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THE COST-EFFECTIVENESS OF THREE PREVENTION STRATEGIES IN ALZHEIMER’S DISEASE: RESULTS FROM THE MULTIDOMAIN ALZHEIMER PREVENTIVE TRIAL (MAPT)

 

N. Costa1,2,3, M. Mounié1,2, A. Pagès2,4,5, H. Derumeaux1, T. Rapp6, S. Guyonnet2,3,5, N. Coley2,3,7, C. Cantet2,3,5, I. Carrié5, S. Andrieu2,3,7, L. Molinier1,2,3 and on behalf of the MAPT/DSA Group*

 

1. Health Economic Unit of the University Hospital of Toulouse, Toulouse 31059, France; 2. INSERM-UMR 1027, Toulouse 31000, France; 3. University of Toulouse III, Toulouse 31330, France; 4. Department of Pharmacy, Toulouse University Hospital, Toulouse, 31000, France; 5. Gérontopôle, Department of Geriatrics, University Hospital of Toulouse, Toulouse 31059, France; 6. Université de Paris (LIRAES EA4470), Paris 75006, Paris, France; 7. Department of Epidemiology and Public Health, university Hospital of Toulouse, Toulouse 31059, France

Corresponding Author: Nadège Costa, Health economist, PhD, Health Economic Unit of the University Hospital of Toulouse, Hôtel Dieu Saint-Jacques, 2, rue viguerie, 31059 Toulouse Cedex 9, France, Email : costa.n@chu-toulouse.fr, Tel: +335 61 77 83 72

J Prev Alz Dis 2021;4(8):425-435
Published online August 2, 2021, http://dx.doi.org/10.14283/jpad.2021.47

 


Abstract

BACKGROUND: To date, no curative treatment is available for Alzheimer’s disease (AD). Therefore, efforts should focus on prevention strategies to improve the efficiency of healthcare systems.
Objective: Our aim was to assess the cost-effectiveness of three preventive strategies for AD compared to a placebo.
Design: The Multidomain Alzheimer Preventive Trial (MAPT) study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with Multidomain Intervention (MI) plus a placebo, one group with Polyunsaturated Fatty Acids (PFA), one group with a combination of PFA and MI) and one placebo group.
Setting: Participants were recruited and included in 13 memory centers in France and Monaco.
Participants: Community-dwelling subject aged 70 years and older were followed during 3 years.
Interventions: We used data from the MAPT study which aims to test the efficacy of a MI along PFA, the MI plus a placebo, PFA alone, or a placebo alone.
Measurement: Direct medical and non-medical costs were calculated from a payer’s perspective during the 3 years of follow-up. The base case incremental Cost-Effectiveness Ratio (ICER) represents the cost per improved cognitive Z-score point. Sensitivity analyses were performed using different interpretation of the effectiveness criteria.
Results: Analyses were conducted on 1,525 participants. The ICER at year 3 that compares the MI + PFA and the MI alone to the placebo amounted to €21,443 and €21,543 respectively, per improved Z score point. PFA alone amounted to €111,720 per improved Z score point.
Conclusion: Our study shows that ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. This information may help decision makers and serve as a basis for the implementation of a lifetime decision analytic model.

Key words: Cost-effectiveness, economics, Alzheimer disease, prevention.


 

Introduction

According to the 2019 World Alzheimer report, 50 million people worldwide and 1.2 millions in France suffer from Alzheimer’s disease (AD) (1). Associated costs of care are consistent and vary from €24,140 for mild and moderate stages to €44,171 for the severe stage at 18 months (2).
According to the latest meta-analyses, specific drugs in the treatment of AD have a low and time-limited efficacy on symptoms, quality of life, institutionalization, mortality and the burden of caregivers (3, 4). In 2016, the French High Authority for Health (HAS) considered that the benefit of these medicines was insufficient to justify reimbursement by the French National Health Insurance (FNHI) (5, 6).
As no curative treatment is available, efforts should focus on prevention strategies. Current evidence suggests that nutrition, physical exercise, cognitive activity and social stimulation may improve cognitive health (7). Results from the Multidomain Alzheimer Preventive Trial (MAPT), which test the effect of Multidomain Intervention (MI) and supplementation using omega 3 polyunsaturated fatty acids (PFA) alone or in combination on cognitive decline alongside a large randomized controlled trial show no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group (8). Nevertheless, this trial shows a trend in z-score differences in favor of MI + PFA and MI alone groups.
Published cost-effectiveness analyses of primary prevention strategies for AD show cost-saving results. Nevertheless, these studies are only based on simulated models and hypothetical interventions indicating potential cost-effectiveness results (9). Interventions tested were physical activity, management of cardiovascular risk factors, vitamin supplementation, and multidomain cardiovascular disease prevention programs (10-13). Currently in France, these interventions are not reimbursed specifically for the prevention of Alzheimer’s disease but they can be offered to the patient for the maintenance of their overall health. More randomized control trials (RCT) are required to reinforce the results cost-effectiveness study of prevention programs for AD.
In the framework of the large MAPT study, we aim to assess the cost-effectiveness of PFA supplementation alone, MI (nutritional counseling, physical exercise, and cognitive stimulation) alone or a combination of both interventions compared to a placebo.

 

Methods

Design, setting and participants

The MAPT study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with MI plus a placebo, one group with PFA, one group with a combination of PFA and MI) and one placebo group. Community-dwelling subjects, followed during 3 years, aged 70 years and older were recruited at 13 memory centers in France and Monaco. In France, memory centers are outpatient structures that performed diagnostic workup and follow-up of elderly subjects. Participants met at least one of three criteria: spontaneous memory complaint, limitation in one instrumental Activity of Daily Living (ADL), or slow gait were eligible to be included in the study. Participants with a Mini Mental State Examination (MMSE) score below 24, those who were diagnosed with dementia, those with any difficulty in basic ADL and those taking PFA supplements at baseline were excluded. Full methods have been previously described elsewhere (8, 14). The trial protocol was approved by the French Ethics Committee in Toulouse (CPP SOOM II) and was authorized by the French Health Authority (8).

Interventions

Participants were randomly assigned to one of the following four groups:
– Multidomain Intervention: consisted of 2 h group sessions focusing on three domains (cognitive stimulation, physical activity, and nutrition) and a preventive consultation (at baseline, 12 months, and 24 months). MI was done twice a week during the first month, once a week during the second month, and one per month for the remainder of the three years study,
– Omega 3 Polyunsaturated Fatty Acids: two capsules per day with 400 mg docosahexaenoic acid (DHA) and no more than 112·5 mg eicosapentaenoic acid (EPA),
– Combined intervention: Multidomain intervention and Omega-3 PFA,
– Placebo: two capsules per day containing flavoured paraffin oil.

More details are given elsewhere (8).

Outcomes

All costs were recorded throughout the MAPT trial at 6, 12, 18, 24, 30 and 36 months using a Case Report Form and were analysed from the FNHI perspective. All monetary values are in 2018 Euros. Costs taken into account were direct medical (hospitalizations, consultations, medical and paramedical procedures and drugs) and non-medical (transportation) costs.
Valuation was based on several sources of unit costs (Appendix 1. Table A1). Hospital stays were valued using the French Disease Related Groups (DRG) including extra charges if applicable (e.g. the cost of days of intensive care) (15). We used mean DRG rates calculated from the national hospitalization database for patients aged 70 or over, according to the medical unit to which the participant was admitted. Rehabilitation and psychiatric hospitalizations were valued using per diem costs. Consultations were valued using the General French Nomenclature for Medical Procedures according to the specialization (16). Medical procedures were valued using the Medical Classification of Clinical Procedures (CCAM) (Version 54.10) and the Nomenclature of Clinical Biological Procedures (NABM) according to the type of medical procedure (imaging, biology, other) (17, 18). Each consultation and medical procedure was valued using the appropriate FNHI reimbursement rate.
No details, except the frequency, were available in the database on transportation and paramedical procedures, therefore valuation was based on means estimate from a sample of the FNHI database, the General Sample of Beneficiaries database (EGB) (19, 20). The gamma distribution shape and scale parameters were derived from the mean and variance observed in the 2018 EGB database for each cost component for the population aged 70 years or older.
For drugs reimbursed by the FNHI, we assumed that the daily dosage was equal to the Daily Defined Dose (DDD) (21). If there was no recommended DDD, we calculated an average daily dose according to the Summary of Product Characteristics (SmPC) (22). We then multiplied the reimbursement price per unit by the daily dosage and the treatment duration (23). For hospital drugs, only the costs of very expensive drugs were taken into account because the others were included in the DRG rate (24).
MI was valued by the mean wage rate for a psychologist, dietician and physical activity facilitator (40€) multiplied by the intervention period (2.30 hours) and the number of prescribed sessions (46) during three years. PFA was valued using the retail price per capsule (€0.50 cents) multiplied by the number of prescribed capsules taken per participant per year (365.5/year), multiplied by 3 years.
The primary efficacy outcome used to determine the ICER consisted of the change from baseline to 36 months in a composite Z score (8). It combines four cognitive tests (free and total recall of the Free and Cued Selective Reminding Test, ten MMSE orientation items, the Digit Symbol Substitution Test score from the Revised Wechsler Adult Intelligence Scale, and the Category Naming Test [2 min category fluency in animals]) (8). Z-scores represent the number of standard deviations above or below the mean. Coley et al estimated that a 0.3-point decrease in Z score is the minimum clinically significant difference, which predicts dementia (25). We used this cut-off, in addition to the Z-score, to define whether a participant presented an aggravation in memory function in order to make the ICER more comprehensive for clinicians and decision makers. Other variables (age, gender, comorbidities, Fried frailty phenotype, educational level and Z score) were collected at baseline.

Statistical analyses

Description and comparison of baseline characteristics were made using mean and standard deviation and occurrences and percentages for continuous and qualitative variables on one hand and using Kruskal Wallis or Chi-squared on the other hand.
Cost components for participants who had a complete follow-up were summarized for each group. Three-year cumulative costs were expressed in terms of mean costs per participant and their bias-corrected and accelerated (BCa) bootstrap 95% confidence intervals (CI). Cost differences between groups where tested using a global non-parametric Kruskal-Wallis test.
Missing data on total cumulative cost at 3 years were accounted for by multiple imputation and predictive mean matching methods (26). Age group tercile, gender, intervention groups, initial frailty score tercile and pooled occurrences of medical history tercile were used in the imputation. We assumed that missing cost data are “Missing At Random” and we used Hausman test to verify whether our results were subject to attrition bias issues (27). Efficacy data used in our analysis were smoothed by a mixed model as described elsewhere (8). The fixed effects used in this model were intervention group, time, and interactions between intervention groups and each time. The random effects used were center-specific and participant-specific variables. In order to include adjusted outcomes in both the numerator and denominator of the ICER, we used a Generalized Linear Model (GLM) with a gamma distribution and a log link that allowed the use of fitted cost data (28). The same variables used for imputation were also used for adjustment. Fitted and imputed costs as well as fitted Z scores were then described using mean and BCA bootstrap CI.
We used non-parametric bootstrap outputs to graphically determined the 95% confidence ellipses and illustrate the uncertainty around the ICER (29, 30). ICERs with a positive value were compared to a Willingness-To-Pay (WTP) threshold set up at 50,000€ per Quality Adjusted Life Years (31-33). Additionally, the cost-effectiveness acceptability curve (CEAC) showed the probability that an intervention was cost-effective compared with the alternative according to a range of WTP thresholds (34). Moreover, sensitivity analysis was conducted using the data for patient with a complete follow-up.

 

Results

Patient’s characteristics

Between 30 May 2008 and 24 February 2011, 1,680 participants were enrolled and randomly assigned to four arms. Participants were excluded from the modified intention-to-treat efficacy analysis because no cognitive assessment was available after baseline for 154 participants, and one participant in the PFA group withdrew their consent. One thousand two hundred and eighty-six participants completed the final visit and economic data were available for 1,320 participants (Figure 1). Missing economic data accounted for 12% to 15% in each group. A full description of the population was provided in prior work (14). The baseline characteristics of our sample are summarized in Table 1. No substantial difference was noted in any demographic or clinical characteristics between the arms.

Figure 1. Flow chart for patient’s selection

*The intention-to-treat analysis included assigned participants with a composite score at baseline who had at least one post-baseline visit.

Table 1. Participants’ characteristics at baseline

*p-value of khi2 or Kruskal Wallis test according to variables; † Gastrointestinal; ‡Ear Nose and Throat; §Polyunsaturated Fatty Acids; || Multidomain intervention

Three years costs description

The observed costs for the three-year follow-up period for 1,320 participants with complete economic data are presented in table 2. Total costs without intervention amounted to €7,702; €7,951; €7,845 and €7,106 for PFA + MI, PFA, MI and the placebo group, respectively (p=0.77). When the intervention cost was included in the total costs, they were significantly different and amounted to €9,171; €8,500; €8,765 and €7,106, respectively (p=0.001). The main cost driver in each group was inpatient stays which accounted for approximately 50% of the total cost in all groups. The second cost driver was medication, which accounted for 24% to 30% of the total cost depending on the group.
At 3 years, the placebo group had the lowest inpatient costs of the three groups, and particularly for psychiatric hospitalizations that were higher in the three other groups. The PFA group had significantly higher GP, cardiologist and lab test costs than others groups (p= 0.026, p= 0.018 and p=0.090, respectively). Finally, cardiovascular medication costs were higher in the PFA + MI group (p=0.018).

Table 2. Total costs over the three-year follow-up period

*Confidence Interval; †p-value of Kruskal-Wallis rank sum test; ‡Medical Surgical and Obstetrics; §Polyunsaturated Fatty Acids; ||Multidomain Intervention

 

Three years costs analysis

Detailed costs for every 6 months show a substantial increase in total costs for each group between 24 and 36 months of follow-up, which was mainly due to a substantial increase in hospital costs (Appendix 2. Table A2).
Table 3 presents the results of the GLM for the whole population (1,525) and show that total costs including intervention costs increased with age, number of medical conditions and the type of intervention. It was significantly higher in the PFA + MI group and the MI group. The GLM regression of total costs without intervention costs shows that only age and the number of medical conditions increased healthcare costs significantly.

Table 3. Multivariate analysis of total cost with and without intervention over the 3-year follow-up period (N= 1,525)

*Relative Risk; †Confidence Interval; ‡p-value; §Polyunsaturated Fatty Acids; ||Multidomain Intervention

 

Cost-effectiveness analysis

Differences in total costs including intervention costs between the intervention groups and the placebo group were €1,237, €1,705 and €1,986 for the PFA, MI and PFA + MI groups, respectively ( Appendix 3. Table A3). Changes in Z scores between the intervention groups and the control group were 0.011 for PFA, 0.079 for MI and 0.093 for PFA + MI, respectively (Appendix 3. Table A3).
As presented in the base case ICER scatter plot (Figure 2-a), the ICER comparing combined intervention and MI alone with placebo amounted to €21,443 and €21,543 per improved Z score point, respectively. The confidence ellipses of the ICERs comparing the PFA + MI and MI strategies overlap. All dots that represent the results of the 1,000 replications of ICERs for the PFA + MI and the MI strategies alone vs. placebo are concentrated in the northeast quadrant. As presented in the CEAC (Appendix 4. Figure A4.a), PFA + MI and MI alone have a probability of 95% to be cost-effective at a €50,000 WTP threshold. When the percentage of patients with no aggravation of cognitive functions between baseline and year 3 (Figure 2.b) is used, it can be noted that all the bootstrapped ICERs of the PFA + MI strategy vs. placebo are located in the northeast quadrant. The probability that PFA + MI and MI alone are cost-effective at a €50,000 threshold is 90% and 65%, respectively. (Appendix 4. Figure A4.b).
Results for the sensitivity analysis using the complete data set show an ICER amounting to €19,638 and €20,595 per improved Z score point for combined intervention and MI alone compared to placebo. All dots that represent the results of the 1,000 replications of ICERs for the PFA + MI and the MI strategies alone vs. placebo are concentrated in the northeast quadrant (Appendix 5).

Figure 2. Confidence ellipses of intervention strategies versus placebo

 

Discussion

This study provides first time evidence on the cost-effectiveness of preventive interventions for AD. Our study showed that PFA + MI and MI alone have an ICER of €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000. Clinical results from the MAPT study showed that in the modified intention-to-treat population (n=1525), there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group, explaining the impossibility to conclude that an intervention was most efficient than another (8). Between-group differences compared with the placebo were 0.093 (95% CI 0.001 to 0.184; adjusted p=0.142) for the combined intervention group, 0.079 (-0.012 to 0.170; adjusted p=0.179) for the MI plus placebo group, and 0.011 (-0.081 to 0.103; adjusted p=0.812) for the PFA group. Although the clinical results do not show any significant differences in efficacy between the different interventions studied, we can note a trend regarding the increase in efficacy for the combined intervention and MI groups in comparison with placebo, with a p value less than 0.2. In this context, the implementation of a cost-minimisation analysis was not appropriate, because interventions effectiveness were not strictly equivalent, that is why we choose to implement cost-effectiveness analyses. Additionally, clinical efficacy and efficiency are different measurement tools that have different aims. Efficiency measurement provides information on whether healthcare resources are used to get the best value for money while efficacy measurement determines whether an intervention produces the expected result under ideal circumstances (35).
Two efficiency studies with interventions to reduce risk factors for dementia showed cost-saving results (11, 13). The Lin et al. study used a cohort-based simultaneous equation system in United States with a lifetime time horizon. The intervention (disease management of overweight, diabetes, hypertension and other cardiovascular diseases) was cost saving (-9,259 US$ for a gain of 0.03 LY without dementia) (11). The Zhang et al. study used a Markov model in Sweden and Finland with a 20-year time horizon. The intervention (health promotion program combined with pharmacological treatment of cardiovascular risk factors) was cost saving (-21,974 SEK for a gain of 0.0511 QALY) (13). In another study on physical activity, van Baal and colleagues used a Markov model in United Kingdom with a lifetime time horizon. They calculated incremental costs of -4600 GBP to 1500 GBP depending on the scenarios (physical activity levels and adherence to recommendations), the interventions were cost saving or cost-effective depending on the context, and the maximum ICER was £2,777/LY (10). Finally, an economic evaluation of nutritional supplementation (B-vitamins) in the prevention of dementia based on stochastic decision model in United Kingdom with a lifetime time horizon was tested. Contrary to our study, the intervention was cost saving (-502 GBP for 0.008 QALY gained) (12). However, this supplementation was based on B-vitamins and not PFA. Caution should be exercised in comparing because all these studies were based on hypothetical interventions in decision models and were not RCT like our study (9).
Three years total costs amounted from €7,106 for the placebo group to €7,951 for the PFA group. Costs differences between groups were not statistically significant when interventions costs are not included and becomes significant after the inclusion of these costs. This results show that intervention costs is the main cost component, which explain the difference in total costs. Nevertheless, we can note a cost difference of at least €596 between placebo group and the other three groups. This difference is mainly lead by psychiatric hospitalizations (p=0.012). We can explain this difference by the fact that few patients are hospitalized for psychiatric reasons in each group. In the placebo group, only two psychiatric hospitalizations were found during the three years follow-up period while between four and eight psychiatric hospitalizations were found for the other groups. Moreover, we can note a significant cost difference between groups for consultation costs. This is led by the cost of general practitioner cardiologist, which were higher for PFA group compared with other groups. However, this cost difference from a clinical perspective, correspond between 0.5 to 1.5 consultations in terms of frequency during the three years follow-up period. Annualized costs amounted to €2,567; €2,650; €2,618 and €2,369, for PFA + MI, PFA alone, MI alone and placebo groups, respectively. As shown in the original clinical paper, 45% of the participants included in the MAPT study had at least one Fried frailty criterion and the other participants had none of those criteria. The sample of participants included in the MAPT study was considered as pre-frail or robust [8]. A meta-analysis published in 2019 showed that annual healthcare costs for the elderly varied from €1,217 to €2,056 for a Spanish study and from €9,193 and to €18,525 for a study performed in the USA, for robust and pre-frail older adults, respectively [36]. All the studies included in this meta-analyse took into account inpatient stays, ER and outpatient care. Total costs for Mexican and German studies, which also included formal and informal care costs, varied from €1,248 to €1,775 and from €2,568 to €3,284 for robust and pre-frail older adults, respectively (36). In a French study, the authors demonstrated that annual costs for outpatient care were €1,254 for a robust population of older adults (37). This cost was higher for participants 70-74 years of age and amounted to €1,432. In our study, the mean annualized outpatient care costs amounted to €1,315. A comparison with other studies shows that our cost results are consistent with results in published papers.
The efficacy of MI and/or PFA supplementation was estimated using a Z score. Some countries, such as the UK (NICE), recommend the use of QALY to inform decision-makers for resource allocation. We chose not to use QALY in our study because it is very limited for the elderly. Health related quality of life instruments such as EQ-5D-5L measures do not capture the maintenance of independence or the social effects of interventions, which are particularly important dimensions for the elderly [38]. The QALY metric has also been criticized for being insufficiently sensitive to measure small but clinically meaningful changes in health status or utility (39, 40). In order to provide an ICER that can be informative for clinicians and decision makers, sensitivity analyses were performed on different interpretation of effectiveness using the 0.3-point Z-score as a cut-off (25). ICERs were €434/percent of participants with no aggravation of cognitive functions between baseline and 3 years for PFA + MI compared to the placebo. The use of different interpretation of effectiveness did not change the results and confirmed that the PFA + MI strategy present an ICER under the WTP threshold.
Informal and formal care costs were not included in our analysis. Unlike for demented people for which formal and informal care costs can constitute more than 50% of total costs, these type of costs are very low in older people without dementia (41, 42). As stated in the Panaponaris et al study, only 10% of the older people without dementia needed assistance with ADL and less than 25% needed assistance with IADL (42).
Healthcare consumption was measured using ad hoc questionnaires and was based on declarative data. In order to take into account the uncertainty, we implemented probabilistic sensitivity analyses. We used Probabilistic Sensitive Analysis (PSA) instead of Determinist Sensitive Analysis (DSA) because in DSA analysis the analyst himself chooses parameters and their variation (which leads to selection bias); it only allows the simultaneous variation of a few parameters and cannot take into account the interaction between parameters (43-46). Moreover, the Missing at Random characteristics of our data were verified and the issue of missing data was addressed through multiple imputation. In addition, the sensitivity analysis of the ICERs calculated with the 1,320 participants for whom economic data were available was performed and confirmed our results. Nevertheless, results are based on individual data recorded alongside an RCT, which provided us with robust data analysed using adapted statistical methods.

 

Conclusions

Results show ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. These results are consolidated through the sensitivity analyses performed on different effectiveness criteria and ICER calculated using observed data on 1320 participants. The article provides additional information to strictly medical data and may serve as a basis for decision making for the FNHI and more widely for other relevant policy makers. Further results, using lifetime horizon analytical model, are necessary to complete information provided as part of this RCT based study. This study was the first to collect economic and clinical data of older people probably at risk of developing AD during a three years follow-up period. This study may help the scientific community to access additional economic data in the field of AD prevention which can be used on the one hand to build lifetime model and on the other hand, to compare results between different countries and finally contribute to improve the economic research on AD.

 

* MAPT/DSA Group: Principal investigator: Bruno Vellas (Toulouse); Coordination: Sophie Guyonnet; Project leader: Isabelle Carrié; CRA: Lauréane Brigitte; Investigators: Catherine Faisant, Françoise Lala, Julien Delrieu, Hélène Villars; Psychologists: Emeline Combrouze, Carole Badufle, Audrey Zueras; Methodology, statistical analysis and data management: Sandrine Andrieu, Christelle Cantet, Christophe Morin; Multidomain group: Gabor Abellan Van Kan, Charlotte Dupuy, Yves Rolland (physical and nutritional components), Céline Caillaud, Pierre-Jean Ousset (cognitive component), Françoise Lala (preventive consultation) (Toulouse). The cognitive component was designed in collaboration with Sherry Willis from the University of Seattle, and Sylvie Belleville, Brigitte Gilbert and Francine Fontaine from the University of Montreal. Co-Investigators in associated centres: Jean-François Dartigues, Isabelle Marcet, Fleur Delva, Alexandra Foubert, Sandrine Cerda (Bordeaux); Marie-Noëlle-Cuffi, Corinne Costes (Castres); Olivier Rouaud, Patrick Manckoundia, Valérie Quipourt, Sophie Marilier, Evelyne Franon (Dijon); Lawrence Bories, Marie-Laure Pader, Marie-France Basset, Bruno Lapoujade, Valérie Faure, Michael Li Yung Tong, Christine Malick-Loiseau, Evelyne Cazaban-Campistron (Foix); Françoise Desclaux, Colette Blatge (Lavaur); Thierry Dantoine, Cécile Laubarie-Mouret, Isabelle Saulnier, Jean-Pierre Clément, Marie-Agnès Picat, Laurence Bernard-Bourzeix, Stéphanie Willebois, Iléana Désormais, Noëlle Cardinaud (Limoges); Marc Bonnefoy, Pierre Livet, Pascale Rebaudet, Claire Gédéon, Catherine Burdet, Flavien Terracol (Lyon), Alain Pesce, Stéphanie Roth, Sylvie Chaillou, Sandrine Louchart (Monaco); Kristelle Sudres, Nicolas Lebrun, Nadège Barro-Belaygues (Montauban); Jacques Touchon, Karim Bennys, Audrey Gabelle, Aurélia Romano, Lynda Touati, Cécilia Marelli, Cécile Pays (Montpellier); Philippe Robert, Franck Le Duff, Claire Gervais, Sébastien Gonfrier (Nice); Yannick Gasnier and Serge Bordes, Danièle Begorre, Christian Carpuat, Khaled Khales, Jean-François Lefebvre, Samira Misbah El Idrissi, Pierre Skolil, Jean-Pierre Salles (Tarbes). MRI group: Carole Dufouil (Bordeaux), Stéphane Lehéricy, Marie Chupin, Jean-François Mangin, Ali Bouhayia (Paris); Michèle Allard (Bordeaux); Frédéric Ricolfi (Dijon); Dominique Dubois (Foix); Marie Paule Bonceour Martel (Limoges); François Cotton (Lyon); Alain Bonafé (Montpellier); Stéphane Chanalet (Nice); Françoise Hugon (Tarbes); Fabrice Bonneville, Christophe Cognard, François Chollet (Toulouse). PET scans group: Pierre Payoux, Thierry Voisin, Julien Delrieu, Sophie Peiffer, Anne Hitzel, (Toulouse); Michèle Allard (Bordeaux); Michel Zanca (Montpellier); Jacques Monteil (Limoges); Jacques Darcourt (Nice). Medico-economics group: Laurent Molinier, Hélène Derumeaux, Nadège Costa (Toulouse). Biological sample collection: Bertrand Perret, Claire Vinel, Sylvie Caspar-Bauguil (Toulouse). Safety management: Pascale Olivier-Abbal. DSA Group: Sandrine Andrieu, Christelle Cantet, Nicola Coley.

Acknowledgments: The present study called ECO-MAPT study was supported by grants from the French Ministry of Health (PHRC 2008) and the France Alzheimer Association (Doctoral Scholarship 2010). The MAPT study was supported by grants from the Gérontopôle of Toulouse, the French Ministry of Health (PHRC 2008, 2009), the Pierre Fabre Research Institute (manufacturer of the polyunsaturated fatty acid supplement), Exhonit Therapeutics, and Avid Radiopharmaceuticals. No sponsor placed any restriction on this study or had any role in the design of the study, data collection, data analyses or interpretation, or in the preparation, review, or approval of the manuscript. The promotion of this study was supported by the University Hospital Center of Toulouse. We are indebted to the investigators from CHU de Toulouse, Centre Hospitalier Lyon-Sud, Hôpital de Tarbes, Hôpital de Foix, Hôpital de Castres, CHU de Limoges, CHU de Bordeaux, Hôpital de Lavaur, CHU de Montpellier, Hôpital Princesse Grace, Hôpital de Montauban, CHU de Nice, and CHU de Dijon for their participation in this study.

Funding: The present study called ECO-MAPT study was supported by grants from the French Ministry of Health (PHRC 2008) and the France Alzheimer Association (Doctoral Scholarship 2010). The original MAPT study was supported by grants from the Toulouse Geriatric Center, the French Ministry of Health (PHRC 2008, 2009), Pierre Fabre Research Institute (manufacturer of the omega-3 supplement), ExonHit Therapeutics SA, and Avid Radiopharmaceuticals Inc. Trial registration number: NCT00672685, first registered in May 6, 2008

All authors meet criteria for authorship as stated in the COI form, as well as their contributions to the manuscript. All authors’ specific areas of contributions is listed, using categories below: – Study concept and design: Nadège Costa, Hélène Derumeaux, Sophie Guyonnet, Isabelle Carrié, Sandrine Andrieu, Laurent Molinier; – Acquisition of data: Nadège Costa, Hélène Derumeaux, Sophie Guyonnet, Isabelle Carrié, Sandrine Andrieu, Laurent Molinier; – Analysis and interpretation of data: Nadège Costa, Michael Mounié, Arnaud Pagès, Hélène Derumeaux, Nicola Coley, Chrsitelle Cantet, Sandrine Andrieu, Laurent Molinier; – Drafting of the manuscript: Nadège Costa, Michael Mounié, Arnaud Pagès, Hélène Derumeaux, Laurent Molinier; – Critical revision of the manuscript for important intellectual content: Thomas Rapp, Nicola Coley, Sandrine Andrieu.

Ethics approval and consent to participate: The investigating physicians, who verified inclusion and exclusion criteria and obtained written informed consent, recruited all participants. The trial protocol was approved by the French Ethical Committee located in Toulouse (CPP SOOM II) and was authorised by the French Health Authority.

Conflict of interest: Authors report no conflict of interest.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

 

SUPPLEMENTARY MATERIAL1

SUPPLEMENTARY MATERIAL2

SUPPLEMENTARY MATERIAL3

SUPPLEMENTARY MATERIAL4

SUPPLEMENTARY MATERIAL5

 

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DETERMINANTS OF MEDICAL DIRECT COSTS OF CARE AMONG PATIENTS OF A MEMORY CENTER

 

V. Dauphinot1, A. Garnier-Crussard1, C. Moutet1, F. Delphin-Combe1, H.-M. Späth2, P. Krolak-Salmon1,3,4

 

1. Clinical and Research Memory Center of Lyon, Lyon Institute For Elderly, University hospital of Lyon, Lyon, France; 2. EA 4129 “Parcours Santé Systémique”, University Lyon 1, Lyon, France; 3. Clinical Research Centre CRC – VCF (Vieillissement – Cerveau – Fragilité), Hospital of Charpennes, University Hospital of Lyon, Lyon, France; 4. Neuroscience Research Centre of Lyon, Inserm 1048, CNRS 5292, Lyon, France

Corresponding Author: Dr Virginie Dauphinot, Hôpital des Charpennes, 27 rue Gabriel Péri, 69100 Villeurbanne, France, Tel: +33 (0) 472433114. Fax: +33 (0) 472432054, E-mail address: virginie.dauphinot@chu-lyon.fr
J Prev Alz Dis 2021;3(8):351-361
Published online April 10, 2021, http://dx.doi.org/10.14283/jpad.2021.16

 


Abstract

Background: Alzheimer’s disease and related diseases (ADRD) are a major cause of health-related cost increase.
Objectives: This study aimed to estimate the real medical direct costs of care of patients followed at a memory center, and to investigate potential associations between patients’ characteristics and costs.
Design: Cross-sectional analyses conducted on matched data between clinical data of a cohort of patients and the claims database of the French Primary Health Insurance Fund.
Setting: Memory center in France
Participants: Patients attending a memory center with subjective cognitive complaint
Measurements: Medical or nonmedical direct costs (transportation) reimbursed by the French health insurance during the one year after the first memory visit, and socio-demographic, clinical, cognitive, functional, and behavioral characteristics were analyzed.
Results: Among 2,746 patients (mean ± SD age 79.9 ± 8 years, 42.4% of patients with dementia), the total direct cost was on average € 9,885 per patient during the year after the first memory visit: € 7,897 for patients with subjective cognitive complaint, € 9,600 for patients with MCI, and € 11,505 for patients with dementia. A higher functional and cognitive impairment, greater behavioral disorders, and a higher caregiver burden were independently associated with a higher total direct cost. A one-point decrease in the Instrumental Activities of Daily Living score was associated with a € 1,211 cost increase. The cost was higher in patients with Parkinson’s disease, and Lewy body disease compared to patients with AD. Diabetes mellitus, anxiety disorders and number of drugs were also significantly associated with greater costs.
Conclusions: Higher real medical direct costs were independently associated with cognitive, functional, and behavioral impairment, diabetes mellitus, anxiety disorders, number of drugs, etiologies as well as caregiver burden in patients attending a memory center. The identification of factors associated to higher direct costs of care offers additional direct targets to evaluate how interventions conducted in patients with NCD impact direct costs of care.

Key words: Costs of care, dependence, cognitive status, economics, Alzheimer’s disease.


 

Introduction

Alzheimer’s disease and related diseases (ADRD) are considered as the main cause of health-related cost increase in developed countries (1, 2). Dementia represented a total cost of € 105.2 billion in Europe in 2010 (3). In France, the prevalence of dementia has been estimated to 7.9% among people aged 65 and over, and it is expected to reach 9.6% by 2050 (4). To anticipate and optimize interventions targeting patients developing neurocognitive disorders (NCD)(5), it is of crucial importance to evaluate the cost of resources associated with the main characteristics of NCD. Cost-of-illness studies for ADRD appear essential to anticipate future resource needs, nevertheless they remain difficult to conduct as aging is related to various health conditions and comorbidities, and it is unclear whether comorbidities should be directly linked to ADRD (6, 7). In cost-of-illness studies, costs of care have been mainly estimated from self-reported resource utilization by patients and/or their informal caregivers (8-10). The use of real costs associated to patients’ care (estimated from claims data) offers an objective evaluation of costs related to patient care, independently of the possible recall bias that self-report might induce (11). Most previous studies have estimated the average cost per patient selected with a specific diagnosis (12-14), and costs of care in patients with ADRD were generally related to symptoms severity such as cognitive, functional and behavioral impairment (6, 12-23). These costs were presented with different amplitudes depending on the study population characteristics, the perspective of the study (payer, societal), the components of the costs (direct, indirect, informal), and the time of evaluation, which makes difficult any comparisons (12, 24, 25). Analyses of economic data of patients suffering from neurocognitive disorders with real-world data are scare in France while they are needed to evaluate the economic impact of interventions and for policy makers (26). The present study aimed at estimating the real medical direct costs of care of patients of a memory center at all stages of cognitive impairment during the one year after their first memory visit, and at investigating the potential associations between patient socio demographic and clinical characteristics and the average real medical and non-medical direct costs. Furthermore, these associations were assessed in the sub-group of patients with Alzheimer’s disease (AD).

 

Methods

Study design and setting

The present study was a cross-sectional analysis conducted on matched data between the MEMORA cohort including patient clinical data and the claims database of the French Primary Health Insurance Fund (PHIF). The protocol of the MEMORA cohort has been published previously (27). The match between the two databases was performed using the date of the 1st visit at a memory center. The claims database includes real medical and nonmedical direct costs of care for patients. Claims data were analyzed for one year after the first visit at a memory center. The present study was conducted at the University Clinical and Research Memory Centre of Lyon (University Hospital of Lyon, France), in collaboration with the regional PHIF of Rhône (Lyon, France). Around 90% of the French population is covered by the PHIF (28).

Study population

The study population included consecutive patients who underwent a medical examination in a memory center with a neurologist, geriatrician, or psychiatrist between 2014 and 2017. The inclusion criteria of patients were: to attend a memory visit, to have an evaluation of the functional autonomy level, not to live in a nursing home, and to be covered by the PHIF. Patients under legal protection were excluded from the study. The ethics Committee for the Protection of Persons Lyon Sud-Est IV was consulted on the 21st June 2013, and as the study was not classified as an interventional study, no written consent was required for participation. Written information regarding collection of individual data was provided to the patients and their informal caregivers and they were given the possibility to decline participation. Authorization for handling these data has been granted by the French Data Protection Authority (CNIL: Commission Nationale de l’Informatique et Libertés).

Real medical and nonmedical direct costs of cares

Source of cost data

This study was carried out from the perspective of the main payer of cares in France: the PHIF. The PHIF collects for each patient the real costs in Euros (€) of each care, act, and treatment that are reimbursed to patients. The costs included all the medical direct costs supported by the PHIF and one nonmedical direct cost (medical transportation). The others nonmedical direct costs such as home support and the indirect costs were not included since they are not covered by the PHIF.

Collected items of costs

The collected items of costs were grouped as medical direct costs ((1) outpatient cares, i.e. consultations and cares provided by general practitioners or specialists, surgical procedures in private practice, ophthalmological and hearing devices, dental cares, laboratory analyses, radiology examinations (radiology, scanners, MRI, PET, echography, bone densitometry), immunization, home dialysis, at-home hospitalizations, and health cures, (2) paramedical cares, i.e. nursing, physiotherapist, speech therapist, orthoptist, (3) pharmaceutical treatment in retail pharmacies, (4) public hospital stays, and (5) private hospital stays) and nonmedical direct costs (the medical transportations).

Valorization of the costs

The total cost per patient was estimated by adding all the costs of care, act, and treatment that occurred during the first year after the first memory center visit. The costs were presented as constant costs after adjustment using the value of Euro in 2017 as a reference, this value was available from the French national institute for statistical and economic studies (INSEE: Institut National de la Statistique et des Etudes Economiques) (https://www.insee.fr/fr/information/2417794). For each care, act, and treatment, the PHIF applies a specific reimbursement level, which is similar nationally.

Socio-demographic and clinical data at the memory center

Socio-demographic and clinical data were collected from the MEMORA cohort database, upon the first visit to the memory center (27). Socio-demographic data were: gender, age, marital status, and educational level.
Diagnosis etiologies and stages were determined by the specialist physician (neurologist, geriatrician, or psychiatrist) in charge of the patient (29-33). Patients with a cognitive complaint and normal neuropsychological performances were considered as having subjective cognitive complaint. A time to death variable was considered and calculated as the number of months between the first visit to the memory center and either the occurrence of the death or the last time the patient was known to be alive (corresponding to the end of the study period).
The following comorbidities information was collected: hypertension, hypercholesterolemia, diabetes mellitus, anxiety disorders and depressive disorders using medical report, as well as the number of drugs. The functional autonomy level was assessed during the interview with the primary caregiver with the Instrumental Activities of Daily Living (IADL) scale, including 8 activities (34). The IADL score ranges from 0 (dependent) to 8 (independent). Overall cognitive performances were assessed using the Mini Mental State Examination (MMSE), which ranges from 0 to 30 (35). The behavioral and psychological symptoms of dementia were assessed using the Neuropsychiatric Inventory (NPI) (36). A higher overall NPI score (maximum 144) is indicative of more severe behavioral disorders. The caregiver burden was assessed using the mini-Zarit scale, ranging from 0 to 7 (37). MMSE, IADL, NPI, and mini-Zarit scores were considered as continuous scores and as tertiles. MMSE scores were also considered using categories i.e. <10 (severe), 10-20 (moderate), >20 (mild).

Statistical analysis

The study population characteristics were described using the mean value ± standard deviation (SD) or the percentage, as appropriate. The costs per patient were expressed in euros and decomposed according to the origin of the costs, using means and their 95% confidence intervals (CI), medians, the 25th and 75th percentiles, and the minimum and maximum values. As the nonmedical direct costs of medical transport did not represent a large amount of the total cost, they were added, after description, to the medical direct costs to obtain a global cost per patient for further analyses.
As the distribution of the global cost was skewed, the relationship between each patient’s characteristics and the global cost was studied using generalized linear model (GLM) with log link and gamma distribution (38, 39). All significant variables associated with the total cost were then modeled together in multivariate GLM. Due to missing values for NPI and mini-Zarit scores, two different multivariate models were performed: the model 1 did not take into account the NPI and mini-Zarit scores, the model 2 did. The same multivariate models were performed within the sub-group of patients with AD. Results were summarized and presented as unadjusted and adjusted mean total cost, 95% CI, and p value. Additionally, the adjusted cost per 1 unit of IADL decrease was estimated and represented graphically.
A sensitivity analysis was conducted to examine the effect of potential “outliers” on the results. The “outliers” were identified as individual total cost greater than 3SD from the mean. The characteristics of the patients with outlier costs were compared to the characteristics of other patients, using Student t test or Pearson’s chi-square test. A new model was then performed after excluding the costs from the patients with outliers to verify whether the associations remained similar. P values below 0.05 were considered as statistically significant. Analyses were performed using STATA version 13 for Windows (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP), and SPSS (Statistical Package for the Social Sciences) version 19.0 for Windows (SPSS Inc., Chicago, Illinois, USA).

 

Results

Study population characteristics

The study population included 2,746 patients (Table 1). Overall, 62.8% of patients were female; the mean age was 79.9 ± 8 years. The mean MMSE score was 19.7 ± 7, the mean IADL score was 4.2 ± 2, and the mean NPI score was 19.8 ± 17. In terms of etiology, 27.6% of patients had probable AD with or without cerebrovascular component, 6.4% had vascular encephalopathy (with no AD), 1.5% had Lewy body disease, and 0.4% had fronto temporal dementia. For 53.5% of the patients, the diagnosis etiology could not be established at the 1st visit at the memory center.

Table 1. Characteristics of the study population

* Time to death was the number of months from the first visit to the memory center until either the occurrence of the death or the last time the patient was known to be alive; IADL: Instrumental Activities of Daily Living; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory

 

Real direct costs of care

The total direct cost of cares was on average € 9,885 [9,175; 10,594] per patient during the year after the first memory center visit (including € 9,647 [8,946; 10,350] for medical direct costs and € 238 [213; 263] for the medical transport considered as nonmedical cost (Table 2). Most of the direct medical cost was attributable to the hospital care in public hospital (€ 6,158 [5,492; 6,824]), representing 62% of the total direct cost, followed by the cost of paramedical care (€ 1,933 [1,816; 2,050]), to the pharmaceutical treatment in retail pharmacies (€ 725 [671; 779]), to the ambulatory medicine (€ 595 [553; 637]), and finally to the care in private hospital (€ 238 [177; 299]).

Table 2. Direct costs of cares according to the origin of the cost (in Euros)

* It includes consultations and cares provided by general practitioners or specialists, surgical procedures in private practice, ophthalmological and hearing devices, dental cares, biological analyses, radiology examinations (radiology, scanners, MRI, PET, echography, bone densitometry), vaccinations, home dialysis, at-home hospitalizations, and SPA treatments; † It includes nursing, physiotherapy, speech therapy, orthoptist.

 

Unadjusted associations between patient characteristics and the mean total cost of cares

The mean total cost was significantly higher with increasing age (p<0.0001), whereas no difference was found between genders (p=0.53; Table 3). The mean total cost was significantly higher when the educational level was lower (p<0.0001) e.g. € 10,782 [9,850; 11,714] for patients with primary educational level vs. € 6,938 [5,909; 7,967] for patients with tertiary educational level. The mean total cost was also significantly associated with the marital status (p<0.0001) and it was higher for patients with diabetes mellitus (€ 12,042 [10,580; 13,505], p<0.0001) or anxiety disorders (€ 12,557 [11,388; 13,725], p<0.0001) compared to those without (€ 9,491 [8,963; 10,018] and € 8,844 [8,314; 9,375] respectively). The mean total cost was higher when the number of drugs increased (p<0.0001). The mean total cost varied depending on the diagnosis etiology (p<0.0001): € 10,444 [9,444; 11,444] for patients with AD, while it was the highest for patients with Parkinson’s disease (€ 21,155 [11,443; 30,866]) and Lewy body disease (€ 20,433 [11,913; 28,951]). The mean total cost increased with the diagnosis severity (p<0.0001): the mean total cost was € 7,897 [7,142; 8,651] for patients with subjective cognitive complaint, € 9,600 for patients with MCI [8,714; 10,487], and € 11,505 [10,614; 12,396] for patients with dementia. The mean total cost was higher when the cognitive performance was lower (based on the MMSE score, p<0.0001); a one-point decrease of the MMSE score was associated with an increase cost of € 288 [170; 408]. The mean total cost was higher when the functional autonomy level was lower (based on the IADL score, p<0.0001), and a one-point decrease of the IADL score was associated with an increase cost of € 1,359 [1,069; 1,648]. The mean total was higher when the behavioral disturbances were higher (based on the NPI score, p=0.0001).

Table 3. Unadjusted relationships between patient’s characteristics and costs of care (in Euros) (n=2,746)

* Generalized linear model with log-normal link and gamma distribution; † Time to death was the number of months from the first visit to the memory center until either the occurrence of the death or the last time the patient was known to be alive; IADL: Instrumental Activities of Daily Living; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory

 

Adjusted associations between patient characteristics and the mean total cost of care

When all the variables that were significantly associated with the mean total cost in the unadjusted models were modeled together, all the variables still contributed significantly to the model, and the adjusted mean total cost was 13,057 [10,957; 15,168] per patient (Table 4). More precisely, the IADL score was negatively correlated to the mean cost, and a one-point decrease in the IADL score corresponded to an increase of the cost of € 1,211 [890; 1,532], after adjustment for age, educational level, diabetes mellitus, anxiety disorders, number of drugs, marital status, diagnosis etiology, time to death variable and MMSE score (Figure 1).

Figure 1. Adjusted means* of medical costs according to the IADL score

*Adjusted for age, educational level, diabetes mellitus, anxiety disorders, number of drugs, marital status, diagnosis etiology, MMSE score and time to death; IADL: Instrumental Activities of Daily Living

Table 4. Adjusted relationships between patient’s characteristics and costs of care (in Euros)

* Model 1: Generalized linear model (GLM) with log-normal link and gamma distribution including age, educational level, marital status, diabetes mellitus, anxiety disorders, number of drugs, etiology, time to death, IADL score and MMSE score tertiles; † Model 2: GLM with log-normal link and gamma distribution including the variables of the model 1, and NPI score and mini-Zarit score tertiles; IADL: Instrumental Activities of Daily Living; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory

 

In the sub-group of patients with AD (n=758), the adjusted mean total cost was 11,421 [9,982; 12,859]; a higher age (p=0.002), the presence of hypercholesterolemia (p=0.045), the presence of anxiety disorders (p<0.0001), a higher number of drugs (p<0.0001), and a lower IADL score (p<0.0001) were independently associated with higher costs of care (Supplement Table 1). The multivariate model found higher costs for patients with a MMSE score between 13 and 18 (€ 11,918 [9,687; 14,149]) compared to patients with lower and higher MMSE score: € 7,913 [6,425; 9,401] (MMSE≤13), and € 8,400 [7,165; 9,636] (MMSE>18). When including the NPI score and the mini-Zarit score tertiles in the model (Model 2), higher behavioral disorders (p=0.003) and higher caregiver burden (p<0.0001) were significantly associated with higher cost of cares. For patients with AD, the IADL score was negatively correlated to the mean cost, and a one-point decrease in the IADL score corresponded to a cost increase of € 1,096 [372; 1,820], after adjustment for age, number of drugs, time to death variable, anxiety, hypercholesterolemia, and MMSE score (Supplement Figure 1).

Sensitivity analysis

Among the 2,746 patients included in the present study, 88 were identified as having outlier costs (Supplementary Table 2). These patients were characterized by a slightly older age (81.9 ± 7.5 years vs. 79.9 ± 7.9 years, p=0.02), a higher number of drugs (13.4 ± 5.8 vs. 11 ± 5.5, p<0.0001), a worse functional impairment (IADL≤3 in 69.4% vs. 40.8% patients, p<0.0001), a lower MMSE score (MMSE≤17 in 52.3 vs. 33.1% patients, p<0.0001) compared to the group of patients without outlier costs. Among these patients, the proportion of dementia was higher (56.8% vs. 41.9% patients, p=0.02). Caregiver burden was higher in the group with outliers compared to the group without (Mini-Zarit>4: 43.1% vs. 29.4%). The multivariate model without outliers found similar associations between characteristics and total costs (Supplementary Table 3) as obtained with the complete set of patient data, excepted for the educational level and the diabetes mellitus for which the statistical significance was not reached anymore.

 

Discussion

The present study provides an estimation of real medical and non-medical (transportation) direct costs of cares occurring during one year after the first memory center visit, for a large sample of outpatients at all stages of cognitive impairment, from the perspective of the main health insurance: annual medical direct cost of € 9,885 per patient varying from € 7,897 in patients cognitively normal but with subjective cognitive complaint, to € 9,600 in patients with MCI and € 11,505 in patients with dementia. The main part of direct costs of cares in our study was related to cares provided in public hospitals. Also, higher direct costs were independently associated with functional, cognitive and behavioral impairments, diabetes mellitus, anxiety disorders, higher number of drugs as well as with higher caregiver burden. The costs also varied across NCD etiologies, in particular they were higher in patients with Parkinson’s disease, and Lewy body disease compared to patients with AD. The associations between higher direct costs and functional, cognitive and behavioral impairments, anxiety disorders, number of drugs as well as with higher caregiver burden remained significant in the sub-group of patients with AD and in the sensitivity analyses restricted to individuals for whom the cost was not considered as outlier.
These results are consistent with the study of Leibson et al. conducted in a US population-based sample, showing that 70% of the direct costs of care was related to public hospitals cares, and which found an annual medical direct cost at $ 11,678 for patients with prevalent dementia, $ 9,431 for patients with newly discovered dementia, $ 6,784 for patients with MCI, and $ 6,042 for patients considered as cognitively normal (11). Besides, one can note that these results are surprisingly close in terms of level of costs, given than healthcare systems differ between countries.
The present study also confirmed and extended findings of others studies conducted in different contexts and from different economic perspectives, showing that the functional abilities was a main cost driver (2, 9, 20, 25, 40-42). In Zhu et al., a decrease of one-point in functional capacities measured with the Blessed Dementia Rating Scale (score out of 22) was associated with an increase of $ 1,406 in medical direct costs among community-dwelling patients with probable AD (15), whereas a decrease of one-point in functional capacities measured with the IADL scale (score out of 8) was associated with an increase of € 1,096 for one-point decrease of IADL in the sub-group of AD patients in the present study.
In the present study, direct medical costs were higher in patients with Lewy body disease or Parkinson’s disease compared to others NCD etiologies such as AD. While sample sizes in these sub-groups were limited, this observation is sustained by previous studies showing that Lewy body dementia was the costliest compared to others dementia’s etiologies (43), explained in part by cost of cares related to falls, urinary incontinence or infection, depression, anxiety, dehydration, and delirium. Another study also showed that Parkinson’s disease was associated with higher direct health care cost per patient compared to dementia without providing possible explanations (3).
Additional evidences of the association between costs and the MMSE were provided herein, in accordance with others studies (12, 25). However, in the study of Lindholm et al., the MMSE was not associated with the costs after adjustment for functional abilities (40). In the latter study, the characteristics of the population (community-dwelling population-based with a mean MMSE score of 26.6 ± 6) differed from the characteristics of the population studied here (patients of a memory center with a mean MMSE score of 19.7 ± 7), and the sample size was smaller, which may partially explain this discrepancy. Interestingly, in adjusted models, higher direct costs were found in patients with a MMSE score in the second tertile in the whole population study as well as in the AD sub-group (i.e. 13-18), whereas costs were lower in patients with lower or higher MMSE. In particular, patients with a MMSE score at 13-18 were found to have higher costs related to hospital stays for surgery and geriatric cares, higher costs for ambulatory cares in linked with visits to physicians, hearing device, radiology, and laboratory evaluations, and higher costs linked with medical transportation compared to patients with lower or higher MMSE score (detailed results not shown). A possible explanation for this finding is that patients at a more advanced stage of NCD may undergo less elective surgery due to higher risks of complications and higher mortality rates following surgical procedures in patients with dementia (44), and they might have lower health care consumption since the diagnosis has been previously made and less exploratory examinations are needed.
Similarly, higher direct costs were significantly associated with behavioral disorders in accordance with some studies (20, 21), but not all (23, 45). The use of reimbursement data from claims database in the present study instead of self-report use of care reinforces the objectivity of the analysis and strengthens the conclusion that behavioral disorders are associated with a significant increase of cost independently of other patient characteristics.
Also, higher costs were associated with higher caregiver burden, as observed in a previous study conducted from a societal point of view (23). Since the association remained significant after adjustment for others characteristics, we hypothesize that higher costs could directly contribute to the higher burden carried by the informal caregiver, independently of the patients’ impairments. This hypothesis is supported by a previous study showing an association between the financial stress and the higher caregiver burden (46). Even though the costs were estimated from the perspective of the national health insurance in the present study, the insurance may not cover the entire cost borne by patients and their caregivers. Nevertheless, further evidences are needed to confirm this hypothesis.
An original result of the present study was that among the comorbidities considered in the present study, diabetes mellitus and anxiety disorders were independently related to higher costs, while hypertension and hypercholesterolemia were not in the whole sample. In patients with AD, diabetes mellitus was not associated with costs, whereas a slight association was observed with hypercholesterolemia. The results are controversial in the literature concerning the link between comorbidities and costs in patients with NCD, e.g. Jutkowitz et al did not find significant link between comorbidities and costs (42), whereas Hill et al did (47).

Strengths and limits of the study

The present study included a large sample of outpatients attending a memory center with matched patient clinical data and costs. Real costs of care were estimated from claims database from the PHIF that is the main insurance in France and covers 90% of the French population (28), this limited the introduction of selection biases in the population other than the ones considered for the study. The study included patients at all stages of cognitive impairment, which allowed to conduct study between stage groups and to have a global overview of the medical direct costs (plus the medical transport) of patients visiting a memory center. According to a previous study based on the French National Alzheimer Database (48), 118,776 patients with AD attended a memory center in 2010, based on the results of the present study, the total direct cost covered by the PHIF for patients with AD one year after the first visit would be estimated to €370,337,356.
Limitations should nevertheless be considered when interpreting the results herein. This study had a cross-sectional design which does not allow causal relationships between the associations to be determined. The study did not include the societal perspective: this cost analysis did not include the indirect costs (e.g. indirect consequences of the disease such as lost work productivity or earning and informal costs), and the others nonmedical direct costs (e.g expenditures linked with the disease but not associated with medical services such as home services, nonmedical transport), except medical transportation, which led to an underestimation of the costs related to NCD, nevertheless it was specified that this study is not a cost-of-illness study. Previous studies have shown that a major part of the cost related to patients with cognitive impairment was supported by informal caregivers (informal care costs), especially when the patients were living at home, and costs estimation required specific surveys, often based on self-reported caregiving time allowed to patient and an extrapolation of the caregiver’s loss of earnings (21). In addition, the interpretation of these results should take into account the fact that a part of the direct medical costs can also be covered by private insurance that the patients can contract, the present study is from the point of view of the main French public health insurance. This study should also be interpreted in regards of the setting since all patients with cognitive impairment are not managed in memory centers and a part are followed by community practitioners, the care and then the costs may differ. Finally, mean costs should be interpreted with caution as the distribution of costs was skewed, nevertheless the statistical models took into account this data distribution.

 

Conclusion

This large study showed that functional and cognitive impairment, behavioral disorders, caregiver burden, diabetes mellitus, anxiety disorders, and the number of drugs were independently associated with higher direct cost of care for patients attending a memory center, from the payer perspective (French health insurance). The identification of these factors associated to higher direct costs of care offers additional direct targets to evaluate how interventions conducted in patients with NCD impact direct costs of care. Further researches are needed to broaden the economic perspective to the societal one and verify whether societal costs remain driven by the same factors.

 

Funding: The MEMORA study has received funding supports from MSD Avenir Fund, and Biogen Inc. These sponsors enabled the funding of nurses to carry out the research and questionnaires; they had no role in the design, conduct, collection, analysis and interpretation of the data, as well as in the preparation of the manuscript, its review and approval.

Acknowledgements: We thank Mrs. Pascale Gauthier-Robino and Mr. Laurent Colas from the Primary Health Insurance Fund of the Rhône (CPAM Rhône, France) for their collaboration during this research, Dr Michele Potasham for her advice, Mrs. Hélène Boyer (Direction de la Recherche Clinique et Innovation, Hospices Civils de Lyon, Lyon, France) for her help in the manuscript preparation and Mrs. Sarah Achi for her help in data management. We are grateful to the participants and the hospital staff.

Conflict of interest: The authors declare that they have no competing interests.

Study registration: ClinicalTrials.gov Identifier: NCT02302482. Registered: 27th November 2014, https://clinicaltrials.gov/ct2/show/NCT02302482.

Ethical standards: Written information regarding collection of individual data was provided to the patients and their informal caregivers and they were given the possibility to decline participation. This research conducted in routine care was considered as non-interventional by the local ethics committee CPP Lyon Sud-Est IV (Comité de Protection des Personnes / committee for the protection of people). Authorization for handling these data has been granted by the French Data Protection Authority (CNIL: Commission Nationale de l’Informatique et Libertés).

Supplementary Material

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