Abstract
Background
The GERAS II study aimed to assess societal costs and resource use associated with Alzheimer's disease (AD) for patients and their primary caregivers in Italy and Spain, stratified for different severity stages of AD at baseline. This report presents baseline results for Italy.
Design
GERAS II was a prospective, multicentre, observational study of routine care in AD.
Setting
Community-dwelling patients attending specialist secondary care centres (memory clinics/Alzheimer's Evaluation Units) and their primary informal caregivers were recruited into the study.
Participants
Patients were aged ≥55 years, presented within the normal course of care, had a diagnosis of probable AD and a Mini-Mental State Examination (MMSE) score of ≤26. Patients and caregivers were stratified according to patient AD dementia severity at baseline: mild, MMSE score 21–26; moderate, MMSE score 15–20; or moderately severe/severe, MMSE score <15.
Measurements
Data collected for patients and caregivers included demographics/clinical characteristics; current medication; patient cognitive, functional and behavioural assessments; patient and caregiver health-related quality of life (HRQoL); and patient and caregiver resource use. The costs associated with the resources used were calculated. Costs were broken down into patient healthcare costs, patient social care costs and caregiver informal care costs.
Results
Of 198 patients enrolled from Italy, 29 (15%) had mild AD dementia, 80 (40%) had moderate AD dementia, and 89 (45%) had moderately severe/severe AD dementia. Patient and caregiver characteristics showed some differences between AD dementia severity groups; for example, a numerically higher proportion of patients with mild and moderately severe/severe AD dementia were taking memantine compared with those with moderate AD dementia. Patient functioning and behavioural and psychological symptoms worsened with increasing AD dementia severity (p<0.05 between groups for all measures). No significant difference between the disease severity groups was observed in patient HRQoL, and there was no clear pattern in resource use. However, all measures of caregiver time spent helping the patient differed significantly between groups (p<0.05) and were highest in patients with moderately severe/severe AD dementia. Mean (standard deviation) total monthly societal costs per patient (2013 values) were €1850 (1901), €1552 (1322) and €2728 (2184) for patients with mild, moderate and moderately severe/severe AD dementia, respectively (p<0.001 between groups). Caregiver informal care costs were the greatest contributor to total societal costs and amounted to €1370, €1223 and €2223 per patient per month for mild, moderate and moderately severe/severe AD dementia groups, respectively (p<0.001 between groups).
Conclusion
Total Italian societal costs generally increased with increasing AD dementia severity. However, costs were slightly lower for moderate than for mild AD dementia, possibly reflecting the observed unusual trend of greater caregiver time and higher memantine use in patients with mild versus moderate AD dementia.
Key words: Alzheimer's disease, observational study, Italy, resource use, costs
Introduction
Dementia was estimated to affect approximately 8.4 million people aged ≥60 years in the European Union (EU) in 2012 (1), although the reported prevalence of the disease varies between studies (2). Italy has been reported as having the highest prevalence of dementia in the EU, at approximately 7.7% of the population aged ≥60 years (compared with an overall EU prevalence of ~7.0%) (1). It was recently estimated that 1.1 million people in Italy live with dementia (3), and the prevalence of the disease is predicted to rise in line with the aging population (1).
Around 60-80% of dementia cases are caused by Alzheimer’s disease (AD) (1), which is associated with a heavy societal burden in terms of costs and resource use (4, 5, 6, 7, 8, 9, 10). Italy comprises 20 regions and 21 healthcare providers. As a result, there is large geographical variation in healthcare provision, services and access across the country (11, 12), and the cost of AD may vary between regions (13).
The GERAS studies were performed to better understand the economic impact of AD in Europe. These studies were designed to assess the costs and resource use associated with AD for patients and their primary caregivers in selected European countries. The first GERAS study was an 18-month multicentre, prospective observational study conducted in France, Germany and the UK (7). A similar 6-month study (GERAS II) was planned in Italy and Spain. This manuscript presents baseline results from Italy. Baseline results from Spain will be reported elsewhere.
Methods
Study Design and Objectives
The design of GERAS II was based on that of the main GERAS study, as reported previously (7), but it was planned to last for 6 months only. The primary objective of the current analysis was to describe resource use and assess the costs associated with AD for enrolled patients and caregivers at baseline in Italy, stratified for different patient AD dementia severity stages at baseline. Secondary objectives, also stratified for patient disease severity at baseline, included the assessment of patient and caregiver characteristics, treatment patterns in AD and patient and caregiver health-related quality of life (HRQoL).
Study centres were located across Italy and were predominantly specialist secondary care centres (memory clinics/Alzheimer Evaluation Units). Patients were recruited by participating physicians between April 2013 and January 2014. Community-dwelling patients aged ≥55 years presenting within the normal course of care, with a diagnosis of probable AD (according to National Institute of Aging–Alzheimer’s Association criteria (14)) and a Mini-Mental State Examination (MMSE) score of ≤26 (15), were included. Each patient also had to have an informal (i.e. non-professional) caregiver who was willing to take responsibility for the patient for at least 6 months of the year (primary caregiver) and to participate in the study. Treatment decisions were made at the discretion of the physician following standard care procedures during the course of normal clinical practice. No treatment intervention was required, and all commercially available medications or treatments were allowed. Patients and caregivers were stratified according to patient AD dementia severity at baseline: mild AD dementia, MMSE score 21–26; moderate AD dementia, MMSE score 15–20; or moderately severe/severe AD dementia, MMSE score <15.
Ethical review board approval of the study was obtained according to Italian regulations. Written informed consent was obtained from all participants. In some instances, patient consent was obtained from the patient’s legal representative, but patients were asked to give at least co-consent where able.
Assessments
Data collected for patients and caregivers included demographics and clinical characteristics; current medication (for AD, psychiatric symptoms and other medical conditions); patient cognitive, functional and behavioural assessments; patient and caregiver HRQoL; and patient and caregiver resource use, as reported in Wimo et al. (7). Cognitive function was assessed using the MMSE (15) and the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog14) (16), although the ADAS-Cog14 was not applied to patients in the group with moderately severe/severe AD dementia. For the ADAS-Cog14 (score range 0–90), higher scores indicate greater cognitive impairment.
The Alzheimer’s Disease Co-operative Study Activities of Daily Living Inventory (ADCS-ADL) was used to assess patient functional ability (17, 18). The total ADCS-ADL score range is 0–78, with higher scores indicating lower functional impairment. Separate scores for basic activities of daily living (ADL) (range 0–22) and instrumental ADL (range 0–56) were also reported. Patient behavioural and psychological symptoms, and caregiver distress, were assessed using the caregiver interview-based Neuropsychiatric Inventory (NPI)-12 (19, 20). Total NPI-12 scores range from 0 to 144, while NPI-12 caregiver distress scores range from 0 to 60. In both cases, higher scores indicate increased impairment/distress.
HRQoL was evaluated in patients and caregivers using the EuroQoL-5D (EQ-5D) (21) Italy-specific health state index and visual analogue scale (VAS) scores. The weighted EQ-5D total health status index score (EQ-5D index) ranges from 0 (dead) to 1 (perfect health) (22), while the VAS (EQ-VAS), which assesses perceived overall health status, uses a scale of 0 (worst imaginable health state) to 100 (best imaginable health state) (23). Caregivers completed the EQ-5D proxy version for the patient (24) and the caregiver version for themselves.
Subjective caregiver burden was measured using the shortened 22-item version of the original 29-item Zarit Burden Interview (ZBI) (25). The ZBI is a self-report inventory administered to caregivers during an assessment interview in which they are asked to rate their feelings regarding their health and psychological wellbeing, finances, social life and relationship with the patient. The ZBI total score ranges from 0 to 88, with higher scores indicating greater burden.
Resource Utilisation and Cost Estimates
Resource use information for both the patient and the caregiver was obtained using the Resource Utilization in Dementia (RUD) instrument (26), version RUD Complete 3.1, through interview with the caregiver. Costs were calculated based on the resource use information obtained, which included patient health (AD medications, antipsychotic/hypnotic medications, medications for comorbidities, nights in hospital, and emergency room [ER] and outpatient visits) and social (patient living accommodation, community care services, structural adaptations to the patient’s living accommodation, consumables and financial support) care use, and caregiver informal care (caregiver time and work loss) in the month before baseline. Caregiver time was recorded as the total number of caregiving hours, including the number of hours spent on basic ADL (e.g. providing help with eating and dressing), instrumental ADL (e.g. cooking, shopping) and patient supervision (i.e. supervising the patient to prevent dangerous events).
Italian-specific costs associated with the resources used were taken from various references, including Gazzetta Ufficiale, L’Informatore Farmaceutico (OEMF) and The Italian National Institute of Statistics (ISTAT) (see Appendix). Monthly societal costs (2013 values) were estimated by applying unit costs of services and products to the recorded healthcare resource use in the month before baseline. Societal costs were stratified by disease severity at baseline and were broken down into patient healthcare costs, patient social care costs and caregiver informal care costs. These costs formed the base-case analysis.
Two sensitivity analyses were performed using Italian unit costs. One used an opportunity cost approach as for the base-case analysis but included caregiver supervision time, whereas the other used full replacement costs (i.e. costs for caregiver time were valued based on the costs of an untrained carer, which were based on the 2010 mean national wage/hour inflated to a 2013 value) but excluded caregiver supervision time (7). The two sensitivity analyses were repeated using French unit costs to assess an alternative costing schedule.
Sample Size
Sample size calculations were based on the number of patients required to determine 6-month direct country costs associated with resource use. Patients were planned to be enrolled in equal numbers in the three AD dementia severity groups (based on MMSE scores). The study aimed to recruit a minimum of 117 patients per AD dementia severity group (total 350 patients) to provide country-specific mean cost estimates with a precision of ±11%.
Statistical Analysis
All results were based on non-missing observations. Data were compared between AD dementia severity groups using the Cochran–Mantel–Haenszel (CMH) test for categorical data and analysis of variance (ANOVA) for continuous data. Resource utilisation data (patient and caregiver healthcare resource use [nights in hospital, and ER and outpatient visits], and patient social care resource use [district nurse and home aid/orderly visits, food deliveries, day care use and use of public-paid transportation]) were compared between AD dementia severity groups using a zero-inflated Poisson regression model that included AD dementia severity group as an explanatory factor because of the high number of zero events for the resource-use data. The level of significance was taken as p≤0.05. All data were analysed using SAS software version 9.2 (SAS Institute, Cary, NC, USA).
Results
Although patients were recruited from across Italy, more study sites were based in northern (eight centres) and central (eight centres) than in southern Italy (three centres; Figure 1) because not all planned sites were able to recruit patients within the allotted study recruitment period. As a result, patient numbers were also not equally balanced between the three AD dementia severity groups.
Figure 1.
Location of study centres and patient recruitment across Italy
Investigators and Patients
A total of 19 investigators from Italy were involved in this study: 12 were neurologists (63.2%) and seven were geriatricians (36.8%). Investigators had worked for a mean (standard deviation [SD]) of 25.7 (9.38) years. Most worked in a public practice (68.4% vs. 31.6% who worked in a combined public and private practice), and most practices (84.2%) were based in an urban location.
Of 198 patients from Italy enrolled in the study, 29 (14.6%) had mild AD dementia, 80 (40.4%) had moderate disease and 89 (44.9%) had moderately severe/severe disease (Table 1). All enrolled patients were included in the analyses.
Table 1.
Patient and caregiver characteristics
| Characteristic |
AD dementia severity |
p Value1 |
Overall population |
||
|---|---|---|---|---|---|
| Mild | Moderate | Moderately severe/severe | |||
| Patients | |||||
| No. of patients | 29 | 80 | 89 | 198 | |
| Age, years (mean [SD]) | 76.2 (7.12) | 77.0 (7.65) | 78.3 (6.85) | 0.290 | 77.5 (7.23) |
| Sex, n (%) female | 14 (48.3) | 49 (61.3) | 56 (62.9) | 0.364 | 119 (60.1) |
| Time since diagnosis, years (mean [SD]) | 1.6 (1.55) | 1.5 (1.69) | 2.5 (1.99) | <0.001 | 2.0 (1.88) |
| Fell in last 3 months, n (%) yes | 0 (0.0) | 13 (16.3) | 16 (18.0) | 0.052 | 29 (14.6) |
| Neuropsychological assessment in last 6 months, n (%) yes | 15 (51.7) | 58 (72.5) | 47 (52.8) | 0.019 | 120 (60.6) |
| Marital status, married/cohabiting, n (%) | 22 (75.9) | 55 (68.8) | 51 (57.3) | 0.0702 | 128 (64.6) |
| Living location, n (%) urban | 27 (93.1) | 74 (92.5) | 79 (88.8) | 0.6363 | 180 (90.9) |
| Living in own home, n (%) | 27 (96.4) | 78 (97.5) | 81 (93.1) | 0.3134 | 186 (95.4) |
| Education, years (mean [SD]) | 8.8 (4.81) | 7.9 (4.01) | 6.4 (3.94) | 0.008 | 7.3 (4.18) |
| Comorbidities, n (%) yes | 26 (89.7) | 70 (87.5) | 73 (82.0) | 0.471 | 169 (85.4) |
| Patients receiving any psychiatric/hypnotic treatment, n (%) | 10 (34.5) | 33 (41.3) | 47 (52.8) | 0.142 | 90 (45.5) |
| Antidepressants | 9 (31.0) | 27 (33.8) | 35 (39.3) | 0.485 | 71 (35.9) |
| Antipsychotics | 1 (3.4) | 4 (5.0) | 10 (11.2) | 0.469 | 15 (7.6) |
| Anxiolytics, sedatives, hypnotics | 1 (3.4) | 10 (12.5) | 9 (10.1) | 0.310 | 20 (10.1) |
| Patients receiving any AD treatment, n (%) | 21 (75.0) | 68 (86.1) | 81 (96.4) | 0.004 | 170 (89.0) |
| Category/type of AD treatment, n (%) of patients receiving AD treatment | 0.086 | ||||
| One AchE inhibitor | 13 (61.9) | 48 (70.6) | 44 (54.3) | 105 (61.8) | |
| Memantine only | 7 (33.3) | 13 (19.1) | 19 (23.5) | 39 (22.9) | |
| One AChE inhibitor + memantine | 1 (4.8) | 7 (10.3) | 18 (22.2) | 26 (15.3) | |
| Rivastigmine5 | 6 (28.6) | 28 (41.2) | 28 (34.6) | 0.513 | 62 (36.5) |
| Galantamine5 | 0 (0.0) | 1 (1.5) | 1 (1.2) | 0.860 | 2 (1.2) |
| Donezepil5 | 8 (38.1) | 26 (38.2) | 33 (40.7) | 0.945 | 67 (39.4) |
| Memantine5 | 8 (38.1) | 20 (29.4) | 37 (45.7) | 0.128 | 65 (38.2) |
| Caregivers | |||||
| No. of caregivers | 29 | 80 | 89 | 198 | |
| Age, years (mean [SD]) | 61.7 (10.96) | 61.7 (13.37) | 62.3 (12.16) | 0.939 | 62.0 (12.46) |
| Sex, n (%) female | 19 (67.9) | 51 (63.8) | 57 (65.5) | 0.921 | 127 (65.1) |
| Marital status, married/cohabiting, n (%) | 24 (85.7) | 68 (85.0) | 72 (82.8) | 0.658 | 164 (84.1) |
| Caregiver relationship to patient, n (%) | 0.227 | ||||
| Spouse | 17 (60.7) | 35 (43.8) | 35 (40.2) | 87 (44.6) | |
| Child | 10 (35.7) | 40 (50.0) | 41 (47.1) | 91 (46.7) | |
| Other | 1 (3.6) | 4 (5.0) | 11 (12.6) | 16 (8.2) | |
| Caregiver lives with patient, n (%) yes | 20 (71.4) | 48 (60.0) | 58 (66.7) | 0.480 | 64.6 |
| Sole caregiver, n (%) yes | 17 (60.7) | 25 (31.3) | 20 (23.0) | <0.0016 | 62 (31.8) |
AChE=acetylcholinesterase; AD=Alzheimer's disease; ANOVA=analysis of variation; BMI=body mass index; MMSE=Mini-Mental State Examination; NA=not applicable; SD=standard deviation. Percentages calculated based on total population of severity group with available data (0–3% missing), unless stated otherwise. 1p Value for comparison between AD dementia severity groups (ANOVA for continuous variables and Cochran–Mantel–Haenszel test for categorical variables). 2p Value for comparison between AD dementia severity groups for marital status (all categories, including married/cohabiting, never married, divorced/separated and widowed). 3p Value for comparison between AD dementia severity groups for living location (urban or rural). 4p Value for comparison between AD dementia severity groups for living accommodation (all categories, including own home, intermediate forms of accommodation [not dementia-specific], dementia-specific residential accommodation and other). 5Includes all patients taking this medication, either alone or in combination with another treatment. 6p Value for comparison between AD dementia severity groups for how many other caregivers are involved in caring for the patient (0, 1, 2, 3 or ≥4). ‘Mild’ AD dementia severity = MMSE score of 21–26 points; ‘Moderate’ AD dementia severity = MMSE score of 15–20 points; ‘Moderately severe/severe’ AD dementia severity = MMSE score of <15 points.
Patient and Caregiver Characteristics
Most differences in patient characteristics between the AD dementia severity groups did not reach statistical significance due to the small sample sizes (Table 1). However, statistically significant differences were observed between the groups in time since AD diagnosis, which was longest in patients with moderately severe/ severe disease (p<0.001); in the proportion of patients who had a neuropsychological assessment in the last 6 months, which was greatest in patients with moderate disease (p=0.019); and in the mean number of years of education, which decreased with increasing AD dementia severity (p=0.008). Patients with moderate AD dementia had experienced fewer falls in the last 3 months than patients with moderately severe/severe disease, but the difference was not statistically significant.
Overall, 169 patients (85.4%) had at least one comorbidity (mean [SD] of 1.8 [1.18] comorbidities per patient). No significant differences were observed between the patient groups in the number or type of comorbidities.
The proportion of patients receiving any AD treatment increased with AD dementia severity (p=0.004), but the category/type of AD treatment did not differ between patient groups. However, memantine use was numerically higher in patients with mild AD dementia than in those with moderate AD dementia.
Caregiver characteristics were also generally similar between AD dementia severity groups (Table 1), although the proportions of patients with different numbers of caregivers differed significantly between the groups (p<0.001); the proportion of caregivers who were the sole caregiver decreased with increasing AD dementia severity. Overall, most caregivers were the patient’s adult child (46.7%) or spouse (44.6%), and 64.6% of caregivers lived with the patient. These proportions differed between AD dementia severity groups, the proportion of spousal caregivers being higher and the proportion of child caregivers lower in the mild AD dementia group than in the other two disease severity groups. However, the results did not reach statistical significance.
Overall, 86 caregivers (43.4%) had at least one medical condition (mean [SD] of 0.7 [1.04] medical conditions per caregiver). No significant differences were observed between the caregiver groups in the number or type of conditions.
Patient and Caregiver Assessment
Patient functioning (basic, instrumental and total ADCS-ADL) and cognition (ADAS-Cog14) worsened with increasing AD dementia severity (all p<0.001; Table 2). Patient behavioural and psychological symptoms (NPI-12) also showed greater impairment with greater AD dementia severity (p=0.011; Table 2). No significant differences between the groups were observed in patient HRQoL (EQ-5D health status index and VAS scores), although the proportion of patients with “some problems” or “unable to perform” in the ‘self-care’ or ‘usual activities’ domains increased with increasing AD dementia severity (p=0.048 and 0.011, respectively; data not shown).
Table 2.
Clinical outcomes
| Outcome | AD dementia severity | p Value1 | Overall population | ||
|---|---|---|---|---|---|
| Mild | Moderate | Moderately severe/severe | |||
| No. of patients | 29 | 80 | 89 | 198 | |
| MMSE | 23.0 (22.3; 23.6) | 17.8 (17.4; 18.1) | 10.4 (9.7; 11.1) | 2 | 15.2 (14.5; 16.0) |
| ADCS-ADL – basic | 17.9 (16.2; 19.6) | 16.7 (15.6; 17.8) | 12.0 (10.8; 13.2) | <0.001 | 14.8 (13.9; 15.6) |
| ADCS-ADL – instrumental | 32.9 (29.0; 36.8) | 25.5 (22.4; 28.5) | 13.5 (11.1; 16.0) | <0.001 | 21.2 (19.2; 23.2) |
| ADCS-ADL – total | 50.8 (45.5; 56.1) | 42.2 (38.3; 46.2) | 25.5 (22.1; 29.0) | <0.001 | 36.0 (33.3; 38.8) |
| ADAS-Cog14 | 35.2 (32.5; 37.9) | 47.0 (45.0; 49.0) | Not applied | <0.001 | 43.8 (41.9; 45.7) |
| NPI-12 total | 15.5 (11.4; 19.6) | 20.0 (16.5; 23.5) | 25.5 (21.5; 29.5) | 0.011 | 21.8 (19.4; 24.2) |
| EQ-5D country-specific index score (proxy) | 0.81 (0.76; 0.85) | 0.79 (0.76; 0.82) | 0.76 (0.72; 0.80) | 0.248 | 0.78 (0.75; 0.80) |
| EQ-VAS (proxy) | 61.2 (54.7; 67.7) | 63.7 (59.0; 68.3) | 59.8 (54.5; 65.2) | 0.544 | 61.6 (58.4; 64.8) |
AD=Alzheimer's disease; ADAS-Cog14=14-item cognitive subscale of the Alzheimer's disease assessment scale; ADCS-ADL=Alzheimer's Disease Co-operative Study Activities of Daily Living Inventory; ANOVA=analysis of variance; EQ-5D=EuroQoL-5D; EQ-VAS=EQ-5D visual analogue scale; MMSE=Mini-Mental State examination; NPI=neuropsychiatric inventory. Data are presented as means (95% confidence interval) for the total population of each severity group with available data (0–3% missing). 1p Value for comparison between AD dementia severity groups (ANOVA). 2No statistical analysis performed. ‘Mild’ AD dementia severity = MMSE score of 21–26 points; ‘Moderate’ AD dementia severity = MMSE score of 15–20 points; ‘Moderately severe/severe’ AD dementia severity = MMSE score of <15 points. Reduced functioning is indicated by lower scores for MMSE and ADCS-ADL; greater cognitive impairment is indicated by higher scores for ADAS-Cog14; increased impairment is indicated by higher scores for NPI-12 total score; reduced quality of life is indicated by lower scores for EQ-5D.
Caregiver distress (NPI-12) increased with increasing AD dementia severity (p=0.033), whereas caregiver ZBI total score did not differ significantly between AD dementia severity groups (Table 3). However, there was a significant difference between groups in responses to the ZBI question “Overall, how burdened do you feel in caring for your relative?”, the mean score for this question being lowest (indicating lower burden) for caregivers of patients with moderate AD dementia (p=0.025).
Table 3.
Caregiver outcomes
|
Variable |
AD dementia severity |
p Value1 |
Overall population |
||
|---|---|---|---|---|---|
| Mild | Moderate | Moderately severe/severe | |||
| No. of caregivers | 29 | 80 | 89 | 198 | |
| Caregiver burden and quality of life | |||||
| Total NPI-12 caregiver distress score | 9.4 (6.5; 12.2) | 11.9 (10.0; 13.7) | 14.3 (12.1; 16.5) | 0.033 | 12.6 (11.3; 13.9) |
| ZBI total score | 26.8 (21.1; 32.4) | 29.4 (25.9; 32.8) | 33.0 (29.3; 36.7) | 0.143 | 30.6 (28.3; 32.9) |
| Response to ZBI question: Overall, how burdened do you feel in caring for your relative? | 1.2 (0.83; 1.53) | 1.0 (0.76; 1.26) | 1.5 (1.23; 1.72) | 0.025 | 1.2 (1.09; 1.40) |
| EQ-5D country-specific index score | 0.87 (0.84; 0.90) | 0.90 (0.88; 0.93) | 0.86 (0.84; 0.89) | 0.044 | 0.88 (0.86; 0.89) |
| EQ-VAS | 68.5 (61.0; 76.0) | 73.5 (69.8; 77.3) | 72.7 (68.9; 76.5) | 0.422 | 72.4 (69.9; 74.9) |
| Caregiver work variables and resource use | |||||
| Caregivers working for pay, n (%) | 9 (32.1) | 32 (40.0) | 32 (36.8) | 0.751 | 73 (37.4) |
| Caregivers not working and reasons, n (%) | 19 (67.9) | 48 (60.0) | 55 (63.2) | 0.263 | 122 (62.6) |
| Never worked | 4 (21.1) | 15 (31.3) | 7 (12.7) | 26 (21.3) | |
| Retirement age | 12 (63.2) | 26 (54.2) | 34 (61.8) | 72 (59.0) | |
| Other2 | 3 (15.8) | 7 (14.6) | 14 (25.5) | 24 (19.7) | |
| Work loss, if caregiver is working, hours/month3 | 15.8 (−11.1; 42.7) | 47.8 (23.1; 72.5) | 37.0 (17.8; 56.2) | 0.457 | 40.4 (26.4; 54.3) |
| No. of missed working days in last month (for working caregivers) | 2.1 (0.4; 3.9) | 2.6 (0.7; 4.6) | 3.3 (1.4; 5.2) | 0.787 | 2.9 (1.7; 4.0) |
| Caregivers paid to care for patient, if applicable, n (%) | 1 (11.1) | 5 (15.6) | 6 (18.8) | 0.852 | 12 (16.4) |
| Amount of time caregiver paid to care for patient, if applicable (hours/week) | 3.0 (−; −)4 | 11.2 (−8.8; 31.2) | 10.5 (−0.3; 21.3) | 0.851 | 10.2 (2.4; 17.9) |
| No. of outpatient visits (including GP visits) in previous month | 1.6 (0.2; 2.9) | 0.9 (0.4; 1.5) | 1.0 (0.6; 1.5) | 0.062 | 1.1 (0.7; 1.4) |
AD=Alzheimer's disease; ANOVA=analysis of variance; EQ-5D=EuroQoL-5D; EQ-VAS=EQ-5D visual analogue scale; GP=general practitioner; MMSE=Mini-Mental State Examination; ZBI=Zarit burden interview. Data are presented as means (95% confidence intervals) unless otherwise indicated for the total population of each severity group with available data (0-90% missing). 1p Value for comparison between AD dementia severity groups (ANOVA for continuous variables and Cochran-Mantel-Haenszel test for categorical variables). 2‘Other’ category included early retirement, being laid off, health problems and to care for patient. 3Based on reported number of hours lost per week in last month prior to baseline visit by caregivers who were working. 4As n=1 for this parameter, no confidence interval is presented. ‘Mild’ AD dementia severity = MMSE score of 21-26 points; ‘moderate’ AD dementia severity = MMSE score of 15-20 points; ‘moderately severe/severe’ AD dementia severity = MMSE score of <15 points. Increased burden is indicated by higher ZBI scores; reduced quality of life is indicated by lower scores for EQ-5D.
Caregiver EQ-5D index scores were highest (indicating better HRQoL) for caregivers of patients with moderate AD dementia (p=0.044), but EQ-5D VAS scores did not differ significantly between groups. ‘Pain/discomfort’ was the only domain that differed significantly between the groups (p=0.049), with pain being reported by a higher proportion of caregivers of patients with mild AD dementia (data not shown).
Resource Utilisation
Overall levels of resource use were low, although several measures of patient resource use in the month before baseline showed significant differences between AD dementia severity groups. The total number of nights spent in hospital was highest for patients with mild AD dementia. For these patients, the mean (SD) number of nights in hospital was 0.5 (1.5) compared with 0.0 (0.2) for patients with moderate AD dementia and 0.0 (0.0) for those with moderately severe/severe AD dementia (p<0.001). Patients with moderate AD dementia had the most outpatient visits: a mean of 3.6 (9.4) compared with 2.4 (3.4) for mild AD dementia and 1.2 (1.4) for moderately severe/severe AD dementia (p<0.001). The mean number of emergency room visits did not differ significantly between the groups (0.1 for all three groups; p=0.930).
Limited use of social care services was also observed; therefore, results for social care resource use are not presented.
Overall, 37.4% of caregivers were working for pay (Table 3). Employed caregivers worked a mean of 35.7 hours/week, and 53.4% lost working hours due to caregiving. All measures of caregiver time spent helping the patient differed significantly between AD dementia severity groups, and all measures were highest for caregivers of patients with moderately severe/severe AD dementia (Figure 2). Although time for basic ADL increased with AD dementia severity (p=0.002), mean time for instrumental ADL (p=0.003), supervision time (p<0.001) and overall caregiver time (p<0.001) were lowest for caregivers of patients with moderate AD dementia.
Figure 2.
Caregiver time spent on caring for patients with AD dementia
AD=Alzheimer’s disease; ADL=activities of daily living; ANOVA=analysis of variance. *p Value for comparison between AD dementia severity groups (ANOVA) of mean overall monthly caregiver time (value above each column). p Values for individual time components were as follows: basic ADL, p=0.002; instrumental ADL, p=0.003; supervision time, p<0.001). Note: overall caregiver time is based on data provided for the last month prior to the baseline visit. Error bars represent 95% confidence intervals for overall caregiver time. Each of the time components is calculated for those with non-missing data (data missing for one caregiver [3%] in the mild AD dementia group, no missing data in the moderate AD dementia group, data missing for two caregivers [2%] in the moderately severe/severe AD dementia group).
Cost Estimates
Estimated mean monthly total societal costs differed significantly between the AD dementia severity groups (p<0.001). Mean (SD) monthly total costs were lowest for patients with moderate AD dementia (€1552 [1322] per patient) and highest for patients with moderately severe/severe AD dementia (€2728 [2184] per patient). Mean total costs for mild AD dementia were €1850 (1901) per patient (Figure 3). Caregiver informal care costs were the highest contributor to total societal costs; they were lowest in the moderate AD dementia group and highest in the moderately severe/severe AD dementia group (p<0.001). Patient healthcare costs decreased with increasing AD dementia severity (p=0.018). Patient social care costs were lowest in the moderate AD dementia group and highest in the moderately severe/severe AD dementia group but did not differ significantly between groups.
Figure 3.
Mean monthly societal costs (2013 values) for each of the three cost components associated with AD, by AD dementia severity
AD=Alzheimer’s disease; ANOVA=analysis of variance. *p Value for comparison between severity groups (ANOVA) of total monthly societal costs (value in italics above each column). Caregiver informal care costs (p<0.001) and patient healthcare costs (p=0.018) differed significantly between the groups, but patient social care costs did not. Note: supervision time is excluded from caregiver time in the caregiver informal care cost calculation. The value above each column is the mean total monthly societal costs, calculated for those who have data for all three cost components. Error bars represent 95% confidence intervals for mean total monthly societal costs. Each of the individual cost components is calculated for those with non-missing data (numbers with missing data were one [3%] in the mild AD dementia group, none in the moderate AD dementia group and two [2%] in the moderately severe/severe AD dementia group for each cost component). The n value given under each column is the total number of patients in each severity group.
Sensitivity Analysis
The base-case analysis gave the most conservative estimate of costs, total monthly societal costs being higher for all AD dementia severity groups in both sensitivity analyses. However, in both sensitivity analyses, monthly costs followed the same pattern as those in the base-case analysis (i.e. were lowest for patients with moderate AD dementia and highest for those with moderately severe/severe disease) and were significantly different between the AD dementia severity groups (ANOVA p<0.001 in both analyses). For the sensitivity analysis that used Italian unit costs and included caregiver time spent on supervising the patient (opportunity cost approach), total monthly societal costs (SD) were €2704 (3124), €2075 (2047) and €4148 (3420) for the mild, moderate and moderately severe/severe AD dementia groups, respectively. For the sensitivity analysis that used Italian unit costs, excluded caregiver supervision time and valued the costs for caregiver time based on the costs of a paid caregiver (replacement cost approach), corresponding values were €2137 (1616), €1832 (1608) and €2965 (1824), respectively. Results from the sensitivity analyses using French unit costs were almost identical to those obtained using Italian unit costs.
Discussion
This study provides up-to-date data that are useful to inform the Italian public and decision makers about the costs and resource use associated with AD in Italy. These data are particularly important given that the few available studies on the socioeconomic impact of AD in Italy were conducted about 20 years ago (27, 28, 29). Approval of the Italian Dementia National Plan (Piano Nazionale Demenze (30)) in October 2014 is evidence of the country’s commitment towards improving provision for patients with AD and their families/caregivers. The plan has four main objectives that focus on promoting policies for a public health and social approach, strengthening the network of integrated services, promoting appropriate high-quality care and improving the quality of life of patients and their families (31).
The majority of patients in the current study had moderate or moderately severe/severe AD dementia (40.4% and 44.9%, respectively); only 14.6% (N=29) had mild AD dementia (MMSE score of 21–26). As the number of patients with mild AD dementia was low, the results for this group should be interpreted with caution. As not all planned sites were able to recruit patients within the allotted study recruitment period, this could have impacted on the enrolment of patients with mild AD dementia in particular, because such patients and their caregivers may be less likely to seek treatment than patients with more severe disease. According to a survey of physicians, caregivers, payers and the general public, it is believed that most people are unable to distinguish the initial symptoms of AD from those associated with normal ageing (32) and that in the specialist memory centres of western Europe, a diagnosis of AD is often only made when the disease severity is at least moderate (MMSE score of 16–20) (33, 34). Indeed, the average time from the recognition of symptoms of AD to initiation of contact with a physician can be close to 1 year (43 weeks) in some European countries, ranging from 33 weeks in Germany to 56 weeks in Italy (32). In addition, the greatest time interval between the first emergence of AD symptoms and a diagnosis of AD being made occurs in Italy (63 weeks), a phenomenon that has not improved over time (11, 32, 35).
As found in the main GERAS study for France, Germany and the UK (7), total Italian societal costs generally increased with AD dementia severity, being highest in patients with moderately severe/severe disease. However, in contrast to data from the other GERAS countries, costs in Italy were slightly higher for mild than for moderate AD dementia. Caregiver informal care costs were the greatest contributor to total societal costs in all AD dementia severity groups.
The elevated costs in the mild AD dementia group compared with the moderate AD dementia group were probably due to the greater amount of caregiver time spent caring for patients with mild disease (Figure 2), despite them being similar in age to the other patient groups and showing less functional impairment. This Italy-specific phenomenon could be due to less formalised healthcare services in the country, meaning that patients with dementia are cared for by their relatives for longer than in other countries, with social care services only being used when the dementia becomes more severe (36). Alternatively, since there were more spousal caregivers in the mild AD dementia group than in the other two disease severity groups, it could be due to spousal caregivers having more time for caregiving than adult-child caregivers.
The majority of sites (and hence patients) participating in the study were located in northern (42.1%) and central (42.1%) Italy (see Figure 1), where memory clinics are more concentrated in hospitals and universities than in territorial and extra-hospital units, which is more typical in southern Italy (12, 37). Clinics in northern Italy are therefore more likely to participate in research studies. In addition, patients from southern Italy are more likely to live with their families (11) and less likely to attend memory clinics (12, 13). Interestingly, and possibly linked to the geographic distribution of memory clinics in Italy, most sites participating in the study (N=16; 84.2%) were located in an urban area. Families of patients living in urban areas have been found to show greater distress and sensitivity about their relative’s AD than rural families (38) and may therefore be more willing to attend a memory clinic.
The finding that caregiver informal care costs were the greatest contributor to total societal costs in all AD dementia severity groups is consistent with data from studies on the socioeconomic burden of dementia in Italy (27–29) and from the main GERAS study (7). In addition, data from an Italian study of patients with moderate-stage AD (5) showed that the yearly societal costs of moderate-stage AD were €20,128, which is similar to the societal costs associated with moderate AD dementia in the current study (€1552 per month, giving a yearly amount of €18,624). As in our study, informal care also accounted for the largest proportion of the total societal costs (€13,590 per year, amounting to 68% of the total societal costs (5).
Over one-third (37.4%) of caregivers were working for pay in Italy, which is higher than the proportions previously observed in Germany (28.5%), France (21.5%) and the UK (20.5%) (7), although, as previously, this proportion did not differ across AD dementia severity groups. The difference in the proportion of caregivers working for pay between Italy and other countries may be due to a higher proportion of adult-child caregivers in Italy (46.7% vs. 32.8% in France, 24.0% in Germany and 25.9% in the UK) (7), who are more likely to be of working age than a patient’s spouse. Indeed, there was a slightly higher proportion of adult-child than spousal caregivers in our Italian population, with each accounting for just under half of the overall caregiver population (46.7% and 44.6%, respectively), whereas proportions of approximately two-thirds spousal caregivers and one-third adult-child caregivers were observed in the main GERAS study (7).
Although the difference in proportion of spousal caregivers between AD dementia severity groups did not reach statistical significance in the current study, the proportion of spousal caregivers was substantially higher in the mild AD dementia group (61%) than in the other two disease severity groups (approximately 40%). The higher proportion of spousal caregivers in the mild AD dementia group could explain our finding of greater caregiver time in the mild versus moderate AD dementia group. Both instrumental ADL and supervision time were higher for patients with mild than for those with moderate AD dementia. It is likely that spouses would spend more time with the patient than other caregivers because of their partnership and living arrangements rather than because of AD specifically.
In the current study, no clear overall pattern was observed for patient resource use according to AD dementia severity. In the main GERAS study, resource use generally increased with increasing AD dementia severity (7). The lack of a pattern for patient resource use according to AD dementia severity in Italy could again be due to the small sample size but also to the overall low levels of resource use, possibly resulting from less formalised healthcare services and greater reliance on family assistance (36).
As observed previously (7), patient scores for ADCS-ADL measures, ADAS-Cog14 and the NPI-12 worsened with increasing AD dementia severity. However, in contrast to the results from other countries (France, Germany and the UK), patient EQ-5D index and VAS scores did not differ between AD dementia severity groups. This difference in HRQoL results between Italy and the other GERAS countries may be due to the small sample size in the current analysis, as the differences in HRQoL results between AD dementia severity groups were very small in the other countries.
Strengths of the current study include the provision of real-world data from Italy, which were previously lacking. Real-world observational studies include patients who are more representative of those seen in usual clinical practice and are important for determining typical costs and resource use in community-dwelling AD patients and their caregivers. In addition, the study used the RUD to capture information on resource utilisation. This instrument provides a standardised scale for assessing the time spent by caregivers on giving informal care and is suitable for use across multiple countries (39).
Limitations of the study include the small sample size, especially for patients with mild AD dementia, which may limit the conclusions that can be drawn. The study planned to recruit equal numbers of participants in each AD dementia severity group, but patients with mild AD dementia were the most under-represented. This may have been due to individuals with mild AD dementia being less likely to seek assistance. In addition, although the study aimed to recruit patients in a balanced way from across Italy, a larger group of subjects was recruited from northern and central regions than the south, possibly due to the greater likelihood that patients in the south of the country are cared for in a family environment than in AD-specific centres and are therefore less likely to be contacted for participation in clinical trials (11, 13). Healthcare services also vary considerably between the north and south of Italy (11–13, 37). A further limitation of the study is the lack of longitudinal follow-up data and hence prospective data collection. However, even with the limitation of a cross-sectional approach, the results observed in the Italian GERAS patients appear to be generally consistent with those observed in GERAS patients from other countries, apart from the unusual findings for patients with mild AD dementia.
In conclusion, total Italian societal costs for patients with AD dementia generally increased with increasing disease severity, although costs were slightly lower for patients with moderate AD dementia than for those with mild AD dementia. This pattern may reflect the observed unusual trend of increased caregiver time for patients with mild AD dementia than for those with moderate disease. However, the low number of patients with mild AD dementia makes it difficult to draw any firm conclusions for this group. The study provides previously lacking information on real-world patients with AD and cross-sectional cost data that may be useful to the Italian public and decision makers. Furthermore, our method of analysis for evaluating resource use and costs could be applied to future studies comparing different regions within countries.
Acknowledgements: The authors would like to acknowledge Dr Sue Chambers and Dr Claire Lavin for medical writing assistance with the preparation of this manuscript, funded by Eli Lilly and Company.
Conflicts of interest: M. Mancini, C. Reed, G. Bruti and G. Dell’Agnello are employees of Eli Lilly and Company. G. Bruno has received financial compensation from Eli Lilly for participation on the GERAS Advisory Board. All authors who are employees of Eli Lilly and Company were involved in the study design, the collection, analysis and interpretation of data, writing the article and the decision to submit the article for publication. All authors approved the final article.
Ethical standards: The study was conducted in accordance with current Italian laws.
Funding sources: The study was sponsored by Eli Lilly and Company.
Author disclosures: Dr Reed is an employee and minor shareholder of Eli Lilly and Company. Dr Bruti was an employee and shareholder of Eli Lilly and Company at the time the study was conducted and when the paper was drafted. Dr Dell’Agnello is an employee and shareholder of Eli Lilly and Company. Dr Mancini is an employee and shareholder of Eli Lilly and Company. Professor Bruno has received financial compensation from Eli Lilly and Company for participation on the GERAS Advisory Board.
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