denmark (≥65 years) conducted in 2012. Data included place of residence, prescriptions filled, and hospital discharge diagnoses. Antipsychotic drug use among elderly with (n = 34,536) and without (n = 931,203) a dementia diagnosis was compared across the five regions and 98 municipalities in Denmark, adjusted for age and sex. RESULTS: In 2012, the national prevalence of antipsychotic drug use was 20.7% for elderly patients with dementia, with a national incidence of 3.9%. The prevalence ranged from 17.0% to 23.3% in the five regions and from 7.5% to 33.1% in the 98 municipalities, demonstrating an over four-fold difference. CONCLUSION: The observed geographical variation was more pronounced at municipal level as compared to regional level, suggesting that the variation may be related to variances in clinical practice in primary care. This study highlights an urgent need for further educating professional carers and physicians to guide non-pharmacological as well as pharmacological management of neuropsychiatric symptoms in elderly patients with dementia.

Time trends in antipsychotic drug use in patients with dementia: a nationwide study.

BACKGROUND: Antipsychotics are often used to treat neuropsychiatric symptoms in dementia, but the evidence for effect is limited. Antipsychotics have been associated with increased risk of adverse events and mortality in patients with dementia, leading to safety regulations worldwide. OBJECTIVE: To investigate time trends in use of antipsychotics and other psychotropic drugs in dementia care. METHODS: The study included longitudinal data on all Danish residents ≥65 years. The study population was defined on January 1 of each year from 2000-2012. Data included prescriptions, discharge diagnoses, and somatic and psychiatric comorbidities. Multivariate time trend analyses of psychotropic drug use in patients with dementia within 4-year age bands were performed. RESULTS: Overall, among patients with dementia the prevalence of antipsychotic drug use decreased from 31.3% in 2000 to 20.4% in 2012. The decreasing use of antipsychotics was accompanied by decreasing use of anxiolytics and hypnotics/sedatives, but an increase in the use of antidepressants from 43.3% in 2000 to 53.8% in 2012. These changes were significant across almost all age groups. Treatment intensity among patients using antipsychotics increased as the annual median number of defined daily doses (DDD) increased from 33.3 to 42.0 DDD. CONCLUSIONS: The changing patterns of psychotropic drug use may be caused by warnings against use of antipsychotics. Further research is needed to explore the implications for patient safety.