Informal Care Time and Cost in a Large Clinical Trial Sample of Patients with Mild to Moderate Alzheimer's Disease: Determinants and Level of Change Observed.

INTRODUCTION: We evaluate the association between caregiver (informal) time/cost and illness severity from two recently completed clinical trials of an investigational drug for Alzheimer's disease (AD). METHODS: Changes from baseline caregiver time were calculated and treatment effects analyzed using a restricted maximum likelihood-based mixed model for repeated measures. Four separate models were then estimated to examine the association between caregiver time costs and the clinical endpoints measured during the trials, including cognition (MMSE), function (DAD), behavior (NPI), global disability (CDR) and dependence (DS). RESULTS: Caregiver time cost was significantly associated with all clinical measures of illness severity with a 1-unit change in MMSE, DAD, NPI, CDR and DS associated with a 11.57%, 4.81-4.97%, 3.58-3.67%, 42.52% and 71.05% change, respectively, in primary caregiver time cost. The association between caregiver time cost and DS was the strongest of all the associations examined. CONCLUSION: Caregiver time costs increase with increasing AD severity in all key domains of AD (cognition, function, behavior, global disability and dependence on others). Our analysis demonstrated that patient dependence is a particularly important predictor of caregiver time costs and should be considered as a potential outcome measure in intervention clinical trials in AD. FUNDING: Pfizer Inc. and Janssen Alzheimer Immunotherapy Research and Development.

Frailty: a costly phenomenon in caring for elders with cognitive impairment.

OBJECTIVES: Dementia draws on a variety of public and private resources. There is increasing pressure to define the cost components in this area to improve resource allocation and accountability. The aim of this study was to characterize frailty in a group of cognitively impaired community-dwelling elders and evaluate its relationship with cost and resource utilization. METHODS: We assessed a cross-sectional, convenient sample of 115 cognitively impaired patients of age >55 years who attended the National Memory Clinic in St James' University Hospital, a Trinity College-affiliated hospital in Dublin, Ireland. Participants had a clinical diagnosis of possible Alzheimer's disease or mild cognitive impairment. Frailty was measured using the biological syndrome model. Formal health and social care costs and daily informal caregiving costs were collected and the total costs of care estimated by applying the appropriate unit cost estimate for each resource activity. Stepwise regression models were constructed to establish the factors associated with increased care costs. RESULTS: Patient dependence, frailty and number of co-morbid illnesses explained 43.3% of the variance in observed daily informal care costs in dementia and cognitively impaired patients. Dependence was the sole factor retained in an optimal model explaining 19% of the variance in formal health and social care costs. CONCLUSION: Frailty retained a strong association with daily informal care costs even in the context of other known risk factors for increasing care costs. Interventions that reduce frailty as well as patient dependence on others may be associated with cost savings.

An Analysis of the Public Financial Support Eligibility Rule for French Dependent Elders with Alzheimer's Disease.

BACKGROUND: It is crucial to define health policies that target patients with the highest needs. In France, public financial support is provided to dependent patients: it can be used to finance informal care time and nonmedical care use. Eligibility for public subsidies and reimbursement of costs is associated with a specific tool: the autonomie gérontologie groupes iso-ressources (AGGIR) scale score. OBJECTIVE: Our objective was to explore whether patients with Alzheimer's disease who are eligible for public financial support have greater needs than do noneligible patients. METHODS: Using data from the Dépendance des patients atteints de la maladie d'Alzheimer en France study, we calculated nonmedical care expenditures (in €) using microcosting methods and informal care time demand (hours/month) using the Resource Use in Dementia questionnaire. We measured the burden associated with informal care provision with Zarit Burden Interview. We used a modified two-part model to explore the correlation between public financial support eligibility and these three variables. RESULTS: We find evidence of higher informal care use, higher informal caregivers' burden, and higher care expenditures when patients have an AGGIR scale score corresponding to public financial support eligibility. CONCLUSIONS: The AGGIR scale is useful to target patients with the highest costs and needs. Given our results, public subsidies could be used to further sustain informal caregivers networks by financing programs dedicated to lowering informal caregivers' burden.

Quality of Life and Utility Measurement in a Large Clinical Trial Sample of Patients with Mild to Moderate Alzheimer's Disease: Determinants and Level of Changes Observed.

OBJECTIVE: To evaluate the performance (in terms of responsiveness to change, associations with other criterion standards, and indicators of Alzheimer's disease [AD] severity) of a quality-of-life measure (Quality of Life in Alzheimer's Disease [QOL-AD]) and a health utility measure (Health Utilities Index Mark 3 [HUI-3]) from two recently completed clinical trials of a new drug for AD. METHODS: Change from baseline scores was calculated, and treatment effects were analyzed using mixed models for repeated measures. Three separate models were then estimated to examine the association between the quality-of-life/utility end points and the clinical and other health outcome end points measured during the trials, including cognition, function, behavior, and dependence. RESULTS: The performance of the two measures differed. Subject-assessed QOL-AD was found to be weakly associated with clinical measures of cognition, and with caregiver reports of function, behavior, and dependence, and showed little movement over time and did not appear to differ by baseline AD severity. Proxy-assessed QOL-AD scores were consistently lower than subject-assessed scores, and the level of decline in QOL-AD was greater using proxy-assessed QOL-AD. Proxy-assessed HUI-3 scores were more strongly associated with clinical measures of cognition, function, behavior, and dependence than the subject- and proxy-assessed QOL-AD scores. Larger proportionate changes over 78 weeks were observed with HUI-3 scores and greater separation in HUI-3 scores by baseline severity. CONCLUSIONS: Subject-assessed QOL-AD is less likely than proxy-assessed QOL-AD to respond to changes in clinical measures used to track progression in clinical trials of subjects with mild to moderate AD. Proxy-assessed HUI-3 assessments were more in line with other outcome assessments and could therefore be better outcome measures to evaluate clinical progression in mild to moderate AD.

Medical management, costs, and consequences of Alzheimer's disease in Germany: an analysis of health claims data.

OBJECTIVE: The main objective of this analysis was to assess the medical and economic differences between patients with and without diagnosed Alzheimer's Disease (AD). Analysis included co-morbidities, patterns of drug use, and clinical course, as well as the magnitude of these differences attributable to AD. METHODS: This evaluation is based on retrospective analyses of anonymized claims data from 2005-2008 provided by a large German Statutory Health Insurance (SHI). Cross-sectional analyses were performed with the following data: demographics, number of hospitalizations, number of in-patient days, number of ambulatory physician visits, number of drugs used, total number of defined daily doses (DDD) of prescribed drugs, and costs. A propensity score model was used to assess costs attributable to AD. RESULTS: Patients with AD caused substantially higher costs from the perspective of a SHI. The differences in long-term care costs explained 70-75% of the total cost difference, with being responsible for about half of the total costs in AD patients. Comparing matched AD patients with controls resulted in 2.2-2.4-fold higher costs in the cross-sectional analysis, €7413-€9207 for AD patients vs €3378-€3850 for controls. The propensity score model resulted in a difference of €3771 attributable to AD. These costs are mainly caused by differences in hospitalization and long-term care costs. CONCLUSION: This analysis is one of the largest health economic studies of AD in Germany. The limitations of this study include the fact that reported diagnosis couldn't be validated and disease severity was not taken into account. Despite these methodological constraints, it can be concluded that AD is a substantial cost driver from the SHI payer perspective in Germany.

Longitudinal costs of caring for people with Alzheimer's disease.

BACKGROUND: There has been an increasing interest in the relationship between severity of disease and costs in the care of people with dementia. Much of the current evidence is based on cross-sectional data, suggesting the need to examine trends over time for this important and growing cohort of the population. METHODS: This paper estimates resource use and costs of care based on longitudinal data for 72 people with dementia in Ireland. Data were collected from the Enhancing Care in Alzheimer's Disease (ECAD) study at two time points: baseline and follow-up, two years later. Patients' dependence on others was measured using the Dependence Scale (DS), while patient function was measured using the Disability Assessment for Dementia (DAD) scale. Univariate and multivariate analysis were used to explore the effects of a range of variables on formal and informal care costs. RESULTS: Total costs of formal and informal care over six months rose from €9,266 (Standard Deviation (SD): 12,947) per patient at baseline to €21,266 (SD: 26,883) at follow-up, two years later. This constituted a statistically significant (p = 0.0014) increase in costs over time, driven primarily by an increase in estimated informal care costs. In the multivariate analysis, a one-point increase in the DS score, that is a one-unit increase in patient's dependence on others, was associated with a 19% increase in total costs (p = 0.0610). CONCLUSIONS: Higher levels of dependence in people with Alzheimer's disease are significantly associated with increased costs of informal care as the disease progresses. Formal care services did not respond to increased dependence in people with dementia, leaving it to families to fill the caring gap, mainly through increased supervision with the progress of disease.

Dependence in Alzheimer's disease and service use costs, quality of life, and caregiver burden: the DADE study.

BACKGROUND: Most models determining how patient and caregiver characteristics and costs change with Alzheimer's disease (AD) progression focus on one aspect, for example, cognition. AD is inadequately defined by a single domain; tracking progression by focusing on a single aspect may mean other important aspects are insufficiently addressed. Dependence has been proposed as a better marker for following disease progression. METHODS: This was a cross-sectional observational study (18 UK sites). Two hundred forty-nine community or institutionalized patients, with possible/probable AD, Mini-Mental State Examination (3-26), and a knowledgeable informant participated. RESULTS: Significant associations noted between dependence (Dependence Scale [DS]) and clinical measures of severity (cognition, function, and behavior). Bivariate and multivariate models demonstrated significant associations between DS and service use cost, patient quality of life, and caregiver perceived burden. CONCLUSION: The construct of dependence may help to translate the combined impact of changes in cognition, function, and behavior into a more readily interpretable form. The DS is useful for assessing patients with AD in clinical trials/research.

The relationship between changes in quality of life outcomes and progression of Alzheimer's disease: results from the dependence in AD in England 2 longitudinal study.

OBJECTIVE: The relationship between conventional indicators of Alzheimer's disease (AD) progression and quality of life (QoL) outcomes is unclear. Dependence on others has been recommended as a unifying construct in defining AD severity. This study examined the relationship between indicators of disease severity (including dependence) and changes in QoL and utility over 18 months. METHODS: A multi-centre, cohort study was conducted across 18 UK sites. One hundred and forty-five patients with possible/probable AD and their caregivers completed assessments of disease severity (Dependence Scale, Mini-mental state examination, Neuropsychiatric Inventory, Disability Assessment for Dementia), dementia-specific QoL (DEMQOL, DEMQOL-Proxy) and generic health-related utility (EQ-5D) at both time points. RESULTS: There was evidence of individual change in QoL over 18 months, with over 50% of patients reporting either maintenance or improvement of life quality. The EQ-5D proxy suggested a mean decline in QoL, whereas the DEMQOL-Proxy indicated overall improvement. In the subsample of people who self-reported QoL and utility, no mean change was evident. Changes in dependence did not explain changes on any QoL or utility outcome. There was a weak association between the EQ-5D proxy and changes in cognition, whereas changes on the DEMQOL-Proxy were partly explained by changes in behavioural disturbance. CONCLUSIONS: The natural progression of AD over 18 months does not lead to inevitable decline in QoL or utility. There are no clear or consistent direct relationships between changes in disease severity and QoL outcomes. The impact of increasing dependence and worsening disease severity is likely buffered by a combination of psychological, social and environmental factors.

Evaluating disease-modifying agents: a simulation framework for Alzheimer's disease.

BACKGROUND: Considerable advances have been made in modeling Alzheimer's disease (AD), with a move towards individual-level rather than cohort models and simulations that consider multiple dimensions when evaluating disease severity. However, the possibility that disease-modifying agents (DMAs) may emerge requires an update of existing modeling frameworks. OBJECTIVES: The aim of this study was to develop a simulation allowing for economic evaluation of DMAs in AD. METHODS: The model was developed based on a previously published, well-validated, discrete event simulation which measures disease severity on the basis of cognition, behaviour, and function, and captures the interrelated changes in these measures for individuals. The updated model adds one more domain, patient dependence, in addition to cognition, behaviour, and function to better characterize disease severity. Furthermore, the model was modified to have greater flexibility in assessing the impact of various important assumptions, such as the long-term effectiveness of DMAs and their impact on survival, on model outcomes. A validation analysis was performed to examine how well the model predicted change in disease severity among patients not receiving DMA treatment by comparing model results to those observed in two recent phase III clinical trials of bapineuzumab. In addition, various hypothetical scenarios were tested to demonstrate the improved features of the model. RESULTS: Validation results show that the model closely predicts the mean changes in disease severity over 18 months. Results from different hypothetical scenarios show that the model allows for credible assessment of those major uncertainties surrounding the long-term effectiveness of DMAs, including the potential impact of improved survival with DMA treatment. They also indicate that varying these assumptions could have a major impact on the value of DMAs. CONCLUSIONS: The updated economic model has good predictive power, but validation against longer-term outcomes is still needed. Our analyses also demonstrate the importance of designing a model with sufficient flexibility such that the model allows for assessment of the impact of key sources of uncertainty on the value of DMAs.

Psychometric properties of the Dependence Scale in large randomized clinical trials of patients with mild and moderate Alzheimer's disease.

OBJECTIVE: The need for assistance from others is a hallmark concern in Alzheimer's disease (AD). The psychometric properties of the Dependence Scale (DS) for measuring treatment benefit were investigated in large randomized clinical trials of patients with mild to moderate AD. METHODS: Reliability, validity, and responsiveness of the DS were examined. Path models appraised relationships and distinctiveness of key AD measures. The responder definition was empirically derived. RESULTS: Generally acceptable reliability (α ≥ .65), significant (P < .001) known-groups tests, and moderate to strong correlations (r ≥ .31) confirmed the DS psychometric properties. Path models supported relationships and distinctiveness of key AD measures. A DS change of ≤ 1 point for patients with limited home care and ≤ 2 points for patients with assisted living care best described stability of the level of dependence on caregivers. CONCLUSION: The DS is a psychometrically robust measure in mild to moderate AD. The empirically derived responder definition aids in the interpretation of DS change.

Reliability, validity, and interpretation of the dependence scale in mild to moderately severe Alzheimer's disease.

INTRODUCTION: The Dependence Scale (DS) was designed to measure dependence on others among patients with Alzheimer's disease (AD). The objectives of this research were primarily to strengthen the psychometric evidence for the use of the DS in AD studies. METHODS: Patients with mild to moderately severe AD were examined in 3 study databases. Within each data set, internal consistency, validity, and responsiveness were examined, and structural equation models were fit. RESULTS: The DS has strong psychometric properties. The DS scores differed significantly across known groups and demonstrated moderate to strong correlations with measures hypothesized to be related to dependence (|r| ≥ .31). Structural equation modeling supported the validity of the DS concept. An anchor-based DS responder definition to interpret a treatment benefit over time was identified. DISCUSSION: The DS is a reliable, valid, and interpretable measure of dependence associated with AD and is shown to be related to--but provides information distinct from--cognition, functioning, and behavior.

Frailty and quality of life for people with Alzheimer's dementia and mild cognitive impairment.

BACKGROUND: Our aim was to investigate the relationship between frailty and health-related quality of life (HR-QOL) in cognitively impaired elderly individuals. METHODS: A cross-sectional observational study of a convenience sample of 115 patients with a diagnosis of Alzheimer's dementia or mild cognitive impairment. Frailty was measured using the biological syndrome model and HR-QOL was measured using the DEMQOL-Proxy. Regression models were constructed to establish the factors associated with HR-QOL. RESULTS: Frailty and neuropsychiatric symptoms were associated with HR-QOL, with Mini-Mental State Examination (MMSE) scores ≥21 (P = .037, P ≤ .001, and R (2) = .362). Functional limitation was associated with HR-QOL, with MMSE scores ≤20 (P = .017 and R (2) = .377). CONCLUSION: Frailty and neuropsychiatric symptoms were the determinants of HR-QOL in the earlier stages of cognitive impairment. Functional limitation predicted HR-QOL in the later stages of cognitive impairment. Frailty may represent a novel modifiable target in early dementia to improve HR-QOL for patients.

Self-efficacy for managing dementia may protect against burden and depression in Alzheimer's caregivers.

BACKGROUND: Self-efficacy is the belief that one can perform a specific task or behaviour and is a modifiable attribute which has been shown to influence health behaviours. Few studies have examined the relationship between self-efficacy for dementia-related tasks and symptoms of burden and depression in caregivers. METHODS: Eighty four patient/caregiver dyads with Alzheimer's disease were recruited through a memory clinic. Patient function, cognition and neuropsychiatric symptoms were assessed together with caregiver burden, personality, depressive symptoms, coping strategies and self-efficacy for completing tasks related to dementia care. RESULTS: 33% (28) of caregivers reported significant depressive symptoms (CES-D ≥ 10). In multivariate analyses, caregiver burden was predicted by self-efficacy for symptom management, neuroticism, patient function and neuropsychiatric symptoms while caregiver depression was predicted by self-efficacy for symptom management, caregiver educational level, neuroticism, emotion-focused coping, dysfunctional coping and patient function. In patients with moderate to severe impairment (MMSE ≤ 20), self-efficacy for symptom management behaved as a mediator between patient neuropsychiatric symptoms and symptoms of burden and depression in caregivers. CONCLUSIONS: Further longitudinal investigation is warranted to determine if self-efficacy might be usefully considered a target in future interventional studies to alleviate symptoms of burden and depression in Alzheimer's caregivers.

Determinants of the desire to institutionalize in Alzheimer's caregivers.

BACKGROUND: The desire to institutionalize is an important predictor of future institutionalization. Few studies have examined potentially modifiable caregiver characteristics which might be the focus of future interventional strategies. METHODS: A total of 102 patient/caregiver dyads with Alzheimer's disease (n = 84) or mild cognitive impairment were recruited through a memory clinic. Cross-sectional analyses of a range of patients, caregivers, and context of care-related characteristics were conducted. RESULTS: Caregiver desire to institutionalize was significantly associated with a number of potentially modifiable variables including caregiver coping style, self-efficacy, depression, burden, and the presence of an unmet service need. In a multivariate analysis, caregiver burden, depression, and nonspousal status were the only significant independent predictors of caregiver desire to institutionalize in a model which correctly classified 80.4% of caregivers. CONCLUSIONS: Interventions which seek to reduce caregiver desire to institutionalize should adopt a multifactorial approach to reduce symptoms of burden and depression in caregivers.

Dependence and caregiver burden in Alzheimer's disease and mild cognitive impairment.

The dependence scale has been designed to be sensitive to the overall care needs of the patient and is considered distinct from standard measures of functional ability in this regard. Little is known regarding the relationship between patient dependence and caregiver burden. We recruited 100 patients with Alzheimer's disease or mild cognitive impairment and their caregivers through a memory clinic. Patient function, dependence, hours of care, cognition, neuropsychiatric symptoms, and caregiver burden were assessed. Dependence was significantly correlated with caregiver burden. Functional decline and dependence were most predictive of caregiver burden in patients with mild impairment while behavioral symptoms were most predictive in patients with moderate to severe disease. The dependence scale demonstrated good utility as a predictor of caregiver burden. Interventions to reduce caregiver burden should address patient dependence, functional decline, and behavioral symptoms while successful management of the latter becomes more critical with disease progression.

A qualitative assessment of the concept of dependence in Alzheimer's disease.

BACKGROUND: The Dependence Scale (DS) was designed to assess levels of patient need for care due to deficits typical of Alzheimer's disease (AD). This study examined content validity of the DS based on input from patients, caregivers, and clinicians. METHODS: Qualitative interviews with experts, patients, and caregivers were used to collect information on the concept of dependence and to assess content validity. RESULTS: Nine clinicians rated item relevance ''high'' with consensus on the primacy of functional abilities and dependence in the measurement of AD progression. Twenty-two US, 11 UK, and 14 informal caregivers from Spain participated in focus groups; 18 patients participated in 3 separate focus groups. Discussion supported DS hierarchy of dependence, capture of mild-to-severe dependence, suitability of response options, and short recall time frame. CONCLUSIONS: Clinicians, caregivers, and patients support content validity of the DS in mild-to-moderate AD. The DS may be valuable to capture dependence within future clinical dementia trials.

Mapping from disease-specific measures to utility: an analysis of the relationships between the Inflammatory Bowel Disease Questionnaire and Crohn's Disease Activity Index in Crohn's disease and measures of utility.

OBJECTIVES: To examine the relationship between the Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn's Disease Activity Index (CDAI) and measures of utility (EQ-5D and the SF-6D indexes), and to estimate algorithms to map the two utility values from IBDQ and CDAI scores. METHODS: A large data set from clinical trials in Crohn's disease provided contemporaneous patient responses to all four questionnaires. Paired observations from multiple time-points were analyzed. We calculated mean utility scores by IBDQ and CDAI score deciles; Spearman correlation coefficients for paired observations between IBDQ and EQ-5D (n = 3320) and IBDQ and SF-6D (n = 3230), and explored regression models using maximum likelihood estimation. The IBDQ/SF-6D model was validated against paired observations from an independent data set. RESULTS: The IBDQ decile analysis demonstrated a consistent positive relationship with both utility indexes. Correlations between the IBDQ and both the EQ-5D and SF-6D were statistically significant (P < 0.0001), with correlation coefficients of 0.76 and 0.85, respectively. A simple linear model between EQ-5D and IBDQ explained 45% of the variance. The residuals plot for the IBDQ/SF-6D model suggested some nonlinearity and a nonlinear model explained 69% of the variance. In the validation analysis, no statistically significant difference was observed between the mean observed SF-6D and the SF-6D scores estimated using the IBDQ/SF-6D regression model. CONCLUSIONS: Given the strength, consistency, and predictable characteristics of the relationships, the algorithms appear to provide valuable and valid methods to estimate utilities from IBDQ scores (but not CDAI) in trials of Crohn's disease patients that have collected IBDQ scores but not utilities.

A model to assess the cost effectiveness of statins in achieving the UK National Service Framework target cholesterol levels.

BACKGROUND: Coronary heart disease (CHD) is a public health priority in the UK. The National Service Framework (NSF) has set standards for the prevention, diagnosis and treatment of CHD, which include the use of cholesterol-lowering agents aimed at achieving targets of blood total cholesterol (TC) < 5.0 mmol/L and low density lipoprotein-cholesterol (LDL-C) < 3.0 mmol/L. In order to achieve these targets cost effectively, prescribers need to make an informed choice from the range of statins available. AIM: To estimate the average and relative cost effectiveness of atorvastatin, fluvastatin, pravastatin and simvastatin in achieving the NSF LDL-C and TC targets. DESIGN: Model-based economic evaluation. METHODS: An economic model was constructed to estimate the number of patients achieving the NSF targets for LDL-C and TC at each dose of statin, and to calculate the average drug cost and incremental drug cost per patient achieving the target levels. The population baseline LDL-C and TC, and drug efficacy and drug costs were taken from previously published data. Estimates of the distribution of patients receiving each dose of statin were derived from the UK national DIN-LINK database. RESULTS: The estimated annual drug cost per 1000 patients treated with atorvastatin was pound 289000, with simvastatin pound 315000, with pravastatin pound 333000 and with fluvastatin pound 167000. The percentages of patients achieving target are 74.4%, 46.4%, 28.4% and 13.2% for atorvastatin, simvastatin, pravastatin and fluvastatin, respectively. Incremental drug cost per extra patient treated to LDL-C and TC targets compared with fluvastatin were pound 198 and pound 226 for atorvastatin, pound 443 and pound 567 for simvastatin and pound 1089 and pound 2298 for pravastatin, using 2002 drug costs. CONCLUSIONS: As a result of its superior efficacy, atorvastatin generates a favourable cost-effectiveness profile as measured by drug cost per patient treated to LDL-C and TC targets. For a given drug budget, more patients would achieve NSF LDL-C and TC targets with atorvastatin than with any of the other statins examined.

Economic impact of treating inhibitor patients.

A literature review of the economics of managing haemophilia patients with inhibitors was conducted. It showed that haemophilia with inhibitors places a burden on the healthcare system and on the patient. Use of rFVIIa compared to 'usual therapy' is associated with improvements on a number of outcomes, including speed of bleed resolution, duration of pain, and quality of life. The extra costs of rFVIIa can be justified by the additional benefits achieved: For example, the extra costs required to achieve a gain of one quality adjusted life year (QALY) in children with inhibitors has been shown to be comparable with that for other reimbursed healthcare strategies. Future research could focus on expanding our understanding of the impact of accelerated bleed resolution on long-term sequelae, including need for surgery and quality of life.