economic evaluation of aerobic exercise training in...

For peer review only

Economic evaluation of Aerobic Exercise Training in Older Adults with Vascular Cognitive Impairment – PROMoTE trial

Journal: BMJ Open

Manuscript ID bmjopen-2016-014387

Article Type: Research

Date Submitted by the Author: 21-Sep-2016

Complete List of Authors: Davis, Jennifer; University of British Columbia, Department of Population & Public Health, Hsiung, Robin Bryan, Stirling; University of British Columbia, Centre for Clinical Epidemiology Best, John Eng, Janice; University of British Columbia, Department of Physical Therapy

Munkacsy, Michelle Cheung, Winnie Chiu, Bryan Jacova, Claudia Lee, Phil Liu-Ambrose, Teresa; University of British Columbia, Department of Physical Therapy,

Primary Subject Heading:

Health economics

Secondary Subject Heading: Geriatric medicine

Keywords: mild cognitive impairment, cost-utility analysis, economic evaluation, older

adults, exercise, aerobic training

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Economic evaluation of Aerobic Exercise Training in Older Adults with Vascular

Cognitive Impairment – PROMoTE trial

Jennifer C Davis 1,2, Ging-Yuek Robin Hsiung 3, Stirling Bryan4, John R Best1, Janice J Eng 1, Michelle Munkacsy2, Winnie Cheung2, Bryan Chiu2, Claudia Jacova3, Philip Lee 5, Teresa Liu-Ambrose1,2 *1,2

1 Department of Physical Therapy, University of British Columbia, Vancouver, Canada 2 Centre for Hip Health and Mobility, Vancouver Coastal Research Institute, Vancouver, Canada 3 Division of Neurology, University of British Columbia, Vancouver, Canada 4 Centre for Clinical Epidemiology and Evaluation, University of British Columbia, Vancouver, Canada 5 Division of Geriatric Medicine, University of British Columbia, Vancouver, Canada

* Corresponding author:

Jennifer C Davis University of British Columbia Djavad Mowafaghian Centre for Brain Health 2215 Wesbrook Mall Vancouver, BC V6T 1Z3 Tel: 1-604-875-4111 ext. 69059 Fax: 1-604-875-4762 Email: [email protected] Keywords: economic evaluation, older adults, cost-effectiveness, cost-utility, mild cognitive impairment

Abstract word count: 250 Text word count: 3183 Number of Tables: 3 Number of Figures: 2 References: 32

Running Head: Economic evaluation of PROMoTE Trial Registration: ClinicalTrials.gov Protocol Registration System: NCT01027858.

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ABSTRACT

Background/Objectives: Aerobic-based exercise training may delay the progression of cognitive decline among seniors with vascular cognitive impairment (VCI). Yet, the economic consequences relating to aerobic training remain unknown. Therefore, our primary objective was to estimate the incremental cost per quality adjusted life years gained of a thrice weekly aerobic training intervention compared with usual care. Design: Cost-utility analysis alongside a randomized trial. Setting: Vancouver, British Columbia, Canada. Participants: Seventy adults (mean age of 74 years, 51% female) who meet the diagnostic criteria for mild Sub-cortical Ischaemic VCI (SIVCI). Intervnetion: A six-month, thrice-weekly, progressive aerobic exercise training program compared with with usual care (CON; comparator) with a follow-up assessment six months after formal cessation of aerobic exercise training. Measurements: Healthcare resource utilization was estimated over the six-month intervention and six-month follow-up period. Health status (using the EQ-5D) at baseline and trial completion and six-month follow-up was used to calculate quality adjusted life years (QALYs). The incremental cost-utility ratio (cost per QALY gained) was calculated. Results: QALYs were both modestly greater indicating a health gain and total healthcare costs (i.e., $1732±1324 at six months) were greater indicating a cost increase for the thrice weekly aerobic training group compared with CON. From the Canadian healthcare system perspective, the incremental cost-utility ratios for thrice weekly aerobic training were cost-effective compared with the comparator group, when using a willingness to pay threshold of $20,000 per QALY gained or higher. Conclusions: Aerobic training represents an attractive and potentially cost-effective strategy for older adults with VCI.

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Strengths and Limitations of this Study

• Aerobic-based exercise training may delay the progression of cognitive decline among

seniors with vascular cognitive impairment. • The economic consequences relating to aerobic training remain unknown. • Very few randomized controlled trials of exercise have been conducted in populations at

high-risk for dementia • There was wide variability in the cost estimates and outliers due to a smaller sample size

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INTRODUCTION

Cerebrovascular disease is the second most common etiology contributing to dementia in older adults [1-4] and may be the most under-diagnosed and yet most treatable form of cognitive dysfunction in older adults [5]. Vascular cognitive impairment (VCI) – defined as the loss of cognitive function due to cerebrovascular disease – is a prevalent condition that places a growing burden on the health care system [6]. Notably, vascular dementia has among the highest annual direct costs and highest hospitalization related costs compared with other dementias such as Alzheimer’ Disease [7]. The average annual cost per patient with VCI was $33 740 [6] compared with a variable range of $1,500 to $91,000 for Alzheimer’s Disease. The costs per VCI admission were approximately $9545 with the average number of admissions increasing through the progression of the disease [6]. Epidemiological data suggest that modification of vascular risk factors may be beneficial in slowing the progression of VCI [8-11]. Hence, aerobic-based exercise training is one promising approach to delay the progression of VCI by reducing key vascular risk factors associated with metabolic syndrome. What remains unknown is whether, aerobic-based exercise training as an intervention strategy compared with ‘usual care’ for individuals with VCI is a cost-effective strategy. To date, the simultaneous impact of health care costs and consequences remain unknown. It is an essential next step to provide an estimate of the costs and consequences (i.e., health gains or losses) related to the aerobic training intervention given that this type of intervention could be delivered at a population-level and thus, have an immense impact. Therefore, we conducted a concurrent economic evaluation with individual level data on cost and effectiveness outcomes collected during a proof-of-concept single-blinded randomized controlled trial—Promotion Of the Mind Through Exercise (PROMoTE) trial [12]. Our primary objective was to determine the incremental cost-utility ratio (incremental cost per incremental quality adjusted life year gained) of thrice weekly aerobic training compared with a ‘do nothing’ comparator, which, in this case, is usual care (CON) among individuals with mild VCI.

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METHODS Overview of economic evaluation

This cost-utility analysis was conducted concurrently with a six-month proof-of-concept single-blinded randomized controlled trial with a six-month follow-up study [12] [13]. The details of the PROMoTE trial are previously reported [12 13]. Measurements were made at three times: baseline, end of the intervention period (six months post-randomization), and six-month follow-up (twelve months post-randomization). Of 440 individuals screened for eligibility, 71 were deemed eligible for this economic evaluation. We obtained approval for this study from the UBC Clinical Ethics Review Board (H13-00715). This economic evaluation used a Canadian healthcare system perspective, and a six-month (i.e., trial completion) and a 12-month (i.e., six-month follow-up) time horizon for the primary economic evaluation assessing the efficiency of the thrice-weekly progressive aerobic training (AT) plus usual care compared with the usual care (CON; comparator) group. The main outcome for the cost-utility analysis was the incremental cost per quality adjusted life year (QALY) gained. We previously describe study design, participant recruitment, randomization, demographics, methods and results of the PROMOTE trial [12]. We recruited participants from the University of British Columbia Hospital Clinic for AD and Related Disorders, the Vancouver General Hospital Stroke Prevention Clinic, and specialized geriatric clinics in Metro Vancouver, BC. Recruitment occurred between December 2009 and April 2014 with randomization occurring on an ongoing basis. The assessors were blinded to the participants’ group allocation. The primary outcome measures for the PROMoTE study were the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog[14]), the Executive Interview (EXIT-25[15]) and the Alzheirmer’s Disease Co-operative Study – Activities of Daily Living (ADCS-ADL[16]). Secondary outcome measures included executive functions, cardiovascular capacity, physical activity level, physiological markers and health related quality of life. We included seventy community dwelling older adults who were diagnosed with Sub-cortical Ischaemic VCI (SIVCI) [17], which requires the presence of both cognitive syndrome [12] and small vessel ischaemic disease [12]. Other inclusion criteria included: 1) Montreal Cognitive Assessment (MoCA) [18] score less than 26 at screening; 2) Mini-Mental State Examination (MMSE) [19] score of > 20 at screening; 3) Community-dwelling; 4) Live in Metro Vancouver; 5) Had a caregiver, family member, or friend who interacted with him/her on a weekly basis; 6) Able to comply with scheduled visits, treatment plan, and other trial procedures; 7) Able to read, write, and speak English in which psychometric tests were provided with acceptable visual and auditory acuity; 8) Stable on a fixed dose of cognitive medications that is not expected to change during the six-month intervention period; 9) Provided a personally signed and dated informed consent document indicating that the individual (or a legally acceptable representative) has been informed of all pertinent aspects of the trial; 10) Able to walk independently; and 11) In sufficient health to participate in the study`s aerobic-based exercise training program. Costs

We tracked healthcare resource utilization prospectively using a health care resource utilization questionnaire for each participant for the duration of the six month intervention period (i.e., trial completion and for the duration of the six-month follow-up period (i.e., six-month follow-up). We analyze these endpoints separately. Participants were asked to recall their health resource utilization based on a 3-month recall period where possible. Participants were also asked to fill

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out a monthly diary detailing any health resource utilization to aid in their 3-month recall. The health care resource utilization questionnaire included the following categories: any visits to healthcare professionals (including general practitioners, specialists, physiotherapists etc); all visits, admissions or procedures carried out in a hospital; and laboratory and diagnostic tests. We calculated the costs of delivering the thrice weekly aerobic training intervention and the CON group. Our base case analysis considered the costs of all healthcare resource use. Research protocol driven costs were excluded from our analysis. A unit cost was assigned for each component of health care resource utilization. Costs for admission to hospital were based on the fully allocated cost model of a tertiary care hospital, Vancouver General Hospital. We based costs on fee for service rates from the British Columbia Medical Services Plan 2013 price list for all health care professional related costs. Unit costs for specialized services (i.e., physiotherapy, chiropractic or naturopathic medicine) were taken from the BC Association website for each specialty. We inflated (where appropriate) costs to 2013 Canadian dollars using the consumer price index reported by Statistics Canada. Given our analytic time horizon was equal to or less than 12 months, discounting was not applied.

Effectiveness outcome

We administered the EQ-5D three level version (EQ-5D-3L) at baseline, trial completion and six-month follow-up period to both patients and a patient proxy (i.e., see below under ‘Caregiver’). From these data points, we calculated the total quality adjusted life years lost or gained at six (trial completion) and 12 (follow-up completion) months for the two experimental groups. We used linear regression to calculate the incremental QALYs based on patient and proxy ratings for each participant adjusted for baseline utility score. All statistical analyses were carried out using STATA version 10.0. Caregiver (proxy)

The caregivers had to be able to read, write, and speak English in which the questionnaires were provided with acceptable visual and auditory acuity. Caregivers completed the EQ-5D-3L from their own perspective of the participant (i.e., proxy’s own perspective). Adverse events and mortality

Participants were advised to report any adverse effects due to the intervention. Our safety monitoring committee reviewed all adverse events on a monthly basis.

Handling missing data

In the PROMoTE study, 17% of participants had incomplete six-month health resource utilization data and 7% had incomplete six-month EQ-5D-3L data at trial completion including drop-outs. For the six month follow-up period, 19% of participants had incomplete six month follow-up health resource utilization data and 19% had incomplete six month follow-up EQ-5D-3L data. The reasons for missing data included: drop out, participant burden and administration error. We calculated the cost and effectiveness estimates for available cases (dropping observations with missing values), complete case sets, as well as an imputed data set. Missing data were imputed using Bayesian analyses following recommendations, [20-23] [24] in which all baseline study variables (including treatment assignment) were used to create 40

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imputed data sets; parameter estimates and standard errors were pooled across the 40 data sets. For all discrete (i.e., trial completion and six-month follow-up) time points, we used a combination of multiple imputation and bootstrapping to estimate uncertainty caused by missing values. Missing data from each follow-up period for each participant were determined separately for both cost and effectiveness outcomes. We imputed missing EQ-5D, and healthcare resource use values at two time points (trial completion and six-month follow-up). For multiple imputation, we used the “mi imput mvn” procedure in STATA. For each missing value, we generated 40 possible values using multiple linear regression. Covariates included age, MoCA, baseline value of HRU or EQ-5D-3L and the weight and value of the missing variable in the preceding period. The final imputed value was the mean of the 40 data sets created. The imputed data is reported as our base case analysis. We report the results using deletion of missing data as as our sensitivity analysis (i.e., complete case analysis).

Cost-utility analysis

We calculated the incremental cost-utility ratio for thrice weekly aerobic training compared with the CON group twice using the patient rated EQ-5D-3L and the caregiver proxy rated EQ-5D-3L. Nested imputation and nonparametric bootstrapping were used to model uncertainty around the estimates for costs and effectiveness. For each of the 40 cycles, we imputed missing values and bootstrapped the complete dataset. For each cycle of imputation and bootstrapping, we calculated the total healthcare resource use cost and QALYs according to group allocation. The results of each cycle of imputation for participants were averaged in each of the two participant groups. The contribution of each cost item in relation to the total healthcare resource use was estimated for each group. Plots of the cost-effectiveness plane and cost-effectiveness acceptability curves were generated based on 5000 iterations of nested imputation/bootstrapping using Fiellers’ method to generate 95% confidence ellipses for the joint distribution of cost and effectiveness outcomes.[25] The differences in mean costs and health outcomes in each group were expressed by reporting the incremental cost per QALY (i.e., the incremental cost-utility ratio). The observed health benefit (i.e., QALY) difference was close to zero; therefore, we used 5000 bootstrapped replications of mean cost and QALY differences.[26] We used these to generate a cost-utility acceptability curves to estimate the probability that thrice weekly aerobic training is considered cost effective compared with CON over a select range of willingness to pay values.[27] Sensitivity analysis

For our sensitivity analysis, we restricted our data to a complete case analysis, thus including only participants for whom we had complete cost and effectiveness data. We applied multiple imputation, bootstrapped confidence interval estimation, adjustment for imbalances in baseline utility and bootstrapped estimates of the incremental cost-utility ratios.

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RESULTS

Baseline characteristics and exercise compliance

Seventy-one eligible participants were randomized to AT or CON. One participant was deemed ineligible due to the presence of mixed-dementia detected after randomization and was excluded from all analyzes. Table 1 provides the baseline descriptive characteristics separated by study group. The groups were well balanced on these variables with the exception that the AT group had a lower waist-to-hip ratio. Average class attendance was 68% for the AT group. Healthcare use and costs

Complete healthcare resource utilization data were provided by 58 (83%) participants at six months and 57 (81%) at 12 months. There were no significant differences in response rates for health care utilization data for the two participant groups. Unit costs for healthcare cost items are provided in Table 2. The mean total healthcare costs were modestly, but not significantly greater for the AT group compared with CON (see Table 3).

Health outcomes

Complete data for the EQ-5D at baseline were provided by 69 (99%) patients and 63 (90%) caregivers. Complete data for the EQ-5D at six-months were provided by 65 (93%) patients and 54 (77%) caregivers. Complete data for the EQ-5D at 12-months were provided by 57 (81%) patients and 49 (70%) caregivers. There were no differences in response rates of patients or caregivers in dropouts between treatment groups. Mean quality adjusted life years calculated from the EQ-5D are provided in Table 3.

Adjusting QALYs for baseline utility in each group

Imputed Case Analysis

After controlling for baseline EQ-5D levels, the mean (SD) incremental QALY after six months calculated using the EQ-5D was 0.82 (0.06) for patients and 0.83 (0.06) using the caregivers proxy for the patients for the AT group and 0.78 (0.09) for patients and 0.79 (0.12) using the caregivers proxy for the patients for the CON group (Table 3). After controlling for baseline EQ-5D levels, the mean (SD) incremental QALY after 12 months calculated using the EQ-5D was 0.82 (0.06) for patients and 0.83 (0.05) using the caregivers proxy for the patients for the AT group and 0.78 (0.08) for patients and 0.79 (0.10) using the caregivers proxy for the patients for the CON group (Table 3).

Complete Cases Analysis

After controlling for baseline EQ-5D levels, the mean (SD) incremental QALY after six months calculated using the EQ-5D was 0.82 (0.06) for patients and 0.83 (0.05) using the caregivers proxy for the patients for the AT group and 0.78 (0.09) for patients and 0.78 (0.12) using the caregivers proxy for the patients for the CON group (Table 3). After controlling for baseline EQ-5D levels, the mean (SD) incremental QALY after 12 months calculated using the EQ-5D was 0.82 (0.03) for patients and 0.82 (0.01) using the caregivers proxy for the patients for the three times weekly aerobic training group and 0.78 (0.05) for patients and 0.78 (0.03) using the caregivers proxy for the patients for the ‘do nothing’ control group.

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Based on the point estimates from our base case analysis, we found that AT is more effective and also more costly than CON alternative. Figure 1a (using the patients own ratings of their health status) demonstrates that for three times weekly aerobic training at 6 months (i.e., intervention completion) compared with CON, most of the bootstrapped cycles (>80% of the 4000 cycles) were represented in the northeast quadrant. Figure 1b (using the caregivers ratings of the patients health status) demonstrates that for three times weekly aerobic training at 6 months (i.e., intervention completion) compared with CON, most of the bootstrapped cycles (>80% of the 4000 cycles) were represented in the northeast quadrant. Figures 1c and 1d (using the patients own ratings and caregiver ratings of their health status, respectively) demonstrates that for three times weekly aerobic training at 12 months (i.e., intervention completion) compared with CON, most of the 4000 bootstrapped cycles were represented in the northeast quadrant. Figures 2a and 2b report the cost-effectiveness acceptability curves highlighting the probability of the AT being cost-effective over different willingness to pay values. Sensitivity analysis

Our complete case analysis demonstrated the same trend with regard to a significant improvement in QALYs and a overall increase in health resource utilization costs for the AT group. DISCUSSION

Among a largely understudied population of individuals at high risk for future cognitive decline, this study demonstrated, using a Canadian healthcare system perspective, that the incremental cost per QALY gained by participating in thrice weekly AT was more effective and more costly than the CON group. We observed a trend toward improvement in the adjusted incremental QALY determined from the EQ-5D (by patients and proxies) for AT group compared with the CON group at trial completion and six-month follow-up. Importantly, aerobic training is an alternative to resistance training and is accessible to older adults with VCI. As such, the results of this economic evaluation represents a substantive contribution to the evidence base on efficiently preventing cognitive decline. The findings of this study build on previous research that demonstrated aerobic training has significant and beneficial effects on overall health related quality of life and quality of life more broadly [28]. The overall incremental cost-utility ratios were not significantly different regardless of whether QALYs were ascertained from patient reported or proxy reported health status using the EQ-5D-3L suggesting that for this population, use of patient or proxy ratings should not alter health care decision making. The cost-effectiveness acceptability curves confirm that AT is the preferred treatment option for a wide range of plausible willingness to pay thresholds.

From both our sensitivity analyses, we found that all analyses supported the conclusions that AT resulted in significant gains in QALYs. However, our imputed case analysis demonstrated the intervention was not cost-saving, while the complete case analysis demonstrated the intervention was cost-saving. One potential explanation for this was that the complete case analysis may better reflect the per protocol findings (i.e., those that had greater adherence to the trial).

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The time horizon of our study was limited to the duration of the intervention (i.e., six months) and the follow-up period (i.e., 12 months). Very few randomized controlled trials of exercise have been conducted in populations at high-risk for dementia [29]. In adults with mild VCI, six months of thrice weekly progressive aerobic training improved cognitive function, relative to CON. Previous research that aerobic training in older adults has longer- term health benefits that we hypothesize would be applicable to adults with mild VCI benefit of the intervention may be ideally captured by a longer time horizon.[30] Further, the sample size of our study was small. As such, there was wide variability in the cost estimates and outliers (i.e., ±3 standard deviations from the mean) had a stronger impact than would be expected in a larger sample. However, we did not have any reason to remove any health resource utilization outliers in our intention to treat analysis. The health resource utilization questionnaire may be subject to recall bias thus causing potential underestimation of costs. To minimize recall bias, participants were provided with a monthly diary to track and report their health care resource utilization. Given that cost-underestimation may have occurred in both groups, we do not estimate any impact on the incremental cost-utility ratio given this was a randomized controlled trial. A key strength of our study is that it deals with a largely understudied, yet important population. Importantly, this population actually may represent an ideal target population both for interventions given that individuals have not yet crossed the dementia threshold. Hence, it is important to gain better understanding of both the effectiveness and efficiency of targeted interventions. Given that even mildly impaired cognition may impede an individual’s ability to self-assess their HRQoL we also used a patient-proxy (i.e., caregiver) assessment of the patients health-status [31 32]. In this study, we found that the use of the patient or the proxy did not significantly alter our findings. In all instances, we observed a significant increase in QALYs at six and 12 months regardless of the rater. This is a useful observation because it suggests that among individuals with VCI, the rater should not result in changes in health care decision making. Our proof-of-concept findings suggest that this exercise (i.e., aerobic training) therapy delivered over a span of six months holds promise for improving cognitive function and health related quality of life in older adults with mild VCI. While our findings suggest that this intervention is not cost-saving, it appears to be cost-effective depending on a decision makers willingness to pay.

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Acknowledgements

We thanks the PROMOTE study participants. Conflict of Interest: The authors have declared that no competing interests exist. Author Contributions: TLA and JCD had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: TLA, JCD Acquisition, analysis, or interpretation of data: TLA, JCD, SB, JRB Drafting of the manuscript: JCD, TLA, SB Critical revision of the manuscript for important intellectual content: JCD, GYR, SB, JRB, JJE, MM, WC, BC, CJ, PL, TLA Statistical analysis: JCD, JRB Obtained funding: TLA, CJ, GRH, JJE, PL, JCD Administrative, technical, or material support: WC, MM, BC Study supervision: TLA, JCD, MM, WC Funding: This study is jointly funded by the Canadian Stroke Network and the Heart and Stroke Foundation of Canada. TLA is a Canada Research Chair in Physical Activity, Mobility, and Cognitive Neuroscience, a Michael Smith Foundation for Health Research (MSFHR) Scholar, a Canadian Institutes of Health Research (CIHR) New Investigator, and a Heart and Stroke Foundation of Canada’s Henry JM Barnett’s Scholarship recipient. These funding agencies did not play a role in study design. Sponsor’s Role: None.

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21. Manca A, Palmer S. Handling missing data in patient-level cost-effectiveness analysis alongside randomised clinical trials. Applied health economics and health policy 2005;4(2):65-75 doi: 421 [pii][published Online First: Epub Date]|.

22. Oostenbrink JB, Al MJ. The analysis of incomplete cost data due to dropout. Health economics 2005;14(8):763-76 doi: 10.1002/hec.966[published Online First: Epub Date]|.

23. Oostenbrink JB, Al MJ, Rutten-van Molken MP. Methods to analyse cost data of patients who withdraw in a clinical trial setting. PharmacoEconomics 2003;21(15):1103-12 doi: 21154 [pii][published Online First: Epub Date]|.

24. Schafer JL. Analysis of incomplete multivariate data. London, England: Chapman & Hall, 1997.

25. Laska EM, Meisner M, Siegel C. Statistical inference for cost-effectiveness ratios. Health economics 1997;6(3):229-42 doi: 10.1002/(SICI)1099-1050(199705)6:3<229::AID-HEC268>3.0.CO;2-M [pii][published Online First: Epub Date]|.

26. Briggs AH, Gray AM. Handling uncertainty when performing economic evaluation of healthcare interventions. Health Technol Assess 1999;3(2):1-134

27. Fenwick E, Claxton K, Sculpher M. Representing uncertainty: the role of cost-effectiveness acceptability curves. Health economics 2001;10(8):779-87 doi: 10.1002/hec.635 [pii][published Online First: Epub Date]|.

28. Awick EA, Wojcicki TR, Olson EA, et al. Differential exercise effects on quality of life and health-related quality of life in older adults: a randomized controlled trial. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation 2015;24(2):455-62 doi: 10.1007/s11136-014-0762-0[published Online First: Epub Date]|.

29. Lautenschlager NT, Cox KL, Flicker L, et al. Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer Disease: A Randomized Trial. JAMA 2008;300(9):1027-37 doi: 10.1001/jama.300.9.1027[published Online First: Epub Date]|.

30. McCartney N, Hicks AL, Martin J, et al. Long-term resistance training in the elderly: effects on dynamic strength, exercise capacity, muscle, and bone. The journals of gerontology. Series A, Biological sciences and medical sciences 1995;50(2):B97-104

31. Makai P, Beckebans F, van Exel J, et al. Quality of life of nursing home residents with dementia: validation of the German version of the ICECAP-O. PLoS One 2014;9(3):e92016 doi: 10.1371/journal.pone.0092016[published Online First: Epub Date]|.

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32. Bryan S, Hardyman W, Bentham P, et al. Proxy completion of EQ-5D in patients with dementia. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation 2005;14(1):107-18

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Table 1. Baseline characteristics of participants

Abbreviations. AT = aerobic exercise training group. CON = nutrition education

CON group

n = 35

AT group

n = 35

Variable M (SD) or n (%) M (SD) or n (%)

Descriptive variables and covariates Age, years 73.7 (8.3) 74.8 (8.4) Gender, female 17 (49%) 19 (54%) Education, > high school 27 (82%) 24 (69%) Functional Comorbidity Index 2.8 (2.2) 2.8 (1.5) Hypertensive, yes 20 (61%) 17 (49%) Mini-mental State Examination 26.4 (3.1) 26.3 (2.7) Montreal Cognitive Assessment 21.7 (4.4) 20.7 (3.3) Waist-to-hip ratio 0.93 (0.07) 0.88 (0.08) Short Physical Performance Battery 10.51 (1.20) 10.62 (1.86) Time-up-and-go (secs) 8.67 (2.26) 8.82 (2.36) Physiological Profile Assessment 0.94 (1.42) 0.94 (1.39) Medications

Taking beta blockers, yes 7 (20%) 7 (20%) Central-effecting medications, No. 0.5 (1.0) 0.6 (0.9) Total medications, No. 4.2 (3.4) 3.5 (2.7)

Primary Outcome Variables Alzheimer’s Disease Assessment Scale, Cognition

10.2 (5.4) 11.7 (5.5)

Executive Interview 13.3 (6.4) 13.7 (4.7) ADCS-ADL 46.5 (5.1) 46.1 (6.8) Secondary Outcome Variables Stroop Test 3-2 (secs) 57.12 (24.13) 67.82 (28.36) Trail Making Test B-A (secs) 75.18 (83.27) 59.70 (42.28) Digit Span Forward - Backward 3.8 (1.95) 3.37 (2.44) 6-minute walk (meters) 486.9 (97.9) 502.8 (98.4) Weight (kgs) 72.39 (14.11) 70.05 (14.31) Body mass index 26.54 (3.97) 25.26 (3.54) Resting heart rate (bpm) 70.24 (15.10) 67.26 (12.38) Resting systolic blood pressure (mm Hg) 132.29 (18.66) 139.80 (17.73) Resting diastolic blood pressure (mm Hg) 76.71 (11.38) 80.26 (10.05) Physical activity scale for the elderly 118.59 (55.41) 124.44 (73.47)

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Table 2. Unit costs for each component of resource utilization Item 6-month HRU

2013 CAN$

Mean (SD)

Median (IQR)

12-month HRU

2013 CAN$

Mean (SD)

Median (IQR)

Unit Reference

Cost of delivering control group

0 - Cost per

person year

Study records

Cost of delivering thrice weekly aerobic training

557 - Cost per

person year

Study records

Health care professional visit, mean (standard deviation)

909 (1155) 567 (1061)

659 (450) 611 (702)

Cost per

person

2013 Medical services plan

Admission to hospital

181 (314) 0 (268)

534 (1594) 0 (200)

Cost per

person

2005 Vancouver General Hospital

fully allocated cost model*

Emergency Department presentations

41 Cost per

hour



Laboratory procedures, mean (standard deviation)

109 (124) 43 (197)

104 (128) 57 (125)

Cost per

person


* Taken from the fully allocated cost model at Vancouver General Hospital. All costs were inflated to 2013 Canadian Dollars.

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Table 3. Results of imputed case analysis CON at

trial

completion

Mean (SD)

CON at

6-month

follow-up

Mean (SD)

AT at

trial

completion

Mean (SD)

AT at

6 months

follow-up

Mean (SD)

Cost of delivering programme per person (2013 CAN $)

0 (usual care)

0 (usual care) 706

706

Mean healthcare resource use cost (2013 CAN $) per person

1387 (1619) 2866 (2850) 924 (833) 2040 (1796)

Adjusted incremental QALY based on:

EQ-5D patient ý 0 (reference)

0 (reference) 0.804 (0.080) 0.800 (0.075)

EQ-5D patient proxy ý 0 (reference)

0 (reference) 0.806 (0.096) 0.810 (0.078)

Incremental cost EQ-5D patient reference reference 1712 (1324) 3009 (2416) EQ-5D patient proxy reference reference 1712 (1324) 3009 (2416) Incremental cost per QALY EQ-5D patient reference reference 2129 3761 EQ-5D patient proxy reference reference 2124 3715 Ý ICER based on total HRU costs, fall related costs and cost of delivering programs ý Incremental QALYs are adjusted for the baseline utility using a linear regression model

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Figure 1a. Cost effective plane (time horizon – 6 months) depicting the 95% confidence ellipses of incremental cost and effectiveness (patient rated health status) for comparison between three times weekly aerobic training and ‘do nothing’ usual care (control, comparator);

Figure 1b. Cost effective plane (time horizon – 6 months) depicting the 95% confidence ellipses

of incremental cost and effectiveness (caregiver (patient-proxy) rated health status) for comparison between three times weekly aerobic training and ‘do nothing’ usual care (control,

comparator);

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Figure 1c. Cost effective plane (time horizon – 12 months) depicting the 95% confidence ellipses of incremental cost and effectiveness (patient rated health status) for comparison

between three times weekly aerobic training and ‘do nothing’ usual care (control, comparator).

Figure 1d. Cost effective plane (time horizon – 12 months) depicting the 95% confidence

ellipses of incremental cost and effectiveness (caregiver (patient-proxy) rated health status) for comparison between three times weekly aerobic training and ‘do nothing’ usual care (control,

comparator).

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Figure 2a. Cost-effectiveness acceptability curve showing the probability that three times resistance training intervention is cost-effective compared to usual care (i.e., a do-nothing’ alternative) over a range of values for the maximum acceptable ceiling ratio (λ – willingness to pay) in the PROMoTE trial (6- month time horizon, patient rated health status).

Figure 2b. Cost-effectiveness acceptability curve showing the probability that three times resistance training intervention is cost-effective compared to usual care (i.e., a do-nothing’ alternative) over a range of values for the maximum acceptable ceiling ratio (λ – willingness to pay) in the PROMoTE trial (6- month time horizon, caregiver (patient-proxy) rated health status).

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Figure 2c. Cost-effectiveness acceptability curve showing the probability that three times resistance training intervention is cost-effective compared to usual care (i.e., a do-nothing’ alternative) over a range of values for the maximum acceptable ceiling ratio (λ – willingness to pay) in the PROMoTE trial (12 month time horizon, patient rated health status).

Figure 2d. Cost-effectiveness acceptability curve showing the probability that three times resistance training intervention is cost-effective compared to usual care (i.e., a do-nothing’ alternative) over a range of values for the maximum acceptable ceiling ratio (λ – willingness to pay) in the PROMoTE trial (12- month time horizon, caregiver (patient-proxy) rated health status).

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Consolidated Health Economic Evaluation Reporting Standards – CHEERS Checklist 1

The CHEERS Checklist is part of the CHEERS Statement. The CHEERS Statement has been

endorsed and co-published by the following journals:

BJOG: An International Journal of Obstetrics and Gynaecology

BMC Medicine 2013; 11:80

BMJ 2013;346:f1049

Clinical Therapeutics 27 March 2013 (Article in Press DOI: 10.1016/j.clinthera.2013.03.003)

Cost Effectiveness and Resource Allocation 2013 11:6.

The European Journal of Health Economics 2013 Mar 26. [Epub ahead of print]

International Journal of Technology Assessment in Health Care

Journal of Medical Economics 2013 Mar 25. [Epub ahead of print]

Pharmacoeconomics 2013 Mar 26. [Epub ahead of print]

Value in Health 2013 March - April;16(2):e1-e5

CHEERS Checklist

Items to include when reporting economic evaluations of health interventions

Section/item

Item

No

Recommendation

Reported

on page No/

line No

Title and abstract

Title 1 Identify the study as an economic evaluation or use more

specific terms such as “cost-effectiveness analysis”, and

describe the interventions compared.

1

Abstract 2 Provide a structured summary of objectives, perspective,

setting, methods (including study design and inputs), results

(including base case and uncertainty analyses), and

conclusions.

2

Introduction

Background and

objectives

3 Provide an explicit statement of the broader context for the

study.

4

Present the study question and its relevance for health policy or

practice decisions.

Methods

Target population and

subgroups

4 Describe characteristics of the base case population and

subgroups analysed, including why they were chosen. 5

Setting and location 5 State relevant aspects of the system(s) in which the decision(s)

need(s) to be made.

5

Study perspective 6 Describe the perspective of the study and relate this to the

costs being evaluated.

5

Comparators 7 Describe the interventions or strategies being compared and

state why they were chosen.

5

Time horizon 8 State the time horizon(s) over which costs and consequences

are being evaluated and say why appropriate.

5

Discount rate 9 Report the choice of discount rate(s) used for costs and 6

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Choice of health

outcomes

10

Measurement of

effectiveness

11a

11b

Measurement and

valuation of preference

based outcomes

12

Estimating resources

and costs

13a

13b

Currency, price date,

and conversion

14

Choice of model 15

Assumptions 16

Analytical methods 17

Study parameters 18

outcomes and say why appropriate.

Describe what outcomes were used as the measure(s) of

benefit in the evaluation and their relevance for the type of

analysis performed.

Single study-based estimates: Describe fully the design

features of the single effectiveness study and why the single

study was a sufficient source of clinical effectiveness data.

Synthesis-based estimates: Describe fully the methods used for

identification of included studies and synthesis of clinical

effectiveness data.

If applicable, describe the population and methods used to

elicit preferences for outcomes.

Single study-based economic evaluation: Describe approaches

used to estimate resource use associated with the alternative

interventions. Describe primary or secondary research methods

for valuing each resource item in terms of its unit cost.

Describe any adjustments made to approximate to opportunity

costs.

Model-based economic evaluation: Describe approaches and

data sources used to estimate resource use associated with

model health states. Describe primary or secondary research

methods for valuing each resource item in terms of its unit

cost. Describe any adjustments made to approximate to

opportunity costs.

Report the dates of the estimated resource quantities and unit

costs. Describe methods for adjusting estimated unit costs to

the year of reported costs if necessary. Describe methods for

converting costs into a common currency base and the

exchange rate.

Describe and give reasons for the specific type of decision-

analytical model used. Providing a figure to show model

structure is strongly recommended.

Describe all structural or other assumptions underpinning the

decision-analytical model.

Describe all analytical methods supporting the evaluation. This

could include methods for dealing with skewed, missing, or

censored data; extrapolation methods; methods for pooling

data; approaches to validate or make adjustments (such as half

cycle corrections) to a model; and methods for handling

population heterogeneity and uncertainty.

Report the values, ranges, references, and, if used, probability

distributions for all parameters. Report reasons or sources for

distributions used to represent uncertainty where appropriate.

Providing a table to show the input values is strongly

recommended.

6

5

N/A

N/A

N/A

5, 6,

Table 2

5/6

N/A

N/A

5,6,7

8,9

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Incremental costs and

outcomes

19

Characterising

uncertainty

20a

20b

Characterising

heterogeneity

21

Study findings,

limitations,

generalisability, and

current knowledge

22

Source of funding 23

Conflicts of interest 24

For each intervention, report mean values for the main

categories of estimated costs and outcomes of interest, as well

as mean differences between the comparator groups. If

applicable, report incremental cost-effectiveness ratios.

Single study-based economic evaluation: Describe the effects

of sampling uncertainty for the estimated incremental cost and

incremental effectiveness parameters, together with the impact

of methodological assumptions (such as discount rate, study

perspective).

Model-based economic evaluation: Describe the effects on the

results of uncertainty for all input parameters, and uncertainty

related to the structure of the model and assumptions.

If applicable, report differences in costs, outcomes, or cost-

effectiveness that can be explained by variations between

subgroups of patients with different baseline characteristics or

other observed variability in effects that are not reducible by

more information.

Summarise key study findings and describe how they support

the conclusions reached. Discuss limitations and the

generalisability of the findings and how the findings fit with

current knowledge.

Describe how the study was funded and the role of the funder

in the identification, design, conduct, and reporting of the

analysis. Describe other non-monetary sources of support. Describe

contributors in accordance with journal policy. In the absence

of a journal policy, we recommend authors comply with

International Committee of Medical Journal Editors

recommendations.

For consistency, the CHEERS Statement checklist format is based on the format of the CONSORT

statement checklist

The CHEERS Statement may be accessed by the publication links above.

The ISPOR CHEERS Task Force Report provides examples and further discussion of the 24-item

CHEERS Checklist and the CHEERS Statement. It may be accessed via the Value in Health link or via the

ISPOR Health Economic Evaluation Publication Guidelines – CHEERS: Good Reporting Practices

webpage: http://www.ispor.org/TaskForces/EconomicPubGuidelines.asp

The citation for the CHEERS Task Force Report is:

Husereau D, Drummond M, Petrou S, et al. Consolidated health economic evaluation reporting standards

(CHEERS)—Explanation and elaboration: A report of the ISPOR health economic evaluations publication

guidelines good reporting practices task force. Value Health 2013;16:231-50.

8,9

8,9, Figures

1a-d

N/A

Fig1, 2

9,10

11

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STUDY PROTOCOL Open Access

Promotion of the mind through exercise(PROMoTE): a proof-of-concept randomizedcontrolled trial of aerobic exercise training inolder adults with vascular cognitive impairmentTeresa Liu-Ambrose1,2*, Janice J Eng1, Lara A Boyd1, Claudia Jacova3, Jennifer C Davis2,4,5, Stirling Bryan5,Philip Lee6, Penny Brasher5, Ging-Yuek R Hsiung3

Abstract

Background: Sub-cortical vascular ischaemia is the second most common etiology contributing to cognitiveimpairment in older adults, and is frequently under-diagnosed and under-treated. Although evidence is mountingthat exercise has benefits for cognitive function among seniors, very few randomized controlled trials of exercisehave been conducted in populations at high-risk for progression to dementia. Aerobic-based exercise training maybe of specific benefit in delaying the progression of cognitive decline among seniors with vascular cognitiveimpairment by reducing key vascular risk factors associated with metabolic syndrome. Thus, we aim to carry out aproof-of-concept single-blinded randomized controlled trial primarily designed to provide preliminary evidence ofefficacy aerobic-based exercise training program on cognitive and everyday function among older adults with mildsub-cortical ischaemic vascular cognitive impairment.

Methods/Design: A proof-of-concept single-blinded randomized trial comparing a six-month, thrice-weekly,aerobic-based exercise training group with usual care on cognitive and everyday function. Seventy older adultswho meet the diagnostic criteria for sub-cortical ischaemic vascular cognitive impairment as outlined by Erkinjunttiand colleagues will be recruited from a memory clinic of a metropolitan hospital. The aerobic-based exercisetraining will last for 6 months. Participants will be followed for an additional six months after the cessation ofexercise training.

Discussion: This research will be an important first step in quantifying the effect of an exercise intervention oncognitive and daily function among seniors with sub-cortical ischaemic vascular cognitive impairment, arecognized risk state for progression to dementia. Exercise has the potential to be an effective, inexpensive, andaccessible intervention strategy with minimal adverse effects. Reducing the rate of cognitive decline among seniorswith sub-cortical ischaemic vascular cognitive impairment could preserve independent functioning and healthrelated quality of life in this population. This, in turn, could lead to reduced health care resource utilization costsand avoidance of early institutional care.

Trial Registration: ClinicalTrials.gov Protocol Registration System: NCT01027858.

* Correspondence: [email protected] of Physical Therapy, University of British Columbia, Vancouver,Canada

Liu-Ambrose et al. BMC Neurology 2010, 10:14http://www.biomedcentral.com/1471-2377/10/14

© 2010 Liu-Ambrose et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

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mailto:[email protected]

http://creativecommons.org/licenses/by/2.0



BackgroundCerebrovascular disease is the second most commonetiology contributing to dementia in older adults [1-4]and may be the most under-diagnosed and yet mosttreatable form of cognitive dysfunction in older adults[5]. Vascular cognitive impairment is defined as the lossof cognitive function resulting from ischaemic, ischae-mic-hypoxic, or hemorrhagic brain lesions as a result ofcerebrovascular disease and cardiovascular pathologicchanges. As vascular cognitive impairment is predomi-nantly a sub-cortical frontal form of cognitive disorderwith prominent executive dysfunction [6], it directlyimpairs everyday function [7], such as managingfinances, transportation, or the telephone. Takentogether, vascular cognitive impairment has the potentialto severely impact the ability to function autonomouslywithin society [8].A number of epidemiological studies suggest that

modification of vascular risk factors, such as hyperten-sion, diabetes mellitus, and hypercholesterolemia may behelpful in slowing down the progression of vascular cog-nitive impairment [9-12]. Hence, one promisingapproach to delay the progression of vascular cognitiveimpairment is aerobic-based exercise training. Critically,evidence is mounting that exercise has benefits for cog-nitive function among seniors. Aerobic-based exercisetraining may be of specific benefit in slowing the pro-gression of cognitive decline among seniors with vascu-lar cognitive impairment by reducing key vascular riskfactors associated with metabolic syndrome. Aerobicexercise may also act specifically on disease pathophy-siology [13], for example, by improving capillarization ormodulating brain neurotrophic factors [14-16], and mayeven decrease brain amyloid load in the brain [17].Finally, aerobic-based exercise training as an interven-tion strategy for individuals with vascular cognitiveimpairment is attractive as it could be delivered at apopulation-level.The growing consensus is that small vessel diseases

have an important role in vascular cognitive impairment[18,19]. Small vessel disease often presents as unde-tected “covert” strokes in the sub-cortical white matter.Compared to other forms of vascular cognitive impair-ment, the sub-cortical ischaemic vascular disease sub-type is a more homogenous form of the disease with amore predictable outcome [20]. While mild Sub-corticalIschaemic Vascular Cognitive Impairment (SIVCI)describes those individuals whose symptoms are notassociated with substantial functional impairment [18],persons with mild SIVCI have a high risk of progressionto dementia [18,21]. Seniors with mild SIVCI are also atrisk for executive dysfunction [18], and subsequently atrisk for decline in everyday function (i.e., ability to

perform instrumental activities of daily living [ADLs])[7]. Instrumental ADLs refer to capacities that arerequired for autonomous function within society [8]; theability to perform instrumental ADLs is a key aspect offunctional independence and health related quality oflife [8]. Thus, persons with mild SIVCI represent anideal target population for intervention strategies, aspreservation of their cognitive and functional status willlikely maintain and prolong their ability to live indepen-dently and with quality. To our knowledge, no rando-mized controlled trial has assessed the effect of aerobic-based exercise training on cognitive and everyday func-tion among seniors with mild SIVCI. Thus, we aim tocarry out a proof-of-concept single-blinded randomizedcontrolled trial primarily designed to provide prelimin-ary evidence of efficacy of a six-month, thrice-weekly,aerobic-based exercise training program on cognitiveand everyday function among older adults with mildSIVCI. In addition, this proof-of-concept study will aimto explore the effect of aerobic-based exercise trainingon: 1) serum glucose, hemoglobin A1c, and lipids; 2)inflammatory biomarkers; 3) physical function; 4) healthrelated quality of life; and 5) health resource utilization.Finally, this study will demonstrate the feasibility of deli-vering the intervention in this population, determine therecruitment rate, determine the rate of withdrawal, andprovide estimates of the variances, co-variances andeffect sizes of the proposed outcome measures to informthe sample size for a larger definitive trial.

Methods/DesignDesign OutlineWe will conduct a six-month proof-of-concept single-blinded randomized trial and follow our study cohortfor an additional six months of follow-up (see Figure 1).

RecruitmentWe will recruit seniors with mild SIVCI through theUniversity of British Columbia Hospital Clinic for Alz-heimer Disease and Related Disorders (UBCH-CARD).All individuals who receive care at the UBCH-CARDhave the option to sign a consent form providing accessto their records for research purposes and indicatingtheir willingness to be approached for research studies.One trained research assistant will review the charts ofpatients at the UBCH-CARD who have expressed inter-ests to participate in research studies. Clinicians at theUBCH-CARD will also be informed of this study andthey will assist in recruitment by flagging the charts oftheir current patients who may qualify for this study toour research assistants. Those who appear eligible basedon detailed chart review will be mailed an informationpackage regarding the study, including the consent form.


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For those who are interested in participating, a onehour consent and screening session will be arranged.Once informed consent is obtained, we will perform thescreening tests. Those who remain eligible after thescreening session and who later provide written recom-mendation from their physician indicating their appro-priateness to participate in an aerobic-based exercisetraining program will proceed to baseline assessments.

EligibilityWe will recruit individuals who fulfill the diagnostic cri-teria for SIVCI as outlined by Erkinjuntti and colleagues[22], which requires the presence of both cognitive syn-drome (as defined in Section A below) and small vesselischaemic disease (as defined in Section B below).A. Cognitive Syndrome defined as:1. Dysexecutive Syndrome: Some impairment in goal

formulation, initiation, planning, organizing, sequencing,executing, set-shifting and maintenance, or abstracting.

2. Memory Deficit: Some impairment in recall in thepresence of relatively intact recognition and benefitfrom cueing.3. Progression: Deterioration of A1 and A2 from a pre-

vious higher level of functioning that are not per seinterfering with complex occupational and socialactivities.B. Small Vessel Ischaemic Disease defined as:1. Evidence of relevant cerebrovascular disease by

brain imaging (in the last 12 months) defined as thepresence of both:

i. Periventricular and deep white matter lesions: Pat-chy areas of low attenuation (intermediate densitybetween that of normal white matter and that ofintraventricular cerebrospinal fluid) or diffuse sym-metrical areas of low attenuation with ill definedmargins extending to the centrum semiovale, plus atleast one lacunar infarct (correlating to the white

Figure 1 Overview of the flow of participants through the Promotion of the Mind Through Exercise (PROMoTE) Trial.


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matter grading scale greater than 3 from the Cardio-vascular Health Study) [23,24]; andii. Absence of cortical and/or cortico-sub-corticalnon-lacunar territorial infarcts and watershedinfarcts, haemorrhages indicating large vessel disease,signs of normal pressure hydrocephalus, or otherspecific causes of white matter lesions (e.g., multiplesclerosis, leukodystrophies, sarcoidosis, brain irradia-tion, etc).

2. Presence or a history of neurological signs as evi-dence for cerebrovascular disease such as lower facialweakness, Babinski sign, sensory deficit, dysarthria, gaitdisorder, or extrapyramidal signs consistent with sub-cortical brain lesion(s).In addition, individuals must meet the following inclu-

sion criteria: 1) Montreal Cognitive Assessment (MoCA)[25] score less than 26 at screening; 2) Mini-MentalState Examination (MMSE) [26] score of ≥ 20 at screen-ing; 3) Community-dwelling; 4) Live in Metro Vancou-ver; 5) Have a caregiver, family member, or friend whointeracts with him/her on a weekly basis; 6) Able tocomply with scheduled visits, treatment plan, and othertrial procedures; 7) Must be able to read, write, andspeak English in which psychometric tests are providedwith acceptable visual and auditory acuity; 8) Stable ona fixed dose of cognitive medications (e.g., donepezil,galantamine, rivastigmine, memantine, etc.) that is notexpected to change during the 12-month study period,or, if they are not on any of these medications, they arenot expected to start them during the 12-month studyperiod; 9) Provide a personally signed and datedinformed consent document indicating that the indivi-dual (or a legally acceptable representative) has beeninformed of all pertinent aspects of the trial. In addition,an assent form will be provided at baseline and again atregular intervals; 10) Able to walk independently; and11) Must be in sufficient health to participate in thestudy’s aerobic-based exercise training program. Thiswill be based on medical history, vital signs, physicalexamination by study physicians, and written recom-mendation by family physician indicating one’s appropri-ateness to participate in an aerobic-based exercisetraining program.The exclusion criteria are: 1) Absence of relevant

small vessel ischaemic lesions on an existing brain com-puted tomography (CT) or magnetic resonance imaging(MRI); 2) Diagnosed with another type of neurodegen-erative (e.g. AD) or neurological condition (e.g., multiplesclerosis, Parkinson’s disease, etc.) that affects cognitionand mobility; 3) At high risk for cardiac complicationsduring exercise and/or unable to self-regulate activity orto understand recommended activity level (i.e., Class Cof the American Heart Risk Stratification Criteria); 4)

Have clinically significant peripheral neuropathy orsevere musculoskeletal or joint disease that impairsmobility; 5) Taking medications that may negativelyaffect cognitive function, such as anticholinergics,including agents with pronounced anticholinergic prop-erties (e.g., amitriptyline), major tranquilizers (typicaland atypical antipsychotics), and anticonvulsants (e.g.,gabapentin, valproic acid, etc.); or 6) Planning to partici-pate, or already enrolled in, a clinical drug trial concur-rent to this study.Ethical approval has been obtained from the Vancou-

ver Coastal Health Research Institute (V07-01160) andthe University of British Columbia’s Clinical ResearchEthics Board (H07-01160).

Sample SizePrior to launching a definitive randomized controlledtrial, it is essential that the feasibility of conducting sucha trial be demonstrated. A sample for a definitive studywith multiple end-points and outcome variables willrequire several hundred participants and warrant amulti-site study. Given that no study has examined theeffect of exercise on cognitive function in SIVCI, wehave selected a sample size of 30 participants per group.Studies have suggested a standard deviation of changeof 6 to 7 [27-29] in Alzheimer Disease Assessment ScaleCognitive (ADAS-Cog) scores among individuals withvascular cognitive impairment. We highlight that arecent exercise trial among seniors at risk for AD withADAS-Cog as the primary outcome measure demon-strated an effect size of 0.60 [30]. Thus, assuming analpha of 0.05, 30 participants per group will provide apower of 0.75 to 0.80. We estimate a drop-out rate of10% during a 12-month period. Hence, we are aiming torecruit 35 participants per group (i.e., 70 participants intotal) which will accommodate a conservative 15% drop-out rate.

MeasurementsBaseline measurements will be obtained prior to rando-mization. There will be three measurement sessions:baseline, 6 months, and 12 months (Figure 1). Out-comes will be assessed by trained assessors blinded togroup allocation.Screening SessionFor the screening session, we will administer the Physi-cal Activity Readiness Questionnaire (PAR-Q) [31], ascreening measure of physical readiness for exercise.Global cognitive function will be assessed using theMMSE [26] and the MoCA [25].DescriptorsUsing a wall mounted stadiometer, standing height willbe measured as stretch stature to the 0.1 cm per stan-dard protocol. Weight will be measured twice to the 0.1


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kg on a calibrated digital scale. General health andsocioeconomic status will be ascertained by a question-naire. Participants will undergo a clinical assessmentwith neurologist and study physicians (G-YRH and PL)at baseline to confirm current health status and eligibil-ity for study, including clinical impressions of overallcognitive and functional status. The NeuropsychiatricInventory (NPI), an informant-rated instrument, will beused to evaluate behavioural and neuropsychiatric symp-toms [32].Physical activity, not including the study-assigned

exercise classes, will be determined by the valid and reli-able Physical Activities Scale for the Elderly (PASE)questionnaire [33,34]. Designed for those aged 65 yearsand older, participants use a 12-item scale to self-reportthe average number of hours per day spent participatingin leisure, household, and occupational physical activ-ities over the previous seven-day period. Accounting forextracurricular physical activities throughout the rando-mized trial is essential to ascertain the specific effects ofthe delivered interventions on cognition and function.Primary OutcomesCognitive Function We will assess cognitive functionusing the cognitive section of the Alzheimer DiseaseAssessment Scale (ADAS-Cog) [35]. The scale consistsof 11 brief cognitive tests assessing memory, language,and praxis. Scores range from 0 to 70, with higherscores indicating greater severity of cognitive impair-ment. The ADAS-Cog has been a significant outcomemeasure in numerous trials with AD [27,36,37] but alsowith vascular dementia [29,38]. The ADAS-Cog hasmarked advantages as an outcome measure, based on itssubstantial data confirming both reliability and validityand its use in measuring longitudinal change togetherwith sensitivity to treatment effects [39].Global Executive Function Because executive dysfunc-tion is common among those with SIVCI [6], we willuse the Executive Interview (EXIT-25) [40] to assessglobal executive function. The EXIT 25 provides a stan-dardized clinical assessment of executive functions. Itcontains 25 items designed to elicit signs of frontal sys-tem pathology. Performance on the EXIT25 correlateswell with standard neuropsychological tests of executivefunctions. The EXIT25 scores range from 0 to 50, withhigh scores indicating impaired global executive func-tion. A cut point of 15 out of 50 is recommended [40].Everyday FunctionBecause executive dysfunction isassociated with impaired everyday function [7], we willuse the ADCS-ADL to assess the ability to performeveryday activities of daily living [41]. The ADCS-ADLis a 23-item informant-rated questionnaire that mea-sures, in a range of 0 to 78, an individual’s performanceof activities of daily living.

Secondary OutcomesBlood Biomarkers Serum glucose, Hgb A1c, and lipidlevel will be measured by conventional methods. SerumHSC, CRP, and IL-6 will be determined by standardELISA methods [42].Physical Function Physical function will be assessedusing a three-instrument performance battery thatincludes:1) Six-Minute WalkThis is a walking test of physical status to assess gen-

eral cardiovascular capacity in seniors [43]. The totaldistance walked in meters in six minutes is recorded inmeters.2) Balance and MobilityGeneral balance and mobility will be assessed with the

National Institute on Aging (NIA) Balance Scale [44].For this Scale, participants are assessed on performancesof standing balance, walking, and sit-to-stand. Eachcomponent is rated out of four points, for a maximumof 12 points. Poor performance on this scale predictssubsequent disability [44].3) Physiological Falls RiskWe will use the Physiological Profile Assessment

(PPA)© [45] (Prince of Wales Medical Research Insti-tute, Randwick, Sydney, NSW, Australia) to assess forphysiological falls risk. The PPA is a valid and reliabletool for assessing fall risk in older people. Based on theperformance of five physiological domains (posturalsway, hand reaction time, quadriceps strength, proprio-ception, and edge contrast sensitivity), the PPA com-putes a fall risk score for each individual and thismeasure has a 75% predictive accuracy for falls in olderpeople [45]. A PPA z-score of 0-1 indicates mild risk, 1-2 indicates moderate risk, 2-3 indicates high risk, and 3and above indicates marked risk [46].4) Quality of LifeWe will evaluate health related quality of life using the

EuroQol 5D (EQ-5D) – a preference-based generic uti-lity instrument that provides weightings for qualityadjusted life year (QALYs). QALYs are defined as thebenefit of a health intervention in terms of time in aseries of quality-weighted health states, in which thequality weights reflect the desirability of living in thestate, typically from “perfect” health (weighted 1.0) todead (weighted 0.0) [47]. QALYs are calculated basedon the quality of life of a patient (measured using healthutilities) in a given health state and the time spent inthat health state. The EQ-5D captures 243 uniquehealth states based on the following domains: 1) mobi-lity; 2) self-care; 3) usual activities; 4) pain and 5) anxi-ety or depression. We will calculate QALYs using thehealth state utility values from the EQ-5D to determineif there is a statistically significant difference in the


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incremental cost per QALY change for participantsreceiving the aerobic-based training compared withthose who are not.5) Health Resource UtilizationThe health resource utilization questionnaire asks

participants to report the following visits over a speci-fied time period: 1) health care professionals; 2) admis-sions or visits to hospital; and 3) laboratory work. Thehealth resource utilization questionnaire has been pre-viously described and supported in previous studies[48]. We will estimate total health care related costsover the 12 months from a Canadian health care sys-tem perspective. Participants will be instructed to spe-cify total health care expenditure and report thereason for each item. Additionally, participants will beinstructed to report health care expenditure due to anyadverse events associated with the aerobic-based train-ing program; this is not anticipated to be a major costdriver. On a per participant basis, costs will beassigned to health care resource utilization using afully allocated hospital cost model (for in-patient costs)and the British Columbia provincial guide to medicalfees (for outpatient costs). Our base case analysis willconsider the costs of all health care resource use andour sensitivity analyses will include only interventionrelated health care resource costs and a complete caseanalysis.

Treatment AllocationRandomizationParticipants will be randomly assigned (1:1) to either theaerobic-based exercise training (AT) group or the usualcare (CON) group. The randomization sequence will begenerated by a central, web-based randomization servicehttp://www.randomization.net; permuted blocks of vary-ing size will be employed to ensure balance over time.After baseline assessment, research personnel notinvolved in measurement or intervention will access theweb-based randomization service to determine thegroup allocation.Allocation ConcealmentRecruitment and enrolment of participants will be man-aged by the research coordinator who will screen forstudy eligibility, obtain informed consent, and conductbaseline assessment. Following completion of baselineassessment, the research coordinator will access theweb-based randomization service and the participantwill be assigned a participant number and allocated tothe intervention or the control group. Research person-nel performing the outcome assessment and data analy-sis will be blinded to group allocation but it is notpossible to blind participants and personnel deliveringinterventions to group allocation.

Experimental GroupsAerobic-Based Training (AT) GroupAll AT group classes will be led by instructors certifiedto instruct seniors. Each 60-minute class will include a10 minute warm-up, a target of 40 minutes of walking,and a 10-minute cool down. Class attendance will berecorded for each participant by the instructorsthroughout the six-month intervention period.Over the six month intervention period, we will use

three complimentary techniques to monitor and pro-gress exercise intensity of the AT program. Each partici-pant will:1) Wear a heart rate monitor and will be asked to

work initially at approximately 40% of his/her age speci-fic target heart rate (i.e., heart rate reserve; HRR) andgradually progress to reach the target of 60% of HRR.Once the target of 60% of HRR is achieved, it will besustained by the participant for the remainder of theintervention period;2) Subjectively monitor the intensity of each workout

using the Borg’s Rating of Perceived Exertion (RPE)[49]. Participants will be gradually progressed to a targetRPE of 14 to 15; and3) Use the simple “talk” test [50,51]. Participants will

be asked to initially walk at a pace where they can con-verse comfortably without effort and gradually progressto a pace where conversation requires a bit of effort.In addition to the formal group classes, all individuals

in the AT group will be given a pedometer to serve asboth an incentive and reminder to partake in walkingon a daily basis. Participants will be asked to record thenumber of steps each day. All pedometers will bereturned to the study coordinator at the 6 month assess-ment session.Usual Care (CON) GroupParticipants in the CON group will receive educationalmaterial about vascular cognitive impairment and aboutstress management, healthful diet, and smoking. How-ever, this group will not receive specific informationregarding physical activity. Participants in the AT groupwill also be offered these educational materials.

Adverse Events MonitoringDr. Philip Lee, in addition to a physician and statisticianexternal to the research team, will review all adverseevents reported in the study on a monthly basis. Theywill inform us to stop the study if the adverse eventsdata are of sufficient concern.

Statistical AnalysesAs a primary objective of this study is to provide preli-minary evidence of efficacy we will compare partici-pants of the AT group who are compliant with the


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intervention (defined as attending 60% of the total exer-cise sessions) to the CON group rather than using anintention-to-treat analysis as would be appropriate in apivotal clinical trial. In addition, no adjustment for mul-tiple endpoints will be made since in a proof-of-conceptstudy a Type II error is of more concern than a Type Ierror [52]. For each of the three primary endpoints (i.e.,ADAS-Cog, EXIT-25, ADCS-ADL), the change frombaseline to six months and 12 months will be assessedusing an analysis of covariance model incorporating thebaseline measurement. Observing a statistically signifi-cant difference on any of the three primary outcomeswill be considered preliminary evidence of efficacy.We will also report variances, co-variances, and effect

sizes, as well as sampling feasibility (i.e., ease of recruit-ment, recruitment rate, withdrawal rate). This informa-tion will inform sampling for future trials.

Economic AnalysisOur economic evaluation will explore incremental costsand health benefits comparing the aerobic-based train-ing intervention with usual care using both cost effec-tiveness and cost utility analyses. A cost utility analysisis a specific type of cost effectiveness analysis wherehealth benefits are measured using QALYs. The out-come of our cost effectiveness analysis is the incremen-tal cost effectiveness ratio (ICER). By definition, anICER is the difference between the mean costs of pro-viding the competing interventions divided by the differ-ence in effectiveness, where ICER = Δ Cost/Δ Effect[53]. We will determine the incremental cost of theaerobic-based training intervention per person experien-cing a clinically significant improvement in cognitiveperformance relative to usual care. Further, for our costutility analysis, we will estimate the incremental cost perquality adjusted life year gained (QALY). We will use acombination of imputation and bootstrapping to quan-tify uncertainty due to missing values and the finitestudy sample size60 61.

Time FrameRecruitment will commence in December 2009. Finalfollow-up assessment is expected to conclude in Febru-ary 2012.

DiscussionAlthough exercise therapy holds promise for delayingthe onset and slowing down the progression of bothcognitive and functional decline, very few randomizedcontrolled trials of exercise have been conducted inpopulations at high-risk for dementia [30]. This researchwill be an important first step in quantifying the effectof an exercise intervention on cognitive and daily func-tion among seniors with SIVCI, as vascular cognitive

impairment is the second most common cause ofdementia in older adults [1-4]. Exercise has the potentialto be an effective, inexpensive, and accessible interven-tion strategy with minimal adverse effects. Retarding therate of cognitive decline among seniors with SIVCIcould preserve independent functioning and quality oflife in this population. This, in turn, could lead toreduced health care utilization costs and avoidance ofearly institutional care. Delaying the onset or retardingthe progression of dementia by only one year wouldreduce the number of clinical cases of dementia by 9.2million by 2050 in the US alone [54].Our interdisciplinary research team will use a multi-

pronged approach to explore the utility of aerobic-basedexercise training among seniors with mild SIVCI. Theimpact of our proposed work may be significant forseniors with mild SIVCI.

AcknowledgementsThis study is jointly funded by the Canadian Stroke Network and the Heartand Stroke Foundation of Canada.TLA and LAB are Michael Smith Foundation for Health Research (MSFHR)Scholars. LAB is also a Canada Research Chair in Neurobiology of MotorLearning. JJE is a MSFHR Senior Scholar.Sponsor’s Role: None.

Author details1Department of Physical Therapy, University of British Columbia, Vancouver,Canada. 2Centre for Hip Health and Mobility, Vancouver Coastal ResearchInstitute, Vancouver, Canada. 3Division of Neurology, University of BritishColumbia, Vancouver, Canada. 4Experimental Medicine, University of BritishColumbia, Vancouver, Canada. 5Centre for Clinical Epidemiology andEvaluation, Vancouver Coastal Research Institute, Vancouver, Canada.6Division of Geriatric Medicine, University of British Columbia, Vancouver,Canada.

Authors’ contributionsTLA, JJE, LAB, G-YRH, CJ, and JB wrote the grant application that was jointlyfunded by the Canadian Stroke Network and the Heart and StrokeFoundation of Canada in 2009. JCD, PhD candidate is affiliated with thePromotion of the Mind Through Exercise (PROMoTE) Trial. The grantapplication formed the bases for the manuscript, which was jointly draftedby TLA and JCD with all other authors contributing to its critical review andapproving the final draft.

Competing interestsThe authors declare that they have no competing interests.

Received: 18 December 2009Accepted: 17 February 2010 Published: 17 February 2010

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51. Foster C, Porcari JP, Anderson J, Paulson M, Smaczny D, Webber H,Doberstein ST, Udermann B: The talk test as a marker of exercise trainingintensity. Journal of cardiopulmonary rehabilitation and prevention 2008,28(1):24-30, quiz 31-22.

52. Schoenfeld D: Statistical considerations for pilot studies. Internationaljournal of radiation oncology, biology, physics 1980, 6(3):371-374.

53. Drummond M, Manca A, Sculpher M: Increasing the generalizability ofeconomic evaluations: recommendations for the design, analysis, andreporting of studies. International journal of technology assessment in healthcare 2005, 21(2):165-171.

54. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi H: Forecasting theglobal burden of Alzheimer’s disease. Alzheimer’s and Dementia 2007,3:186-191.

Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/10/14/prepub

doi:10.1186/1471-2377-10-14Cite this article as: Liu-Ambrose et al.: Promotion of the mind throughexercise (PROMoTE): a proof-of-concept randomized controlled trial ofaerobic exercise training in older adults with vascular cognitiveimpairment. BMC Neurology 2010 10:14.

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http://www.biomedcentral.com/1471-2377/10/14/prepub


Journal: BMJ Open

Manuscript ID bmjopen-2016-014387.R1


Date Submitted by the Author: 30-Nov-2016

Complete List of Authors: Davis, Jennifer; University of British Columbia, Department of Population & Public Health, Hsiung, Robin Bryan, Stirling; University of British Columbia, Centre for Clinical Epidemiology Best, John Eng, Janice; University of British Columbia, Department of Physical Therapy

Munkacsy, Michelle Cheung, Winnie Chiu, Bryan Jacova, Claudia Lee, Phil Liu-Ambrose, Teresa; University of British Columbia, Department of Physical Therapy,

Primary Subject Heading:

Health economics


Keywords: mild cognitive impairment, cost-utility analysis, economic evaluation, older

adults, exercise, aerobic training


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1 Department of Physical Therapy, University of British Columbia, Vancouver, Canada 2 Centre for Hip Health and Mobility, Vancouver Coastal Research Institute, Vancouver, Canada 3 Division of Neurology, University of British Columbia, Vancouver, Canada 4 Centre for Clinical Epidemiology and Evaluation, University of British Columbia, Vancouver, Canada 5 Division of Geriatric Medicine, University of British Columbia, Vancouver, Canada





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ABSTRACT

Background/Objectives: Evidence suggests that aerobic exercise may slow the progression of subcortical ischemic vascular cognitive impairment (SIVCI) by modifying cardiovascular risk factors. Yet, the economic consequences relating to aerobic training remain unknown. Therefore, our primary objective was to estimate the incremental cost per quality adjusted life years gained of a thrice weekly aerobic training intervention compared with usual care. Design: Cost-utility analysis alongside a randomized trial. Setting: Vancouver, British Columbia, Canada. Participants: Seventy adults (mean age of 74 years, 51% female) who meet the diagnostic criteria for mild SIVCI. Intervention: A six-month, thrice-weekly, progressive aerobic exercise training program compared with usual care (CON; comparator) with a follow-up assessment six months after formal cessation of aerobic exercise training. Measurements: Healthcare resource utilization was estimated over the six-month intervention and six-month follow-up period. Health status (using the EQ-5D-3L) at baseline and trial completion and six-month follow-up was used to calculate quality adjusted life years (QALYs). The incremental cost-utility ratio (cost per QALY gained) was calculated. Results: QALYs were both modestly greater indicating a health gain. Total healthcare costs (i.e., 1791±1369 {2015 $CAD} at six months) were greater indicating a greater cost for the thrice weekly aerobic training group compared with CON. From the Canadian healthcare system perspective, the incremental cost-utility ratios for thrice weekly aerobic training were cost-effective compared with CON, when using a willingness to pay threshold of $CAD 20,000 per QALY gained or higher. Conclusions: Aerobic training represents an attractive and potentially cost-effective strategy for older adults with mild SIVCI.

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• Although evidence suggests that aerobic training benefits cognitive and brain health, the

economic consequences relating to aerobic training remain unknown. • Very few randomized controlled trials with concurrent economic evaluations of exercise

have been conducted in populations at risk for dementia such as those with Vascular Cognitive Impairment.

There was wide variability in the cost estimates and outliers due to a smaller sample size.

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INTRODUCTION

Cerebrovascular disease is the second most common etiology contributing to dementia in older adults [1-4] and may be the most under-diagnosed and yet most treatable form of cognitive dysfunction in older adults [5]. Vascular cognitive impairment (VCI) – defined as the loss of cognitive function due to vascular burden in the brain – is a prevalent condition that places a growing burden on the health care system [6]. Cerebral small vessel disease plays a critical role in covert ischemia and the development of Sub-cortical Ischaemic Vascular Cognitive Impairment (SIVCI),[7] the most common form of VCI_[8]. SIVCI is defined by the presence of white matter lesions (WMLs) and lacunar infarcts, and has the clinical consequence of increased dementia risk.[8 9]Research has demonstrated that one third of all dementias are attributable to VCI [10-12]. More specifically, the proportion of vascular dementia attributable to small-vessel disease ranges from 36% to 67% [13 14]. The worldwide economic burden of dementia is increasing at an unprecedented rate. In 2015, a 35% increase led to a worldwide annual estimate of 818 billion US dollars. The worldwide costs of dementia are expected to exceed 1 trillion US dollars by 2018 [15]. Notably, vascular dementia has among the highest annual direct costs and highest hospitalization related costs compared with other dementias such as Alzheimer’ Disease [16]. The average annual cost per patient with VCI was $33 740 [6] compared with a variable range of $1,500 to $91,000 for Alzheimer’s Disease. The costs per VCI admission were approximately $9545 with the average number of admissions increasing through the progression of the disease [6]. Epidemiological data suggest that modification of vascular risk factors may be beneficial in slowing the progression of VCI [17-20]. Hence, aerobic-based exercise training is one promising approach to delay the progression of VCI by reducing key vascular risk factors associated with metabolic syndrome. What remains unknown is whether, aerobic-based exercise training as an intervention strategy compared with ‘usual care’ for individuals with mild SIVCI is a cost-effective strategy. To date, the simultaneous impact of health care costs and consequences remain unknown. It is an essential next step to provide an estimate of the costs and consequences (i.e., health gains or losses) related to the aerobic training intervention given that this type of intervention could be delivered at a population-level and thus, have an immense impact. Therefore, we conducted a concurrent economic evaluation with individual level data on cost and effectiveness outcomes collected during a proof-of-concept single-blinded randomized controlled trial—Promotion Of the Mind Through Exercise (PROMoTE) trial [21]. Our primary objective was to determine the incremental cost-utility ratio (incremental cost per incremental quality adjusted life year gained) of thrice weekly aerobic training compared with usual care among individuals with mild SIVCI.

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This cost-utility analysis was conducted concurrently with a six-month proof-of-concept single-blinded randomized controlled trial with a six-month follow-up study (i.e., 6-months post-intervention) [21] [22]. The details of the PROMoTE trial are previously reported [21 22]. Measurements were made at three times: baseline, end of the intervention period (six months post-randomization), and six-month post-intervention (i.e., twelve months post-randomization). Of 440 individuals screened for eligibility, 70 were deemed eligible for this economic evaluation. This economic evaluation used a Canadian healthcare system perspective, and a six-month (i.e., trial completion) and a 12-month (i.e., six-month post-intervention) time horizon for the primary economic evaluation assessing the efficiency of the thrice-weekly progressive aerobic training (AT) and usual care plus education compared with the usual care plus education (CON; comparator) group. Participants in the CON group received usual care as well as monthly educational materials about VCI and healthy diet. However, no specific information regarding physical activity was provided. Briefly, usual care included whatever health care services that a patient with mild SIVCI would usually receive in their clinical care. The main outcome for the cost-utility analysis was the incremental cost per quality adjusted life year (QALY) gained. We obtained approval for this study from the University of British Columbia Clinical Ethics Review Board (H13-00715). We previously describe study design, participant recruitment, randomization, demographics, methods and results of the PROMOTE trial [21]. We recruited participants from the University of British Columbia Hospital Clinic for AD and Related Disorders, the Vancouver General Hospital Stroke Prevention Clinic, and specialized geriatric clinics in Metro Vancouver, BC. Recruitment occurred between December 2009 and April 2014 with randomization occurring on an ongoing basis. The assessors were blinded to the participants’ group allocation. The primary outcome measures for the PROMoTE study were the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog[23]), the Executive Interview (EXIT-25[24]) and the Alzheirmer’s Disease Co-operative Study – Activities of Daily Living (ADCS-ADL[25]). Secondary outcome measures included executive functions, cardiovascular capacity, physical activity level, physiological markers and health related quality of life. We included seventy community dwelling older adults who were diagnosed with Sub-cortical Ischaemic VCI (SIVCI) [26], which requires the presence of both cognitive syndrome [21] and small vessel ischaemic disease [21]. Other inclusion criteria included: 1) Montreal Cognitive Assessment (MoCA) [27] score less than 26 at screening; 2) Mini-Mental State Examination (MMSE) [28] score of > 20 at screening; 3) Community-dwelling; 4) Live in Metro Vancouver; 5) Had a caregiver, family member, or friend who interacted with him/her on a weekly basis; 6) sufficient ability to read English, write and speak and, acceptable visual and auditory acuity to complete psychometric tests; 8) Stable on a fixed dose of cognitive medications that is not expected to change during the six-month intervention period; 9) Provided a personally signed and dated informed consent document indicating that the individual (or a legally acceptable representative) has been informed of all pertinent aspects of the trial; 10) Able to walk independently; and 11) In sufficient health to participate in the study`s aerobic-based exercise training program. Costs

We tracked healthcare resource utilization prospectively. Our primary method utilized cost

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diaries where participants were asked to fill out a monthly diary detailing any health resource utilization. We also telephoned participants every 3 months using a health resource utilization questionnaire. For individuals who did not fill out their calendars the health resource utilization questionnaire was the primary mode of healthcare resource utilization data collection. For participants who missed the three-month follow-up telephone call and who did not return their calendar, they were asked to recall their healthcare resource utilization over the six-month intervention period. We also collected healthcare resource utilization for the 6-month follow-up period post intervention. We analyze these endpoints separately (i.e., trial completion at 6 months and follow-up completion at 1 year). The health care resource utilization questionnaire included the following categories: any visits to healthcare professionals (including general practitioners, specialists, physiotherapists etc); all visits, admissions or procedures carried out in a hospital; and laboratory and diagnostic tests. We calculated the costs of delivering the thrice weekly aerobic training intervention and the CON group. Our base case analysis considered the costs of all healthcare resource use. Research protocol driven costs were excluded from our analysis. A unit cost was assigned for each component of health care resource utilization. Costs for admission to hospital were based on the fully allocated cost model of a tertiary care hospital, Vancouver General Hospital. We based costs on fee for service rates from the British Columbia Medical Services Plan 2013 price list for all health care professional related costs. Unit costs for specialized services (i.e., physiotherapy, chiropractic or naturopathic medicine) were taken from the BC Association website for each specialty. We inflated costs to 2015 Canadian dollars using the consumer price index reported by Statistics Canada. Given our analytic time horizon was equal to or less than 12 months, discounting was not applied.


Briefly, we assessed health status using the EQ-5D-3L [29]. The EQ-5D-3L is a short five-item multiple choice questionnaire that measures an individual’s health related quality of life (HRQoL) and health status according to the following five domains: mobility, self-care, usual activities, pain and anxiety/depression [29]. Each domain has three possible options: no problems, some problems or severe problems. The EQ-5D-3L health state utility values (HSUVs) at each time point are bounded from -0.54 to 1.00 where a score of less than zero is indicative of a health state worse than death. The HSUVs represent values that individuals within society assign –– these are Canadian societal values for given health states [30]. We administered the EQ-5D-3L at baseline, trial completion and six-month follow-up period to both patients and a patient proxy (i.e., see below under ‘Caregiver’). From these data points, we calculated the total quality adjusted life years lost or gained at six (trial completion) and 12 (follow-up completion) months for the two experimental groups. We used multiple linear regression to calculate the incremental QALYs based on patient and proxy ratings for each participant adjusted for baseline utility score. Baseline utility scores are often imbalanced between treatment arms. Given that a patient’s utility score at baseline is most often highly correlated with that individual’s QALYs over the study period, failure to control for this imbalance can lead to a misleading ICER. As such, we followed the recommendations of Manca et al.[31] using multiple linear regression to control for imbalances in baseline utility scores between the two treatment groups. All statistical analyses were carried out using STATA version

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10.0. Caregiver (proxy)




In the PROMoTE study, 17% of participants had incomplete six-month health resource utilization data and 7% had incomplete six-month EQ-5D-3L data at trial completion including drop-outs. For the six month follow-up period, 19% of participants had incomplete six month follow-up health resource utilization data and 19% had incomplete six month follow-up EQ-5D-3L data. The reasons for missing data included: drop out, participant burden and administration error. We calculated the cost and effectiveness estimates for available cases (dropping observations with missing values), complete case sets and an imputed data set. We examined the pattern of missing data using the STATA code: ‘mvpatterns’. Missing data appeared to be missing at random, and therefore, we imputed missing data using Bayesian analyses following recommendations, [31-34] [35] in which all baseline study variables (including treatment assignment) were used to create 40 imputed data sets; parameter estimates and standard errors were pooled across the 40 data sets. For multiple imputation, we used the “mi imput mvn” procedure in STATA. The imputed data is reported as our base case analysis. We report the results using deletion of missing data as our sensitivity analysis (i.e., complete case analysis).


We calculated the incremental cost-utility ratio for thrice weekly aerobic training compared with the CON group twice using the patient rated EQ-5D-3L and the caregiver proxy rated EQ-5D-3L. Briefly, the incremental cost-utility ratio provides an index of the cost per quality-adjusted life-year gained at intervention completion (i.e., 6 months) and cost per quality-adjusted life year gained at 6-month post intervention (i.e., 12 months). The incremental cost-utility ratio is the ratio between the difference in total mean costs between the AT and the CON groups and the difference in mean quality-adjusted life-years gained between AT and the CON groups.

ICER =CostofAT −CostofCON

EffectofAT −EffectofCON

Nested imputation and nonparametric bootstrapping were used to model uncertainty around the estimates for costs and effectiveness. For each of the 40 cycles, we imputed missing values and bootstrapped the complete dataset. For each cycle of imputation and bootstrapping, we calculated the total healthcare resource use cost and QALYs according to group allocation. The results of each cycle of imputation for participants were averaged in each of the two participant groups. The contribution of each cost item in relation to the total healthcare resource use was estimated

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for each group. Plots of the cost-effectiveness plane and cost-effectiveness acceptability curves were generated based on 5000 iterations of nested imputation/bootstrapping using Fiellers’ method to generate 95% confidence ellipses for the joint distribution of cost and effectiveness outcomes.[36] The differences in mean costs and health outcomes in each group were expressed by reporting the incremental cost per QALY (i.e., the incremental cost-utility ratio). The observed health benefit (i.e., QALY) difference was close to zero; therefore, we used 5000 bootstrapped replications of mean cost and QALY differences.[37] We used these to generate a cost-utility acceptability curves to estimate the probability that thrice weekly aerobic training is considered cost effective compared with CON over a select range of willingness to pay values.[38] Sensitivity analysis


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RESULTS


Seventy-one eligible participants were randomized to AT or CON. One participant was deemed ineligible due to the presence of mixed-dementia detected after randomization and was excluded from all analyzes. Table 1 provides the baseline descriptive characteristics separated by study group. Average class attendance was 68% for the AT group. Healthcare use and costs

Complete healthcare resource utilization data were provided by 58 (83%) participants at six months and 57 (81%) at 12 months. Response rates for health care utilization data were comparable across the two participant groups. Unit costs for healthcare cost items are provided in Table 2. In summary (Table 2), the mean (SD) costs (2015 $CAD) for health care professional visits, admissions to hospital and laboratory test/investigations at 6 months were as follows: 940(1194), 187 (325) and 113 (128). The mean (SD) costs (2015 $CAD) for health care professional visits, admissions to hospital and laboratory test/investigations at 6 months were as follows: 682(465), 554(1648) and 108(132). The mean total healthcare resource utilization costs for the control group (2015 $CAD) at 6 and 12 months were: 1434 (1674) and 2964 (2947). The mean total healthcare resource utilization costs for the AT group (2015 $CAD) at 6 and 12 months were: 1434 (1674) and 2964 (2947).

Health outcomes

Complete data for the EQ-5D-3L at baseline were provided by 69 (99%) patients and 63 (90%) caregivers. Complete data for the EQ-5D-3L at six-months were provided by 65 (93%) patients and 54 (77%) caregivers. Complete data for the EQ-5D-3L at 12-months were provided by 57 (81%) patients and 49 (70%) caregivers. The response rates of patients or caregivers for dropouts was comparable between treatment groups. Mean EQ-5D-3L at 6 and 12 months and adjusted incremental QALYs for patients and caregivers are provided in Table 3.

Adjusting QALYs for imbalances in baseline utility


After controlling for imbalances in baseline utility, the mean (SD) incremental QALY after six months calculated using the EQ-5D-3L was 0.82 (0.06) as rated by patients and 0.83 (0.06) as rated by caregivers perspective for the patients in the AT group and 0.78 (0.09) as rated by patients and 0.79 (0.12) as rated by caregivers perspective for the patients in the CON group (Table 3). After controlling for imbalances in baseline utility, the mean (SD) incremental QALY after 12 months calculated using the EQ-5D-3L was 0.82 (0.06) as rated by patients and 0.83 (0.05) as rated by caregivers perspective for the patients in the AT group and 0.78 (0.08) as rated by patients and 0.79 (0.10) as rated by caregivers perspective for the patients in the CON group (Table 3).


After controlling for imbalances in baseline utility, the mean (SD) incremental QALY after six months calculated using the EQ-5D-3L was 0.82 (0.06) as rated by patients and 0.83 (0.05) as rated by caregivers perspective for the patients in the AT group and 0.78 (0.09) as rated by patients and 0.78 (0.12) as rated by caregivers perspective for the patients in the CON group

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(Table 3). After controlling for imbalances in baseline utility, the mean (SD) incremental QALY after 12 months calculated using the EQ-5D-3L was 0.82 (0.03) as rated by patients and 0.82 (0.01) as rated by caregivers perspective for the patients in the AT group and 0.78 (0.05) as rated by patients and 0.78 (0.03) as rated by caregivers perspective for the patients in the CON group.


From the Canadian healthcare system perspective, the incremental cost-utility ratios for thrice weekly aerobic training were cost-effective compared with the comparator group, when using a willingness to pay threshold of $CAD 20,000 per QALY gained or higher. Specifically, on the point estimates from our base case analysis, we found that AT is more effective and also more costly than CON alternative. Figure 1a (using the patients own ratings of their health status) demonstrates that for three times weekly aerobic training at 6 months (i.e., intervention completion) compared with CON, most of the bootstrapped cycles (>80% of the 4000 cycles) were represented in the northeast quadrant. Figure 1b (using the caregivers ratings of the patients health status) demonstrates that for three times weekly aerobic training at 6 months (i.e., intervention completion) compared with CON, most of the bootstrapped cycles (>80% of the 4000 cycles) were represented in the northeast quadrant. Figures 1c and 1d (using the patients own ratings and caregiver ratings of their health status, respectively) demonstrates that for three times weekly aerobic training at 12 months (i.e., intervention completion) compared with CON, most of the 4000 bootstrapped cycles were represented in the northeast quadrant. Figures 2a and 2b report the cost-effectiveness acceptability curves highlighting the probability of the AT being cost-effective over different willingness to pay values. Sensitivity analysis


Among a population of individuals at high risk for future cognitive decline, this study demonstrated, using a Canadian healthcare system perspective, that the incremental cost per quality adjusted life year gained by participating in thrice weekly aerobic training was more effective and more costly than the usual care plus education group. We observed a trend toward improvement in the adjusted incremental quality adjusted life years determined from the EQ-5D-3L (by patients and proxies) for aerobic training group compared with the usual care plus education group at trial completion and six-month follow-up. Importantly, aerobic training is an alternative to resistance training and is accessible to older adults with mild SIVCI. Further, the delivery of a walking program on an individual basis requires a low financial investment (i.e., the cost of walking poles) by an individual. As such, the results of this economic evaluation represents a substantive contribution to the evidence base on how to efficiently minimize cognitive decline among those with mild SIVCI. The findings of this study build on previous research that demonstrated aerobic training has significant and beneficial effects on overall health related quality of life and quality of life more broadly [39]. The overall incremental cost-utility ratios were not significantly different regardless of whether QALYs were ascertained from patient reported or proxy reported health

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status using the EQ-5D-3L suggesting that for this population, use of patient or proxy ratings should not alter health care decision making. The cost-effectiveness acceptability curves confirm that AT is the preferred treatment option for a wide range of plausible willingness to pay thresholds.

From both our sensitivity analyses, we found that all analyses supported the conclusions that AT resulted in clinically important gains in QALYs. However, our imputed case analysis demonstrated the intervention was not cost-saving, while the complete case analysis demonstrated the intervention was cost-saving. One potential explanation for this was that the complete case analysis may better reflect the per protocol findings (i.e., those that had greater adherence to the trial). The time horizon of our study was limited to the duration of the intervention (i.e., six months) and the follow-up period (i.e., 12 months). The number randomized controlled trials of exercise conducted in populations at high-risk for dementia is accumulating [40]. One study demonstrated that resistance training post a 6-month (frequency of 2-3 times weekly) intervention significantly improved global cognitive function while maintaining executive and global benefits for at least 18 months post intervention [41 42]. However, the number of randomized controlled trials of exercise among individuals diagnosed with SIVCI remains low [22]. Given that cardiovascular risk factors play a primary role in the onset and progression of VCI, examining the cost-effectiveness of AT is a logical starting place. In adults with mild VCI, six months of thrice weekly progressive aerobic training improved cognitive function, relative to CON [22]. Previous research that aerobic training in older adults has longer- term health benefits that we hypothesize would be applicable to adults with mild SIVCI benefit of the intervention may be ideally captured by a longer time horizon.[43] Further, the sample size of our study was small. As such, there was wide variability in the cost estimates and outliers (i.e., ±3 standard deviations from the mean) had a stronger impact than would be expected in a larger sample. However, we did not have any reason to remove any health resource utilization outliers in our intention to treat analysis. The health resource utilization questionnaire may be subject to recall bias thus causing potential underestimation of costs. To minimize recall bias, participants were provided with a monthly diary to track and report their health care resource utilization. Given that cost-underestimation may have occurred in both groups, we do not estimate any impact on the incremental cost-utility ratio given this was a randomized controlled trial. A key strength of our study is that it deals with a largely understudied, yet important population. Importantly, this population actually may represent an ideal target population both for interventions given that individuals have not yet crossed the dementia threshold. Hence, it is important to gain better understanding of both the effectiveness and efficiency of targeted interventions. Given that even mildly impaired cognition may impede an individual’s ability to self-assess their HRQoL we also used a patient-proxy (i.e., caregiver) assessment of the patients health-status [44 45]. In this study, we found that the use of the patient or the proxy did not significantly alter our findings. In all instances, we observed a significant increase in QALYs at six and 12 months regardless of the rater. This is a useful observation because it suggests that among individuals with VCI, the rater should not result in changes in health care decision making. Lastly, a highly relevant strength of this study is that the intervention is widely accessible and relatively easy to implement for any community dwelling older adult that is able

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to walk. The low cost required by an individual to start walking is also appealing from an implementation perspective. Our proof-of-concept findings suggest that this exercise (i.e., aerobic training) therapy delivered over a span of six months holds promise for improving cognitive function and health related quality of life in older adults with mild VCI. While our findings suggest that this intervention is not cost-saving, it appears to be cost-effective depending on a decision makers willingness to pay.

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Acknowledgements


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13. Jokinen H, Kalska H, Mantyla R, et al. Cognitive profile of subcortical ischaemic vascular disease. Journal of neurology, neurosurgery, and psychiatry 2006;77(1):28-33 doi: 10.1136/jnnp.2005.069120[published Online First: Epub Date]|.

14. Kramer JH, Reed BR, Mungas D, et al. Executive dysfunction in subcortical ischaemic vascular disease. Journal of neurology, neurosurgery, and psychiatry 2002;72(2):217-20

15. Wimo A, Guerchet M, Ali GC, et al. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimer's & dementia : the journal of the Alzheimer's Association 2016;Aug 29. pii: S1552-5260(16)30043-7. doi: 10.1016/j.jalz.2016.07.150. [Epub ahead of print]

16. Rojas G, Bartoloni L, Dillon C, et al. Clinical and economic characteristics associated with direct costs of Alzheimer's, frontotemporal and vascular dementia in Argentina.

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International psychogeriatrics / IPA 2011;23(4):554-61 doi: 10.1017/S1041610210002012[published Online First: Epub Date]|.





21. Liu-Ambrose T, Eng JJ, Boyd LA, et al. Promotion of the mind through exercise (PROMoTE): a proof-of-concept randomized controlled trial of aerobic exercise training in older adults with vascular cognitive impairment. BMC neurology 2010;10:14 doi: 1471-2377-10-14 [pii]10.1186/1471-2377-10-14[published Online First: Epub Date]|.

22. Liu-Ambrose T, Best JR, Davis JC, et al. Aerobic exercise and vascular cognitive impairment: A randomized controlled trial. Neurology 2016;Accepted July 5 2016; In Press

23. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry 1984;141(11):1356-64

24. Royall DR, Mahurin RK, Gray KF. Bedside assessment of executive cognitive impairment: the executive interview. J Am Geriatr Soc 1992;40(12):1221-6





29. Dolan P. Modeling valuations for EuroQol health states. Medical care 1997;35(11):1095-108 30. Bansback N, Tsuchiya A, Brazier J, et al. Canadian valuation of EQ-5D health states:

preliminary value set and considerations for future valuation studies. PLOS ONE 2012;7(2):e31115 doi: 10.1371/journal.pone.0031115[published Online First: Epub Date]|.




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41. Fiatarone Singh MA, Gates N, Saigal N, et al. The Study of Mental and Resistance Training (SMART) study-resistance training and/or cognitive training in mild cognitive impairment: a randomized, double-blind, double-sham controlled trial. Journal of the American Medical Directors Association 2014;15(12):873-80 doi: 10.1016/j.jamda.2014.09.010[published Online First: Epub Date]|.

42. Lam LC, Chan WM, Kwok TC, et al. Effectiveness of Tai Chi in maintenance of cognitive and functional abilities in mild cognitive impairment: a randomised controlled trial. Hong Kong medical journal = Xianggang yi xue za zhi 2014;20(3 Suppl 3):20-3




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CON group

n = 35

AT group

n = 35

Variables at baseline Mean (SD) or

n (%) or

Median (IQR)

Mean (SD) or

n (%) or

Median (IQR)



Primary Clinical and Economic Outcome Variables Alzheimer’s Disease Assessment Scale, Cognition

10.2 (5.4) 11.7 (5.5)

Executive Interview 13.3 (6.4) 13.7 (4.7) ADCS-ADL 46.5 (5.1) 46.1 (6.8) EQ-5D-3L (patient rated) 0.797 (0.109)

0.817 (0.135) 0.822 (0.072) 0.826 (0.108)

EQ-5D-3L (caregiver rated) 0.799 (0.136) 0.826 (0.117)

0.829 (0.064) 0.843 (0.108)

Secondary Outcome Variables Stroop Test 3-2 (secs) 57.12 (24.13) 67.82 (28.36) Trail Making Test B-A (secs) 75.18 (83.27) 59.70 (42.28) Digit Span Forward - Backward 3.8 (1.95) 3.37 (2.44) 6-minute walk (meters) 486.9 (97.9) 502.8 (98.4) Weight (kgs) 72.39 (14.11) 70.05 (14.31) Body mass index 26.54 (3.97) 25.26 (3.54) Resting heart rate (bpm) 70.24 (15.10) 67.26 (12.38) Resting systolic blood pressure (mm Hg) 132.29 (18.66) 139.80 (17.73) Resting diastolic blood pressure (mm Hg) 76.71 (11.38) 80.26 (10.05) Physical activity scale for the elderly 118.59 (55.41) 124.44 (73.47)

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2015 CAN$

Mean (SD)

Median (IQR)

12-month HRU

2015 CAN$

Mean (SD)

Median (IQR)

Unit Reference


0 - Cost per

person year

Study records


576 - Cost per

person year

Study records


940 (1194) 586 (1097)

682 (465) 632 (726)

Cost per

person



187 (325) 0 (277)

552 (1648) 0 (207)

Cost per

person




42 Cost per

hour




113 (128) 44 (204)

108 (132) 59 (129)

Cost per

person



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6-months

Mean (SD)

CON at

12months

Mean (SD)

AT at

6-months

Mean (SD)

AT at

12months

Mean (SD)


0 (usual care) 0 (usual care) 730

730


1434 (1674)

2964 (2947)

956 (861)

2110 (1857)


EQ-5D-3L patient ý 0 (reference) 0 (reference) 0.804 (0.080) 0.800 (0.075) EQ-5D-3L caregiver ý 0 (reference) 0 (reference) 0.806 (0.096) 0.810 (0.078)

Incremental cost (2015 $CAD)

EQ-5D-3L patient reference reference 1770 (1369) 3112 (2499) EQ-5D-3L caregiver reference reference 1770 (1369) 3112 (2499)

Incremental cost (2015 $CAD) per QALY based on:

EQ-5D-3L patient reference reference 2129 3761 EQ-5D-3L caregiver reference reference 2124 3715 Ý ICER based on total HRU costs, fall related costs and cost of delivering programs ý Incremental QALYs are adjusted for the baseline utility using a linear regression model

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Figure Legend

Figure 1a. Cost effective plane (time horizon – 6 months) depicting the 95% confidence ellipses of incremental cost and effectiveness (patient rated health status) for comparison between thrice weekly aerobic training and usual care (control, comparator); Figure 1b. Cost effective plane (time horizon – 6 months) depicting the 95% confidence ellipsesof incremental cost and effectiveness (caregiver (patient-proxy) rated health status) for comparison between thrice weekly aerobic training and usual care (control, comparator); Figure 1c. Cost effective plane (time horizon – 12 months) depicting the 95% confidence ellipses of incremental cost and effectiveness (patient rated health status) for comparison between thrice weekly aerobic training and usual care (control, comparator). Figure 1d. Cost effective plane (time horizon – 12 months) depicting the 95% confidence ellipses of incremental cost and effectiveness (caregiver (patient-proxy) rated health status) for comparison between thrice weekly aerobic training and usual care (control, comparator). Figure 2a. Cost-effectiveness acceptability curve showing the probability that thrice aerobic training intervention is cost-effective compared to usual care over a range of values for the maximum acceptable ceiling ratio (λ – willingness to pay) in the PROMoTE trial (6- month time horizon, patient rated health status). Figure 2b. Cost-effectiveness acceptability curve showing the probability that thrice aerobic training intervention is cost-effective compared to usual care over a range of values for the maximum acceptable ceiling ratio (λ – willingness to pay) in the PROMoTE trial (6- month time horizon, caregiver (patient-proxy) rated health status). Figure 2c. Cost-effectiveness acceptability curve showing the probability that thrice aerobic training intervention is cost-effective compared to usual care over a range of values for the maximum acceptable ceiling ratio (λ – willingness to pay) in the PROMoTE trial (12 month time horizon, patient rated health status). Figure 2d. Cost-effectiveness acceptability curve showing the probability that thrice aerobic training intervention is cost-effective compared to usual care over a range of values for the maximum acceptable ceiling ratio (λ – willingness to pay) in the PROMoTE trial (12- month time horizon, caregiver (patient-proxy) rated health status).

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Figure 1a

215x279mm (300 x 300 DPI)

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Figure 1b

215x279mm (300 x 300 DPI)

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Figure 1c

215x279mm (300 x 300 DPI)

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Figure 1d

215x279mm (300 x 300 DPI)

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Figure 2a

215x279mm (300 x 300 DPI)

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Figure 2b

215x279mm (300 x 300 DPI)

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Figure 2c

215x279mm (300 x 300 DPI)

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Figure 2d

215x279mm (300 x 300 DPI)

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BMJ 2013;346:f1049








CHEERS Checklist


Section/item

Item

No

Recommendation

Reported

on page No/

line No

Title and abstract




1




conclusions.

2

Introduction

Background and

objectives


study.

4


practice decisions.

Methods


subgroups




need(s) to be made.

5



5



5



5


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Choice of health

outcomes

10

Measurement of

effectiveness

11a

11b

Measurement and


based outcomes

12


and costs

13a

13b


and conversion

14

Choice of model 15

Assumptions 16


Study parameters 18




analysis performed.






effectiveness data.








costs.






opportunity costs.





exchange rate.
















recommended.

6

5

N/A

N/A

N/A

5, 6,

Table 2

5/6

N/A

N/A

5,6,7,8

9,10

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outcomes

19

Characterising

uncertainty

20a

20b

Characterising

heterogeneity

21

Study findings,

limitations,


current knowledge

22











perspective).








more information.




current knowledge.



analysis. Describe other non-monetary sources of support.

Describe any potential for conflict of interest of study




recommendations.


statement checklist










9,10

9,10, Figures

1a-d

N/A

Fig1, 2

10,11

13

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Journal: BMJ Open

Manuscript ID bmjopen-2016-014387.R2


Date Submitted by the Author: 09-Feb-2017

Complete List of Authors: Davis, Jennifer; University of British Columbia, Department of Population & Public Health, Hsiung, Robin; University of British Columbia, Neurology Bryan, Stirling; University of British Columbia, School of Population and Public Health Best, John; University of British Columbia, Department of Physical Therapy Eng, Janice; University of British Columbia, Department of Physical Therapy

Munkacsy, Michelle; University of British Columbia, Department of Physical Therapy Cheung, Winnie; University of British Columbia, Department of Physical Therapy Chiu, Bryan; University of British Columbia, Department of Physical Therapy Jacova, Claudia; University of British Columbia, Division of Neurology Lee, Phil; University of British Columbia, Division of Geriatric Medicine Liu-Ambrose, Teresa; University of British Columbia, Department of Physical Therapy,

Primary Subject

Heading: Health economics


Keywords: mild cognitive impairment, cost-utility analysis, economic evaluation, older adults, exercise, aerobic training


BMJ Open on 21 A


http://bmjopen.bm

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1 Department of Physical Therapy, University of British Columbia, Vancouver, Canada 2 Centre for Hip Health and Mobility, Vancouver Coastal Research Institute, Vancouver, Canada 3 Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada 4 Centre for Clinical Epidemiology and Evaluation, University of British Columbia, Vancouver, Canada 5 Department of Medicine, Division of Geriatric Medicine, University of British Columbia, Vancouver, Canada





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ABSTRACT

Background/Objectives: Evidence suggests that aerobic exercise may slow the progression of subcortical ischemic vascular cognitive impairment (SIVCI) by modifying cardiovascular risk factors. Yet, the economic consequences relating to aerobic training remain unknown. Therefore, our primary objective was to estimate the incremental cost per quality adjusted life years gained of a thrice weekly aerobic training intervention compared with usual care. Design: Cost-utility analysis alongside a randomized trial. Setting: Vancouver, British Columbia, Canada. Participants: Seventy adults (mean age of 74 years, 51% female) who meet the diagnostic criteria for mild SIVCI. Intervention: A six-month, thrice-weekly, progressive aerobic exercise training program compared with usual care (CON; comparator) with a follow-up assessment six months after formal cessation of aerobic exercise training. Measurements: Healthcare resource utilization was estimated over the six-month intervention and six-month follow-up period. Health status (using the EQ-5D-3L) at baseline and trial completion and six-month follow-up was used to calculate quality adjusted life years (QALYs). The incremental cost-utility ratio (cost per QALY gained) was calculated. Results: QALYs were both modestly greater indicating a health gain. Total healthcare costs (i.e., 1791±1369 {2015 $CAD} at six months) were greater indicating a greater cost for the thrice weekly aerobic training group compared with CON. From the Canadian healthcare system perspective, the incremental cost-utility ratios for thrice weekly aerobic training were cost-effective compared with CON, when using a willingness to pay threshold of $CAD 20,000 per QALY gained or higher. Conclusions: Aerobic training represents an attractive and potentially cost-effective strategy for older adults with mild SIVCI.

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• Our study is one of the first to investigate together the economic and health consequences

relating to aerobic training. • Very few randomized controlled trials with concurrent economic evaluations of exercise

have been conducted in populations at risk for dementia such as those with Vascular Cognitive Impairment.

• There was wide variability in the cost estimates and outliers due to a smaller sample size.

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INTRODUCTION

Cerebrovascular disease is the second most common etiology contributing to dementia in older adults [1-4] and may be the most under-diagnosed and yet most treatable form of cognitive dysfunction in older adults [5]. Vascular cognitive impairment (VCI) – defined as the loss of cognitive function due to vascular burden in the brain – is a prevalent condition that places a growing burden on the health care system [6]. Cerebral small vessel disease plays a critical role in covert ischemia and the development of Sub-cortical Ischaemic Vascular Cognitive Impairment (SIVCI),[7] the most common form of VCI_[8]. SIVCI is defined by the presence of white matter lesions (WMLs) and lacunar infarcts, and has the clinical consequence of increased dementia risk.[8 9]Research has demonstrated that one third of all dementias are attributable to VCI [10-12]. More specifically, the proportion of vascular dementia attributable to small-vessel disease ranges from 36% to 67% [13 14]. The worldwide economic burden of dementia is increasing at an unprecedented rate. In 2015, a 35% increase led to a worldwide annual estimate of 818 billion US dollars. The worldwide costs of dementia are expected to exceed 1 trillion US dollars by 2018 [15]. Notably, vascular dementia has among the highest annual direct costs and highest hospitalization related costs compared with other dementias such as Alzheimer’ Disease [16]. The average annual cost per patient with VCI was $33 740 [6] compared with a variable range of $1,500 to $91,000 for Alzheimer’s Disease. The costs per VCI admission were approximately $9545 with the average number of admissions increasing through the progression of the disease [6]. Epidemiological data suggest that modification of vascular risk factors may be beneficial in slowing the progression of VCI [17-20]. Hence, aerobic-based exercise training is one promising approach to delay the progression of VCI by reducing key vascular risk factors associated with metabolic syndrome. What remains unknown is whether, aerobic-based exercise training as an intervention strategy compared with ‘usual care’ for individuals with mild SIVCI is a cost-effective strategy. To date, the simultaneous impact of health care costs and consequences remain unknown. It is an essential next step to provide an estimate of the costs and consequences (i.e., health gains or losses) related to the aerobic training intervention given that this type of intervention could be delivered at a population-level and thus, have an immense impact. Therefore, we conducted a concurrent economic evaluation with individual level data on cost and effectiveness outcomes collected during a proof-of-concept single-blinded randomized controlled trial—Promotion Of the Mind Through Exercise (PROMoTE) trial [21]. Our primary objective was to determine the incremental cost-utility ratio (incremental cost per incremental quality adjusted life year gained) of thrice weekly aerobic training compared with usual care among individuals with mild SIVCI.

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This cost-utility analysis was conducted concurrently with a six-month proof-of-concept single-blinded randomized controlled trial with a six-month follow-up study (i.e., 6-months post-intervention) [21] [22]. The details of the PROMoTE trial are previously reported [21 22]. Measurements were made at three times: baseline, end of the intervention period (six months post-randomization), and six-month post-intervention (i.e., twelve months post-randomization). Of 440 individuals screened for eligibility, 70 were deemed eligible for this economic evaluation. This economic evaluation used a Canadian healthcare system perspective, and a six-month (i.e., trial completion) and a 12-month (i.e., six-month post-intervention) time horizon for the primary economic evaluation assessing the efficiency of the thrice-weekly progressive aerobic training (AT) and usual care plus education compared with the usual care plus education (CON; comparator) group. Participants in the CON group received usual care as well as monthly educational materials about VCI and healthy diet. However, no specific information regarding physical activity was provided. Briefly, usual care included whatever health care services that a patient with mild SIVCI would usually receive in their clinical care. The main outcome for the cost-utility analysis was the incremental cost per quality adjusted life year (QALY) gained. We obtained approval for this study from the University of British Columbia Clinical Ethics Review Board (H13-00715). We previously describe study design, participant recruitment, randomization, demographics, methods and results of the PROMOTE trial [21]. We recruited participants from the University of British Columbia Hospital Clinic for AD and Related Disorders, the Vancouver General Hospital Stroke Prevention Clinic, and specialized geriatric clinics in Metro Vancouver, BC. Recruitment occurred between December 2009 and April 2014 with randomization occurring on an ongoing basis. The assessors were blinded to the participants’ group allocation. The primary outcome measures for the PROMoTE study were the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog[23]), the Executive Interview (EXIT-25[24]) and the Alzheirmer’s Disease Co-operative Study – Activities of Daily Living (ADCS-ADL[25]). Secondary outcome measures included executive functions, cardiovascular capacity, physical activity level, physiological markers and health related quality of life. We included seventy community dwelling older adults who were diagnosed with Sub-cortical Ischaemic VCI (SIVCI) [26], which requires the presence of both cognitive syndrome [21] and small vessel ischaemic disease [21]. Other inclusion criteria included: 1) Montreal Cognitive Assessment (MoCA) [27] score less than 26 at screening; 2) Mini-Mental State Examination (MMSE) [28] score of > 20 at screening; 3) Community-dwelling; 4) Live in Metro Vancouver; 5) Had a caregiver, family member, or friend who interacted with him/her on a weekly basis; 6) sufficient ability to read English, write and speak and, acceptable visual and auditory acuity to complete psychometric tests; 8) Stable on a fixed dose of cognitive medications that is not expected to change during the six-month intervention period; 9) Provided a personally signed and dated informed consent document indicating that the individual (or a legally acceptable representative) has been informed of all pertinent aspects of the trial; 10) Able to walk independently; and 11) In sufficient health to participate in the study`s aerobic-based exercise training program. Costs

We tracked healthcare resource utilization prospectively. Our primary method utilized cost

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diaries where participants were asked to fill out a monthly diary detailing any health resource utilization. We also telephoned participants every 3 months using a health resource utilization questionnaire. For individuals who did not fill out their calendars the health resource utilization questionnaire was the primary mode of healthcare resource utilization data collection. For participants who missed the three-month follow-up telephone call and who did not return their calendar, they were asked to recall their healthcare resource utilization over the six-month intervention period. We also collected healthcare resource utilization for the 6-month follow-up period post intervention. We analyze these endpoints separately (i.e., trial completion at 6 months and follow-up completion at 1 year). The health care resource utilization questionnaire included the following categories: any visits to healthcare professionals (including general practitioners, specialists, physiotherapists etc); all visits, admissions or procedures carried out in a hospital; and laboratory and diagnostic tests. We calculated the costs of delivering the thrice weekly aerobic training intervention and the CON group. Our base case analysis considered the costs of all healthcare resource use. Research protocol driven costs were excluded from our analysis. A unit cost was assigned for each component of health care resource utilization. Costs for admission to hospital were based on the fully allocated cost model of a tertiary care hospital, Vancouver General Hospital. We based costs on fee for service rates from the British Columbia Medical Services Plan 2013 price list for all health care professional related costs. Unit costs for specialized services (i.e., physiotherapy, chiropractic or naturopathic medicine) were taken from the BC Association website for each specialty. We inflated costs to 2015 Canadian dollars using the consumer price index reported by Statistics Canada. Given our analytic time horizon was equal to or less than 12 months, discounting was not applied.


Briefly, we assessed health status using the EQ-5D-3L [29]. The EQ-5D-3L is a short five-item multiple choice questionnaire that measures an individual’s health related quality of life (HRQoL) and health status according to the following five domains: mobility, self-care, usual activities, pain and anxiety/depression [29]. Each domain has three possible options: no problems, some problems or severe problems. The EQ-5D-3L health state utility values (HSUVs) at each time point are bounded from -0.54 to 1.00 where a score of less than zero is indicative of a health state worse than death. The HSUVs represent values that individuals within society assign –– these are Canadian societal values for given health states [30]. We administered the EQ-5D-3L at baseline, trial completion and six-month follow-up period to both patients and a patient proxy (i.e., see below under ‘Caregiver’). From these data points, we calculated the total quality adjusted life years lost or gained at six (trial completion) and 12 (follow-up completion) months for the two experimental groups. We used multiple linear regression to calculate the incremental QALYs based on patient and proxy ratings for each participant adjusted for baseline utility score. Baseline utility scores are often imbalanced between treatment arms. Given that a patient’s utility score at baseline is most often highly correlated with that individual’s QALYs over the study period, failure to control for this imbalance can lead to a misleading ICER. As such, we followed the recommendations of Manca et al.[31] using multiple linear regression to control for imbalances in baseline utility scores between the two treatment groups. All statistical analyses were carried out using STATA version

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10.0. Caregiver (proxy)




In the PROMoTE study, 17% of participants had incomplete six-month health resource utilization data and 7% had incomplete six-month EQ-5D-3L data at trial completion including drop-outs. For the six month follow-up period, 19% of participants had incomplete six month follow-up health resource utilization data and 19% had incomplete six month follow-up EQ-5D-3L data. The reasons for missing data included: drop out, participant burden and administration error. We calculated the cost and effectiveness estimates for available cases (dropping observations with missing values), complete case sets and an imputed data set. We examined the pattern of missing data using the STATA code: ‘mvpatterns’. Missing data appeared to be missing at random, and therefore, we imputed missing data using Bayesian analyses following recommendations, [31-34] [35] in which all baseline study variables (including treatment assignment) were used to create 40 imputed data sets; parameter estimates and standard errors were pooled across the 40 data sets. For multiple imputation, we used the “mi imput mvn” procedure in STATA. The imputed data is reported as our base case analysis. We report the results using deletion of missing data as our sensitivity analysis (i.e., complete case analysis).


We calculated the incremental cost-utility ratio for thrice weekly aerobic training compared with the CON group twice using the patient rated EQ-5D-3L and the caregiver proxy rated EQ-5D-3L. Briefly, the incremental cost-utility ratio provides an index of the cost per quality-adjusted life-year gained at intervention completion (i.e., 6 months) and cost per quality-adjusted life year gained at 6-month post intervention (i.e., 12 months). The incremental cost-utility ratio is the ratio between the difference in total mean costs between the AT and the CON groups and the difference in mean quality-adjusted life-years gained between AT and the CON groups.

ICER =CostofAT −CostofCON

EffectofAT −EffectofCON

Nested imputation and nonparametric bootstrapping were used to model uncertainty around the estimates for costs and effectiveness. For each of the 40 cycles, we imputed missing values and bootstrapped the complete dataset. For each cycle of imputation and bootstrapping, we calculated the total healthcare resource use cost and QALYs according to group allocation. The results of each cycle of imputation for participants were averaged in each of the two participant groups. The contribution of each cost item in relation to the total healthcare resource use was estimated

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for each group. Plots of the cost-effectiveness plane and cost-effectiveness acceptability curves were generated based on 5000 iterations of nested imputation/bootstrapping using Fiellers’ method to generate 95% confidence ellipses for the joint distribution of cost and effectiveness outcomes.[36] The differences in mean costs and health outcomes in each group were expressed by reporting the incremental cost per QALY (i.e., the incremental cost-utility ratio). The observed health benefit (i.e., QALY) difference was close to zero; therefore, we used 5000 bootstrapped replications of mean cost and QALY differences.[37] We used these to generate a cost-utility acceptability curves to estimate the probability that thrice weekly aerobic training is considered cost effective compared with CON over a select range of willingness to pay values.[38] Sensitivity analysis


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RESULTS


Seventy-one eligible participants were randomized to AT or CON. One participant was deemed ineligible due to the presence of mixed-dementia detected after randomization and was excluded from all analyzes. As such, our analytic sample consisted of 70 participants. Table 1 provides the baseline descriptive characteristics separated by study group. Average class attendance was 68% for the AT group. Healthcare use and costs

Complete healthcare resource utilization data were provided by 58 (83%) participants at six months and 57 (81%) at 12 months. Response rates for health care utilization data were comparable across the two participant groups. Unit costs for healthcare cost items are provided in Table 2. In summary (Table 2), the mean (SD) costs (2015 $CAD) for health care professional visits, admissions to hospital and laboratory test/investigations at 6 months were as follows: 940(1194), 187 (325) and 113 (128). The mean (SD) costs (2015 $CAD) for health care professional visits, admissions to hospital and laboratory test/investigations at 6 months were as follows: 682(465), 554(1648) and 108(132). The mean total healthcare resource utilization costs for the control group (2015 $CAD) at 6 and 12 months were: 1434 (1674) and 2964 (2947). The mean total healthcare resource utilization costs for the AT group (2015 $CAD) at 6 and 12 months were: 1434 (1674) and 2964 (2947).

Health outcomes

Complete data for the EQ-5D-3L at baseline were provided by 69 (99%) patients and 63 (90%) caregivers. Complete data for the EQ-5D-3L at six-months were provided by 65 (93%) patients and 54 (77%) caregivers. Complete data for the EQ-5D-3L at 12-months were provided by 57 (81%) patients and 49 (70%) caregivers. The response rates of patients or caregivers for dropouts was comparable between treatment groups. Mean EQ-5D-3L at 6 and 12 months and adjusted incremental QALYs for patients and caregivers are provided in Table 3.

Adjusting QALYs for imbalances in baseline utility


After controlling for imbalances in baseline utility, the mean (SD) incremental QALY after six months calculated using the EQ-5D-3L was 0.82 (0.06) as rated by patients and 0.83 (0.06) as rated by caregivers perspective for the patients in the AT group and 0.78 (0.09) as rated by patients and 0.79 (0.12) as rated by caregivers perspective for the patients in the CON group (Table 3). After controlling for imbalances in baseline utility, the mean (SD) incremental QALY after 12 months calculated using the EQ-5D-3L was 0.82 (0.06) as rated by patients and 0.83 (0.05) as rated by caregivers perspective for the patients in the AT group and 0.78 (0.08) as rated by patients and 0.79 (0.10) as rated by caregivers perspective for the patients in the CON group (Table 3).


After controlling for imbalances in baseline utility, the mean (SD) incremental QALY after six months calculated using the EQ-5D-3L was 0.82 (0.06) as rated by patients and 0.83 (0.05) as rated by caregivers perspective for the patients in the AT group and 0.78 (0.09) as rated by

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patients and 0.78 (0.12) as rated by caregivers perspective for the patients in the CON group (Table 3). After controlling for imbalances in baseline utility, the mean (SD) incremental QALY after 12 months calculated using the EQ-5D-3L was 0.82 (0.03) as rated by patients and 0.82 (0.01) as rated by caregivers perspective for the patients in the AT group and 0.78 (0.05) as rated by patients and 0.78 (0.03) as rated by caregivers perspective for the patients in the CON group.


From the Canadian healthcare system perspective, the incremental cost-utility ratios for thrice weekly aerobic training were cost-effective compared with the comparator group, when using a willingness to pay threshold of $CAD 20,000 per QALY gained or higher. Specifically, on the point estimates from our base case analysis, we found that AT is more effective and also more costly than CON alternative. Figure 1a (using the patients own ratings of their health status) demonstrates that for three times weekly aerobic training at 6 months (i.e., intervention completion) compared with CON, most of the bootstrapped cycles (>80% of the 4000 cycles) were represented in the northeast quadrant. Figure 1b (using the caregivers ratings of the patients health status) demonstrates that for three times weekly aerobic training at 6 months (i.e., intervention completion) compared with CON, most of the bootstrapped cycles (>80% of the 4000 cycles) were represented in the northeast quadrant. Figures 1c and 1d (using the patients own ratings and caregiver ratings of their health status, respectively) demonstrates that for three times weekly aerobic training at 12 months (i.e., intervention completion) compared with CON, most of the 4000 bootstrapped cycles were represented in the northeast quadrant. Figures 2a and 2b report the cost-effectiveness acceptability curves highlighting the probability of the AT being cost-effective over different willingness to pay values. Sensitivity analysis


Among a population of individuals at high risk for future cognitive decline, this study demonstrated, using a Canadian healthcare system perspective, that the incremental cost per quality adjusted life year gained by participating in thrice weekly aerobic training was more effective and more costly than the usual care plus education group. We observed a trend toward improvement in the adjusted incremental quality adjusted life years determined from the EQ-5D-3L (by patients and proxies) for aerobic training group compared with the usual care plus education group at trial completion and six-month follow-up. Importantly, aerobic training is an alternative to resistance training and is accessible to older adults with mild SIVCI. Further, the delivery of a walking program on an individual basis requires a low financial investment (i.e., the cost of walking poles) by an individual. As such, the results of this economic evaluation represents a substantive contribution to the evidence base on how to efficiently minimize cognitive decline among those with mild SIVCI. The findings of this study build on previous research that demonstrated aerobic training has significant and beneficial effects on overall health related quality of life and quality of life more broadly [39]. The overall incremental cost-utility ratios were not significantly different

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regardless of whether QALYs were ascertained from patient reported or proxy reported health status using the EQ-5D-3L suggesting that for this population, use of patient or proxy ratings should not alter health care decision making. The cost-effectiveness acceptability curves confirm that AT is the preferred treatment option for a wide range of plausible willingness to pay thresholds.

From both our sensitivity analyses, we found that all analyses supported the conclusions that AT resulted in clinically important gains in QALYs. However, our imputed case analysis demonstrated the intervention was not cost-saving, while the complete case analysis demonstrated the intervention was cost-saving. One potential explanation for this was that the complete case analysis may better reflect the per protocol findings (i.e., those that had greater adherence to the trial). The time horizon of our study was limited to the duration of the intervention (i.e., six months) and the follow-up period (i.e., 12 months). The number randomized controlled trials of exercise conducted in populations at high-risk for dementia is accumulating [40]. One study demonstrated that resistance training post a 6-month (frequency of 2-3 times weekly) intervention significantly improved global cognitive function while maintaining executive and global benefits for at least 18 months post intervention [41 42]. However, the number of randomized controlled trials of exercise among individuals diagnosed with SIVCI remains low [22]. Given that cardiovascular risk factors play a primary role in the onset and progression of VCI, examining the cost-effectiveness of AT is a logical starting place. In adults with mild VCI, six months of thrice weekly progressive aerobic training improved cognitive function, relative to CON [22]. Previous research that aerobic training in older adults has longer- term health benefits that we hypothesize would be applicable to adults with mild SIVCI benefit of the intervention may be ideally captured by a longer time horizon.[43] Further, the sample size of our study was small. As such, there was wide variability in the cost estimates and outliers (i.e., ±3 standard deviations from the mean) had a stronger impact than would be expected in a larger sample. However, we did not have any reason to remove any health resource utilization outliers in our intention to treat analysis. The health resource utilization questionnaire may be subject to recall bias thus causing potential underestimation of costs. To minimize recall bias, participants were provided with a monthly diary to track and report their health care resource utilization. Given that cost-underestimation may have occurred in both groups, we do not estimate any impact on the incremental cost-utility ratio given this was a randomized controlled trial. A key strength of our study is that it deals with a largely understudied, yet important population. Importantly, this population actually may represent an ideal target population both for interventions given that individuals have not yet crossed the dementia threshold. Hence, it is important to gain better understanding of both the effectiveness and efficiency of targeted interventions. Given that even mildly impaired cognition may impede an individual’s ability to self-assess their HRQoL we also used a patient-proxy (i.e., caregiver) assessment of the patients health-status [44 45]. In this study, we found that the use of the patient or the proxy did not significantly alter our findings. In all instances, we observed a significant increase in QALYs at six and 12 months regardless of the rater. This is a useful observation because it suggests that among individuals with VCI, the rater should not result in changes in health care decision making. Lastly, a highly relevant strength of this study is that the intervention is widely

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accessible and relatively easy to implement for any community dwelling older adult that is able to walk. The low cost required by an individual to start walking is also appealing from an implementation perspective. Our proof-of-concept findings suggest that this exercise (i.e., aerobic training) therapy delivered over a span of six months holds promise for improving cognitive function and health related quality of life in older adults with mild VCI. While our findings suggest that this intervention is not cost-saving, it appears to be cost-effective depending on a decision makers willingness to pay.

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