Management, Faculty of (Okanagan)
DSpace
UBCO
Adjetey, Cassandra
Master of Arts - MA
University of British Columbia
Background: Cognitive impairment is a common and costly consequence of a stroke, occurring in about 30% of stroke survivors. Evidence suggests exercise and cognitive training can improve cognitive function among individuals with chronic stroke. What remains unknown, is whether exercise and/or cognitive training are cost-effective compared with usual care. Purpose: This study aims to examine the cost-effectiveness of exercise and cognitive training compared with a stretching and tone program from a healthcare system perspective of a 6-month intervention with a six-month follow-up. Method: An economic evaluation alongside a 6-month randomized controlled trial involving 120 community-dwelling adults with chronic stroke (i.e., at least 12 months post-stroke) in Metro Vancouver, Canada. Participants were aged 55 years and older, did not have dementia and were able to walk six meters. Participants were randomly assigned to i) EX, a multi-component exercise of strength, aerobic, and balance training (n=34), ii) ENRICH, cognitive and social enrichment activities (n=34), or iii) BAT, a stretching and toning program (control) (n=52). The economic evaluation assessed cost-effectiveness and cost-utility as the incremental cost per change in the Alzheimer’s Disease Assessment Scale – Cognitive-Plus (ADAS-Cog-Plus) and incremental cost per Quality Adjusted life year (QALY) using the Euro-Qol 5D three-level of the interventions respectively. Costs are reported in 2022 Canadian Dollars. Results: The mean age for all participants was 71 years (SD= 9) with about 46% female participants. At the end of the 6-month intervention, the incremental cost per change in ADAS-Cog-Plus showed that both EX and ENRICH were more effective and more costly compared with the BAT control group. The incremental benefits in ADAS-Cog were not sustained at 12 months. The incremental cost per change in QALY at 6 and 12 months showed that while EX was less costly and ENRICH more costly compared to the BAT group, the incremental QALYs gained for both interventions were negligible and not clinically significant. Conclusion: Compared to stretching and toning, exercise training to improve post-stroke cognitive impairment was cost-effective. The cost-effectiveness of cognitive training activities depends on the decision-makers willingness to pay. This highlights the importance of exercise in stroke rehabilitation.
APPLIED HEALTH ECONOMICS: ECONOMIC EVALUATION OF LIFESTYLE INTERVENTIONS TO PROMOTE COGNITION IN OLDER ADULTS WITH CHRONIC STROKE by Cassandra Adjetey Bachelor of Arts, University of British Columbia, Vancouver, 2019 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS in THE COLLEGE OF GRADUATE STUDIES (Interdisciplinary Studies) (Community Engagement, Social Change, and Equity) THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) June 2023 © Cassandra Adjetey, 2023 ii The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, the thesis entitled: Applied health economics: economic evaluation of lifestyle intervention to promote cognition in older adults with chronic stroke submitted by Cassandra Adjetey in partial fulfillment of the requirements for the degree of Master of Arts in Interdisciplinary Studies – Community Engagement, Social Change, and Equity Examining Committee: Dr. Jennifer Davis (Faculty of Management, University of British Columbia – Okanagan) Supervisor Dr. Teresa Liu-Ambrose (Faculty of Medicine, Department of Physical Therapy, University of British Columbia – Vancouver) Co-supervisor Dr. Min Hu (Irving K. Barber Faculty of Arts and Social Science, Department of Economics, Philosophy and Political Science, University of British Columbia - Okanagan) Supervisory Committee Member Dr. Brodie Sakakibara (Faculty of Medicine, Occupational Science & Occupational Therapy, University of British Columbia – Vancouver) Supervisory Committee Member Dr. Nelly Oelke (Faculty of Health and Social Development, School of Nursing, University of British Columbia – Okanagan) External Examiner iii Abstract Background: Cognitive impairment is a common and costly consequence of a stroke, occurring in about 30% of stroke survivors. Evidence suggests exercise and cognitive training can improve cognitive function among individuals with chronic stroke. What remains unknown, is whether exercise and/or cognitive training are cost-effective compared with usual care. Purpose: This study aims to examine the cost-effectiveness of exercise and cognitive training compared with a stretching and tone program from a healthcare system perspective of a 6-month intervention with a six-month follow-up. Method: An economic evaluation alongside a 6-month randomized controlled trial involving 120 community-dwelling adults with chronic stroke (i.e., at least 12 months post-stroke) in Metro Vancouver, Canada. Participants were aged 55 years and older, did not have dementia and were able to walk six meters. Participants were randomly assigned to i) EX, a multi-component exercise of strength, aerobic, and balance training (n=34), ii) ENRICH, cognitive and social enrichment activities (n=34), or iii) BAT, a stretching and toning program (control) (n=52). The economic evaluation assessed cost-effectiveness and cost-utility as the incremental cost per change in the Alzheimer’s Disease Assessment Scale – Cognitive-Plus (ADAS-Cog-Plus) and incremental cost per Quality Adjusted life year (QALY) using the Euro-Qol 5D three-level of the interventions respectively. Costs are reported in 2022 Canadian Dollars. Results: The mean age for all participants was 71 years (SD= 9) with about 46% female participants. At the end of the 6-month intervention, the incremental cost per change in ADAS-Cog-Plus showed that both EX and ENRICH were more effective and more costly compared with the BAT control group. The incremental benefits in ADAS-Cog were not sustained at 12 months. The incremental cost per change in QALY at 6 and 12 months showed that while EX was less costly and ENRICH more costly compared to the BAT group, the incremental QALYs gained for both interventions were negligible and not clinically significant. Conclusion: Compared to stretching and toning, exercise training to improve post-stroke cognitive impairment was cost-effective. The cost-effectiveness of cognitive training activities depends on the decision-makers willingness to pay. This highlights the importance of exercise in stroke rehabilitation. iv Lay Summary Stroke in older adults can cause cognitive impairment which affects the ability to think, process, or remember information. Cognitive impairment can negatively impact a person's health and result in significant costs for society and the healthcare system. This study looked at how two interventions, exercise and cognitive training can improve health and save costs. The study compared these activities to a stretching and toning program that is commonly available in communities. The study found that exercise was a better option after six months than stretching and toning, while the benefits of cognitive training depended on how much someone was willing to pay for it. However, both exercise and cognitive training were not more efficient after a six-month follow-up period. Additionally, both exercise and brain training did not improve people's overall quality of life in the study. v Preface This thesis is an original and unpublished work by the author, Cassandra Adjetey, a graduate student, Community Engagement, Social Change, and Equity, Interdisciplinary Graduate Studies, University of British Columbia, Okanagan. This thesis is co-supervised by Dr. Jennifer Davis, Assistant Professor, Faculty of Management, University of British Columbia, Okanagan, and Dr. Teresa Liu Ambrose, principal investigator for the study trial and Professor, Department of Physical Therapy, University of British Columbia. Committee members are Dr. Min Hu, Department of Economics, Philosophy and Political Science, University of British Columbia, Okanagan, and Dr. Brodie Sakakibara Faculty of Medicine, Occupational Science & Occupational Therapy, University of British Columbia. Co-investigators for the study trial are Dr. Janice Eng, Professor, Department of Physical Therapy, University of British Columbia; Dr. Ryan Falck, Post-Doctoral Fellow, School of Biomedical Engineering, University of British Columbia; Dr. John Best, Post-Doctoral Fellow, Department of Physical Therapy, University of British Columbia; Dr. Peter Hall, Professor, School of Public Health and Health Systems, University of Waterloo; Dr. Laura Middleton, Associate Professor, Department of Kinesiology, University of Waterloo; Dr. Peter Graf, Professor Emeritus, Department of Psychology, University of British Columbia, and Dr. Charles Goldsmith, Adjunct Professor, Department of Occupational Science and Occupational Therapy, University of British Columbia. Clinical trial registration: NCT01027858 University of British Columbia Clinical Research Ethics Board: H13-00715 Vancouver Coastal Health Research Institute: V13-00715 vi Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ............................................................................................................................... iv Preface ............................................................................................................................................ v Table of Contents ......................................................................................................................... vi List of Tables ................................................................................................................................ ix List of Figures ................................................................................................................................ x List of Abbreviations ................................................................................................................... xi Acknowledgments ....................................................................................................................... xii Dedication ................................................................................................................................... xiii Chapter 1: Introduction ............................................................................................................... 1 1.1 Stroke epidemiology .......................................................................................................................... 1 1.1.1 Burden of stroke......................................................................................................................... 1 1.1.2 Risk factors for stroke ................................................................................................................ 2 1.2 Stages of stroke .................................................................................................................................. 3 1.3 Health consequences of stroke ......................................................................................................... 3 1.3.1 Cognitive deficit ........................................................................................................................ 3 1.3.2 Cognitive deficits associated with stroke. .................................................................................. 4 1.4 Economic consequences of stroke .................................................................................................... 5 1.4.1 Determinants of the economic burden of stroke ........................................................................ 6 1.5 Strategies to improve cognitive function among older adults with chronic stroke. .................... 7 1.5.1 Exercise training ........................................................................................................................ 8 1.5.2 Cognitive interventions .............................................................................................................. 9 1.6 Economic evaluation of interventions to improve cognitive function ........................................ 10 Chapter 2: Research question .................................................................................................... 13 Chapter 3: Research design and methods ................................................................................ 14 3.1 Study design ..................................................................................................................................... 14 3.2 The Vitality study ............................................................................................................................ 14 3.2.1 Participants .............................................................................................................................. 14 3.2.2 Sample size .............................................................................................................................. 15 3.2.3 Exercise intervention ............................................................................................................... 15 3.2.4 Cognitive and social enrichment activities intervention .......................................................... 16 3.2.5 Active control .......................................................................................................................... 16 3.3 Measures .......................................................................................................................................... 16 vii 3.3.1 Descriptive variables................................................................................................................ 16 3.3.2 Health resource utilization ....................................................................................................... 17 3.3.3 Primary outcome measure for cognitive function .................................................................... 17 3.3.4 Secondary clinical measures .................................................................................................... 18 3.3.5 Quality-adjusted life years ....................................................................................................... 18 3.4 Overview of economic evaluation .................................................................................................. 19 3.4.1 Cost-effectiveness analysis ...................................................................................................... 19 3.4.2 Cost-utility analysis ................................................................................................................. 19 3.4.3 Base case analysis .................................................................................................................... 20 3.4.4 Sensitivity analysis .................................................................................................................. 20 3.4.5 Subgroup analysis .................................................................................................................... 21 Chapter 4: Results....................................................................................................................... 22 4.1 Baseline characteristics .................................................................................................................. 22 4.2 Results for cost-effectiveness analysis (CEA): Intervention cessation (at 6 months) ................ 24 4.2.1 Health care resource use and costs........................................................................................... 25 4.2.2 ADAS-Cog-Plus ...................................................................................................................... 26 4.2.3 Cost-effectiveness analysis ...................................................................................................... 28 4.3 Results for cost-utility analysis: Intervention cessation (at 6 months) ....................................... 29 4.3.1 Health care resource use and costs........................................................................................... 30 4.3.2 Quality-adjusted life years ....................................................................................................... 30 4.3.3 Cost-utility analysis ................................................................................................................. 33 4.4 Sensitivity analysis: Intervention cessation (at 6 months) ........................................................... 33 4.4.1 Cost-effectiveness analysis ...................................................................................................... 33 4.4.2 Cost-utility analysis ................................................................................................................. 34 4.5 Subgroup analysis: Intervention cessation (at 6 months) ............................................................ 35 4.5.1 Cost-effectiveness analysis ...................................................................................................... 35 4.5.2 Cost-utility analysis ................................................................................................................. 35 4.6 Results for cost-effectiveness analysis: End of follow-up (at 12 months) ................................... 38 4.6.1 Health care resource use and costs........................................................................................... 38 4.6.2 ADAS-Cog-Plus ...................................................................................................................... 39 4.6.3 Cost-effectiveness analysis ...................................................................................................... 41 4.7 Results for cost-utility analysis: End of follow-up (at 12 months) .............................................. 41 4.7.1 Health care resource use and costs........................................................................................... 42 4.7.2 Quality-adjusted life years ....................................................................................................... 42 viii 4.7.3 Cost-utility analysis ................................................................................................................. 45 4.8 Sensitivity analysis: End of follow-up (at 12 months) .................................................................. 45 4.8.1 Cost-effectiveness analysis ...................................................................................................... 45 4.8.2 Cost-utility analysis ................................................................................................................. 46 4.9 Subgroup analysis: End of follow-up (at 12 months) ................................................................... 46 4.9.1 Cost-effectiveness analysis ...................................................................................................... 46 4.9.2 Cost-utility analysis ................................................................................................................. 47 Chapter 5: Discussion ................................................................................................................. 50 5.1 Summary of results ......................................................................................................................... 50 5. 2 Comparison with other studies ..................................................................................................... 52 5.3 Strengths .......................................................................................................................................... 54 5.4 Limitations ....................................................................................................................................... 55 5.5 Uncertainty in findings ................................................................................................................... 56 5.6 Policy Implications .......................................................................................................................... 57 Chapter 6: Conclusion ................................................................................................................ 59 References .................................................................................................................................... 60 Appendices ................................................................................................................................... 78 Appendix A: Health Economics Analysis Plan for Vitality Study. ................................................... 78 Appendix B: Number and proportion of participants with complete data in Vitality study ......... 79 ix List of Tables Table 1. Baseline characteristics of Vitality randomized clinical trial participants ..................... 22 Table 2. Unit cost items for Vitality study at 6 months for cost-effectiveness analysis, cost per person, CAD$ 2022 ...................................................................................................................... 25 Table 3. Cost-effectiveness analysis for Vitality study at 6 months. ............................................ 26 Table 4. Unit cost items for Vitality study at 6 months for cost-utility analysis, cost per person, CAD$ 2022 ................................................................................................................................... 30 Table 5. Cost-utility analysis for the Vitality study at 6 months. ................................................. 31 Table 6. Results of sensitivity analyses at 6 months. .................................................................... 34 Table 7. Results of subgroup analyses for cost-effectiveness analysis at 6 months ..................... 36 Table 8. Results of subgroup analyses for cost-utility analyses at 6 months. ............................... 37 Table 9. Unit cost items for Vitality study at 12 months for cost-effectiveness analysis, cost per person, CAD$ 2022 ...................................................................................................................... 38 Table 10. Cost-effectiveness analysis for Vitality study at 12 months. ........................................ 39 Table 11. Unit cost items for Vitality study at 12 months for cost-utility analysis, cost per person, CAD$ 2022 ................................................................................................................................... 42 Table 12. Cost-utility analysis for the Vitality study at 12 months. ............................................. 43 Table 13. Results of sensitivity analyses at 12 months ................................................................. 46 Table 14. Results of subgroup analyses for cost-utility analysis at 12 months. ........................... 48 Table 15. Results of subgroup analyses for cost-utility at 12 months. ......................................... 49 x List of Figures Figure 1. Consort flow diagram for cost-effectiveness analysis, adapted from the Vitality primary paper. ............................................................................................................................................. 24 Figure 2. Cost-effectiveness plane for cost-effectiveness analysis at 6 months. .......................... 27 Figure 3. Cost-effective acceptability curve for cost-effectiveness analysis at 6 months. ........... 27 Figure 4. Consort flow diagram for cost-utility analysis, adapted from the Vitality primary paper........................................................................................................................................................ 29 Figure 5. Cost-effectiveness plane for cost-utility analysis at 6 months. ..................................... 32 Figure 6. Cost-effective acceptability curve for cost-utility analysis at 6 months........................ 32 Figure 7. Cost-effectiveness plane for cost-effectiveness analysis at 12 months. ........................ 40 Figure 8. Cost-effective acceptability curve for cost-effectiveness analysis at 12 months. ......... 40 Figure 9. Cost-effectiveness plane for cost-utility analysis at 12 months. ................................... 44 Figure 10. Cost-effective acceptability curve for cost-utility analysis at 12 months.................... 44 xi List of Abbreviations ADAS-COG-PLUS Alzheimer’s Disease Assessment Scale – Cognitive Plus BAT Stretching and toning activities CAD Canadian Dollars CEA Cost-effectiveness analysis CI Confidence Intervals CUA Cost-utility analysis EQ-5D-3L EuroQol-5D-3L ENRICH Social and cognitive enrichment activities EX Exercise HRU Health resource utilization ICER Incremental cost-effectiveness ratio ICUR Incremental cost-utility ratio MMSE Mini-Mental State Examination MoCA Montreal Cognitive Assessment QALY Quality-Adjusted Life Years xii Acknowledgments I wish to thank Dr. Jennifer Davis for her expertise, mentorship, and guidance for this work and throughout my program. I also wish to thank Dr. Teresa Liu-Ambrose for her expertise and mentorship. I am very thankful for her work on the Vitality clinical study and for providing access to the study data to conduct this economic evaluation. Special thanks to my committee members, Dr. Min Hu and Dr. Brodie Sakakibara for their time, expertise, and contributions to this work. I also wish to thank all participants of the Vitality study, co-investigators, and members of the Aging, Mobility, and Cognitive Health lab. A special thank you to Dr. Ryan Falck for your time and support. Thank you to the Jack Brown and Family Alzheimer Research Foundation Society and the Canadian Institute of Health Research for providing funding for the research study. xiii Dedication To my family, partner, and friends. 1 Chapter 1: Introduction 1.1 Stroke epidemiology According to the American Stroke Association, a stroke is defined as “any acute neurological dysfunction that is caused by ischemia or hemorrhage, and persists for 24 hours or more or leads to death”.1,2 Stroke is broadly classified as ischaemic or hemorrhagic depending on the characterization of oxygenated-blood supply to the brain.3 Ischemic stroke is caused by substances that block blood vessels leading to the brain and accounts for about 87% of all stroke cases.4 Hemorrhagic stroke occurs when an artery in the brain leaks or ruptures and accounts for approximately 13% of stroke cases.5,6 1.1.1 Burden of stroke Stroke is a global public health problem with significant health consequences.7,8 The global incidence of stroke reported in 2019 was 101.5 million, resulting in 6.6 million deaths9 making it the second leading cause of death.10 While stroke mortality decreased from 142 to 110 per 100,000 population between 1990 and 2013,11 the burden associated with stroke increased globally.11,12 Stroke is a major contributor to long-term disability on a global scale13 associated with significant disabilities such as cognitive deficits14,15 and reduced mobility that affect activities of daily living.16 The global prevalence of stroke is expected to reach 77 million by 2030, with 23 million first-ever strokes and 7.8 million stroke-related deaths globally.17 Stroke is an aging-related condition, hence the incidence of stroke is expected to rise significantly with the growing population of older adults globally.12,18 The World Health Organization projects that the proportion of adults 60 years and older will reach 1.4 billion by 2030 and double to 2.1 billion by 2050.19 Around 16,000 people die each year in Canada due to stroke,20 making it the third most common cause of death.21 Every year, approximately 62,000 people experience a stroke,22 and after five years, about 36% of those who survive are left with significant disabilities.23 In 2013, it was estimated that 405,000 Canadians had been affected by a stroke, and this number is expected to increase by 79% to 726,000 by 2038.23 The expected rise in the number of Canadians living with stroke effects is attributable to an aging population21 and lower mortality due to improved treatment of stroke.23 2 1.1.2 Risk factors for stroke Risk factors for stroke can be classified into modifiable or non-modifiable risk factors.24 Modifiable risk factors can be altered to change one’s chance of developing a disease or experiencing an event.25 In 2013, a study on the global burden of disease found that 90% of the burden of stroke was due to risk factors that can be modified.26 Modifiable risk factors for stroke include health conditions such as diabetes, cognitive impairment, hypertension, and obesity, as well as lifestyle factors such as diet, smoking, alcohol consumption, stress, poor diet, and physical inactivity.13,27 Cognitive impairment is a modifiable risk factor for stroke. A systematic review that looked at the association between cognitive impairment and the likelihood of having a stroke found that people with cognitive impairment had a 39% higher risk of having a future stroke compared to those with normal cognitive function.28 The frequency of silent brain infarcts,28 and other cardiovascular risk factors29 in individuals with cognitive impairment increases their risk for a stroke. Hypertension is another modifiable risk factor for stroke.30 According to epidemiological research, hypertension is linked to a 5-to-9.7-fold greater risk of developing intracranial stenosis, a narrowing of brain arteries that can lead to a stroke.31 Cardiac disease including atrial fibrillation is also a significant risk factor for stroke.32 The incidence of atrial fibrillation increases with age and has been shown to increase the risk of stroke by three to fivefold.33 There is also a strong association between lifestyle factors such as cigarette smoking (relative risk of 1.5)34 and physical inactivity (hazard ratio of 1.44)35 and an increased risk for stroke. Non-modifiable risk factors cannot be changed or controlled to decrease one’s chance of developing a disease or incurring an event or outcome of interest.32 Non-modifiable risk factors for stroke include one’s age, biological sex, race/ ethnicity, geography, and heredity.24 Age is a significant non-modifiable risk factor for stroke,7 with the risk of stroke doubling every ten years after the age of 55.3,36 About 75% of stroke occurs in adults 65 years and older.37 This may be attributed to microcirculatory changes associated with aging resulting in a decrease in arterial cerebral blood flow.38,39 Furthermore, increasing age is associated with the presence of comorbidities such as diabetes, atrial fibrillation, and hypertension which are also risk factors for stroke.18 Another non-modifiable risk factor for stroke is biological sex.32,40 A study showed that 3 males were 1.25 more likely to have a stroke than females33 However, the higher life expectancy of women contributes to the higher rate of stroke among women compared with men.41 1.2 Stages of stroke The first 6 months post-stroke is commonly referred to as the acute stage.42 The first three months following a stroke are important for recovery as most motor and functional recovery occurs during this time.43 At this stage, patients may either be in an acute in-patient care unit or rehabilitation facility and preparing to return to the community.44 Patients may experience spontaneous recovery as the brain re-learns how to carry out tasks during the acute stage.45 After 6 months, stroke survivors are considered to be in the chronic stage.46 On average, little further recovery is expected beyond 6 months after stroke, with functional recovery plateauing in about 12 months.47,48 While 6 months post-stroke is generally considered the chronic stage, most clinical interventions to improve recovery are set during or after the 12-month chronic phase of stroke as the results are unlikely to be influenced by the neurological recovery process.49 Furthermore, a high prevalence of secondary strokes in the year following an initial stroke makes this extended timeframe feasible.50 1.3 Health consequences of stroke Deficits following a stroke are common; consequences include cognitive decline, as well as impaired physical function, cardiac complications, reduced quality of life, and depression.51–53 This thesis will focus on the cognitive deficits of stroke. Cognitive deficits from stroke have a significant effect on the outcome of individuals with stroke and often impede neurological recovery.54 1.3.1 Cognitive deficit Cognitive function refers to a set of mental processes that allows one to acquire and manipulate information to achieve the desired goal.55 These processes include the domains of attention, working memory, speech and language, decision-making, and executive function.56 Cognitive deficit reflects any lower performance in any domain of cognitive function that may affect activities of daily life.57 Cognitive deficits and dementia are frequent consequences of 4 stroke.58,59 Estimates on cognitive deficits range from 21% to 38% among patients with a stroke, with some estimates as high as 70%.14,15,58,59 Post-stroke dementia is a severe form of cognitive deficit and is a frequent consequence of stroke.60 Studies show that a history of stroke doubles the risk of dementia in older adults.58,61 A population-based study of 971 patients in Minnesota, United States between 1960 and 1984, documented that for each year, dementia occurred twice as frequently in people who had a stroke as people who did not have a stroke.62 Another population-based study in Sweden of 432 community-based individuals with an average age of 82.5 years indicated that stroke survivors were three times more likely to be diagnosed with dementia than those without a stroke.63 According to the study, stroke was responsible for 18% of dementia cases in this population.63 Age is one factor associated with cognitive impairment following a stroke.15 The negative association between age and cognitive performance in stroke patients is well documented.8 Multiple studies demonstrate that patients with post-stroke cognitive impairment are generally older.64,65 A longitudinal study of 1333 patients in Japan demonstrated age-related increases in the proportion of stroke patients with cognitive decline of 33%, 39%, and 67% respectively, in older adults aged 70, 80, and 90 years old, respectively.65 An observational study found that the age of 75 years and older was associated with cognitive impairment following a stroke.15 Older adults are at a higher risk of cognitive decline as they age, and combined with the prevalence of stroke among older adults, there is a greater chance of stroke patients experiencing cognitive impairment.65 1.3.2 Cognitive deficits associated with stroke. Cognitive deficits associated with stroke among older adults are most commonly reported to affect memory, executive function, and attention.66,67 An observational study among 409 patients with an average age of 71 years in an acute-care unit in Finland indicated that about 83% of patients had impairment in at least one cognitive domain, with memory and executive function most commonly affected.68 A community-based prospective study among 458 first-stroke survivors with a mean age of 70.5 years also showed that individuals with stroke exhibited more impairment in attention, spatial ability, language, and executive function than those without a stroke.69 5 Cognitive deficits following a stroke can be associated with a variety of negative effects. People who have significant cognitive impairment have a higher mortality risk and are more likely to suffer a second catastrophic stroke.70,71 An observational cohort study among 486 older adults showed that cognitive impairment following an ischemic stroke was a significant predictor of stroke recurrence during a 12-year follow-up.71 Cognitive deficits are associated with institutionalization,59,72 and increased use of healthcare resources.73 Cognitive deficits result in functional consequences74 that impact an individual's ability to participate in stroke rehabilitation, as well as safely and independently carry out activities of daily living.72,75 These functional consequences result in significant formal and informal care costs.76 Cognitive deficits may also influence quality of life.77,78 An observational study of 66 patients with a mean age of 72 years reported an independent association between cognitive deficits at 3 months and a lower quality of life at 12 months.77 The domain of activities of daily living showed the strongest association between cognitive deficit and quality of life.77 This relationship is confirmed by a systematic review and meta-analysis of 62 studies that reported a significant association between cognition and activities of daily living.78 This suggests that cognitive deficits which relate to a limited ability to complete complex daily tasks can negatively impact quality of life.53 Stroke rehabilitation has traditionally focused more on physical recovery than cognitive recovery, despite the significant impact of cognitive deficits on stroke survivors.79,80 This is problematic because many stroke survivors suffer from cognitive impairment, and they have expressed the need for interventions to detect and improve their cognitive function as one of their top priorities.79,81 1.4 Economic consequences of stroke According to 25 stroke cost studies across 8 countries, stroke care accounts for approximately 3% of total healthcare expenditures, with an average of 0.27% of the Gross Domestic Product spent on stroke.82 The proportion of stroke healthcare expenditure varied by country, with Scotland reporting 6.9% in 1974, and the United States and Canada reporting 2.1% and 2.0% respectively in 1995.82 Healthcare expenses related to stroke may include direct costs covering hospitalization, medical equipment, rehabilitation, and medications.77 The American Heart Association estimated the average direct cost of stroke in the United States from 2011 to 2012 at $21.9 billion (2022 CAD prices).84 In 32 European countries, the healthcare costs for stroke in 6 2017 were estimated at $21.58 billion (2022 CAD), representing 45% of total costs associated with stroke and 1.7% of health expenditures.85 In addition to high healthcare costs, stroke also results in significant individual and societal costs including costs associated with losses in productivity and informal care costs.86 The average total two-year societal costs for stroke survivors in the Netherlands in 2019 was estimated at $35,894.78 (2022 CAD) with a mean non-health cost of about $15,362.32 (2022 CAD).87 About 60% of the non-health costs were related to informal care and paid home care and 40% were attributed to productivity losses.87 Similarly, the aggregate societal costs of stroke in the United Kingdom estimated from discrete event simulation modeling is $21.61 billion per year, with about 61% representing unpaid care and 6% due to lost productivity.88 In Canada, there is a paucity of stroke cost data. The cost of stroke in Ontario in 1994/5 was estimated at $1.5 billion (2022 CAD prices) and accounted for 2.7% of total direct healthcare expenditures.89 Direct costs which included the cost of physicians, acute care, medication, research, and administrative costs accounted for 62% of the total costs of stroke. The remaining cost was due to indirect costs from loss of productivity ranging from morbidity and mortality.89 Another study estimated the annual economic burden of a stroke at 12 Canadian centers of at least $3.7 billion (2022 CAD prices) based on 38,000 stroke admissions per year for incident stroke alone.90 1.4.1 Determinants of the economic burden of stroke The type and severity of stroke are some predictors of costs, one-year following a stroke.21 A 2004 Canadian study estimated that the one-year per-patient cost of a transient ischemic attack was $24,993.57 (2022 CAD prices).21 This was the lowest compared to the other types of stroke; the costs for ischemic and hemorrhagic strokes were $75,359.08 and $79,574.61 respectively.21 Additionally, evidence from emergency department visits of individuals with ischemic stroke suggests that those with minor stroke had a shorter hospital length of stay and incurred less cost than patients with major stroke.91 According to an American Heart Association estimate, the cost of a severe stroke was twice the cost of a mild stroke.92 7 Functional outcome is also a major determinant of the costs of stroke care.93 The interplay between physical and cognitive deficits leads to significant economic consequences. Disabling stroke is associated with a two-fold increase in costs compared to non-disabling stroke.90 The need for support and dependence on activities of daily living due to physical and cognitive impairment is associated with higher costs.93 A Swedish study found that the cost of healthcare resources for chronic stroke patients with cognitive impairment was $85,953.53 (2022 CAD prices), three times higher than that for patients without cognitive impairment.8 Patients with cognitive impairment had higher costs associated with formal and informal care due to dependence on activities of daily living, as well as longer time spent in the hospital for admission and readmission.8 Based on current evidence, we know that cognitive impairment among stroke survivors is costly from an individual, healthcare, and societal perspective. Improvement in cognitive function has the potential to reduce the risk of dementia and support reintegration into work and society.36 Hence, functional improvements are important to increase health outcomes and decrease the economic and societal burden of stroke.93 1.5 Strategies to improve cognitive function among older adults with chronic stroke. Current evidence suggests that certain strategies may be appropriate to improve cognitive impairment among older adults with chronic stroke.94 Strategies to improve post-stroke cognitive impairment may include pharmacological interventions and non-pharmacological interventions.95 A recent meta-analysis of pharmacological strategies suggests that the use of anticholinergic agents can have clinical benefits in improving cognitive function following a stroke.96 However, the presence of side effects, such as dizziness and gastrointestinal problems, is a significant concern associated with these pharmaceutical interventions.97 Non-pharmacological and lifestyle interventions such as exercise,98 computer-assisted cognitive rehabilitation,99 and non-invasive brain stimulation100 have also shown the potential to improve post-stroke cognitive impairment. For my thesis, I will focus on evaluating two of these lifestyle interventions: 1) exercise training and 2) cognitive interventions. These strategies, when provided either as a single intervention or combined interventions have the potential to improve cognition among older adults.101,102 8 1.5.1 Exercise training Physical activity is defined as any human movement produced by the contraction of skeletal muscle to increase energy use.103 Exercise is a type of physical activity that is planned, repeated, and structured to enhance physical fitness.104 For example, physical activity involves movement in a non-resting state such as doing housework, or gardening while exercise involves activities such as intentionally going to work or joining a group workout to improve health.105,106 Targeted exercise interventions may lead to improvement in cognitive function in older adults with chronic stroke.107,108 Evidence from both observational studies and randomized controlled trials suggests that exercise may improve cognitive function following a stroke.109,110 In an observational study among 41 patients in a cardiac rehabilitation program, a 6-month aerobic and resistance exercise training program reduced the proportion of chronic stroke individuals meeting the threshold criteria for Mild Cognitive Impairment.111 Another study demonstrated that a 6-month exercise based on the Fitness and Mobility Exercise (FAME) program improved memory and executive function among 11 community-dwelling older adults with stroke with a mean age 67 years.101 Findings from randomized controlled trials have shown less consistency. A multicentre study among 28 chronic stroke survivors demonstrated that participating in a 6-month exercise and recreation program led to improvements in selective attention, conflict resolution, and working memory compared to those who received usual care.112 In contrast, some studies have not found an association between exercise and post-stroke cognitive function. A life after stroke study among 362 stroke survivors reported non-clinically relevant effect of individualized exercise programmes on cognitive and emotional functioning.113 Exploratory analyses showed that adherence to the intervention was associated with greater cognitive function, suggesting that low adherence may have accounted for the negative finding. Another study among community-dwelling adults with chronic stroke did not find changes in cognitive function following high and low-intensity exercise interventions.114 The study suggested that some factors that may have contributed to a lack of significant findings include the use of outcomes that were not adequately sensitive to detect changes in this population, as well as exercise parameters that were not sufficient to lead to sustained cognitive benefits.114 9 It is postulated that exercise potentially has differential effects on different domains of cognitive function after stroke.114 A meta-analysis with 14 studies (736 participants) synthesizing the effects of exercise on cognitive function among stroke survivors showed positive improvements in measures of attention and processing speed, with non-significant results in the executive function and working memory domains.115 The result of this is mixed as a more recent meta-analysis with 22 studies (1,601 participants) showed that exercise training significantly improved executive function and working memory but not spatial function.116 The recent meta-analysis included studies with patients with cerebrovascular diseases more broadly, suggesting that the differential effects of exercise on cognition may vary among the chronic stroke population.116 1.5.2 Cognitive interventions Although exercise interventions provide accessible and low-cost treatment services, the prevalence of mobility impairment and heightened risk of injury and falls post-stroke limits participation and ability to obtain benefits from physical activity rehabilitation programs.43,94,115 Other strategies such as cognitive interventions are recommended as an alternative strategy to combat cognitive decline post-stroke.117 Cognitive interventions can be classified into three approaches of cognitive stimulation, cognitive rehabilitation, and cognitive training.118 Cognitive stimulation includes group activities that are either supervised or structured to increase cognitive and social functioning while cognitive rehabilitation involves individually tailored programs with a focus on specific activities of daily living.119 Cognitive training involves teaching a series of mental activities or standard tasks designed to improve cognitive functioning.118 Cognitive interventions have the potential to decrease cognitive impairment in stroke patients.115 Evidence from a systematic review show that cognitive interventions including memory rehabilitation120 and cognitive remediation programs79 can be effective to improve cognitive function after stroke.94 Cognitive training is most frequently used as it has established efficacy in individuals with Mild Cognitive Impairment (MCI).119 Cognitive training, when used as a supplementary strategy in addition to exercise, can improve cognition among older adults.121 A meta-analysis with 10 studies revealed that older adults with mild cognitive impairment or dementia had better overall cognitive function after participating in a combined exercise and cognitive training program, 10 compared to those who only did physical exercise or cognitive training alone.102 Another study showed a similar outcome for a chronic stroke population with vascular cognitive impairment where positive outcomes were maintained six months after training.122 Cognitive training combined with environmental enrichment activities can improve cognitive function after stroke.101 Environmental enrichment involves any activity to promote cognitive, motor, sensory and social stimulation compared to a standard environment.123 Evidence from a randomized controlled trial showed that among individuals with stroke, a combination of exercise training, cognitive and social enrichment was associated with improvements in memory and executive function.101 It is not clear what relative improvements in the cognitive function domains were due to exercise or cognitive training activities. While some clinical studies have found non-significant changes in post-stroke cognitive function from environmental enrichment interventions, many studies show that such interventions increase participation in cognitive activities.124 A key methodological limitation of the above studies investigating the efficacy of strategies to improve post-stroke cognitive impairment is that none of them specified cognitive function as a primary outcome measure.107 Most of these studies were secondary analyses of studies with different primary outcome measures specified.113,114 Hence, these studies lacked the power to detect changes in cognitive function from the interventions.107,117 Furthermore, most of these trials were not sufficiently powered to examine changes as a result of the treatment.125 The low methodological quality of current evidence from trials makes it difficult to draw definite conclusions and make recommendations on the efficacy of exercise and cognitive interventions for post-stroke cognitive impairment.94,125 1.6 Economic evaluation of interventions to improve cognitive function While studies have investigated the effects of behavioral interventions such as physical and cognitive training on cognitive function among older adults with chronic stroke, the impact of these interventions on healthcare costs and consequences remains unknown. Economic evaluation is essential for comparing the costs and outcomes of alternative interventions as they provide a framework to make the best use of limited resources.126 An economic evaluation is a way of simultaneously comparing the costs and consequences of a program with competing or 11 known alternative(s).127 Information on healthcare costs and consequences of interventions to improve cognitive function offer important insights regarding potential cost-effective strategies aimed at reducing the health and economic burden on Canadians and the Canadian healthcare system. There are four main types of economic evaluation that differ in the way costs and outcomes are measured.126 These are cost analysis, cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), and cost-utility analysis (CUA). A cost analysis is used when the effectiveness of different interventions is the same, hence any differences between them stem from a comparison in costs. Two interventions rarely have equivalent effectiveness; hence a cost analysis is not frequently used in health economic evaluations.126 A cost-benefit analysis involves measuring and comparing all costs and benefits of a program in monetary terms. This is useful to compare diverse interventions in the same unit, however, CBA has limited application in healthcare due to objections to valuing health benefits in monetary terms.128 When a cost-benefit analysis is conducted, the decision to implement a program is made when the benefit of the programme exceeds the cost.129 A cost-effectiveness analysis is used to compare different interventions with the same health outcome.130 Outcomes are assessed in natural units such as life-years gained, number of falls prevented, and change in cognitive function. A CEA is useful to access relative efficiency by presenting results in a cost-effectiveness ratio (i.e., cost per natural unit).128 The biggest limitation of a CEA is that because outcomes from different interventions are measured in different ways, it is difficult to compare various studies.126 A cost-utility analysis is a variant of a cost-effectiveness analysis that measures outcomes using generic measures of health gain to allow comparison across different health conditions.126 Quality Adjusted Life Years (QALYs) are a common measure of health utility that combines the number of extra years gained and the quality of life of those extra years gained as a result of an intervention. This measures an individual’s preference for different health outcomes by assigning preference weights to different health statuses, with 0 being the worst health state and 1, an optimal health state. While a CUA provides a useful means to compare diverse healthcare interventions, there are methodological and ethical issues with comparing diverse interventions 12 using utility measures such as QALYs.130 Decision-making when using a cost-utility analysis depends on society’s willingness to pay for additional QALY usually determined through a threshold for cost per QALY.129 A limitation of using QALYs includes difficulty in defining cost per QALY for chronic conditions, as well as the lack of a standard threshold to guide resource allocation decision.131 There are a limited number of economic evaluations of cerebrovascular disorders.127 Existing economic evaluations in stroke rehabilitation have examined the cost-effectiveness of self-management intervention on proactive coping,132 cognitive behavioral therapy on depressive symptoms,133 and physical fitness training on general well-being.134 A cost-consequence analysis conducted alongside a randomized controlled trial examined the costs of a community-based exercise and education scheme for stroke survivors, however, this did not include any assessment of benefits.135 None of the identified economic evaluations included cognitive function as an outcome of interest. A recent systematic review of model-based economic evaluation of post-stroke cognitive impairment identified only 2 out of 232 studies included cognitive impairment as a health state.136 These two studies evaluated the cost-effectiveness of screening programs for a select sample of patients at risk of intracranial aneurysms.137,138 Current evidence suggests a dearth of economic evaluations conducted in stroke care that quantify health outcomes in natural units such as changes in cognitive function. Hence, I will conduct a cost-effectiveness analysis to contribute to the gap in this area. Furthermore, to ensure comparability with other health conditions, I will also conduct a cost-utility analysis to provide evidence that will guide the efficient allocation of resources. 13 Chapter 2: Research question This thesis evaluates the efficiency (i.e., value for money), using a cost-effectiveness and a cost-utility analysis, of (a) an exercise (EX) or (b) cognitive and social enrichment activities program (ENRICH) compared with an active control consisting of a stretching and toning program (BAT) at 6 months (intervention cessation) and at 12 months (i.e., six-month follow-up) among community-dwelling older adults with chronic stroke. My primary objective was to determine the incremental cost-effectiveness ratio (i.e., cost per incremental change in Alzheimer’s Disease Assessment Scale – Cognitive-Plus (ADAS-Cog-Plus) score and the incremental cost-utility ratio (i.e., cost per incremental QALY gained/ lost) of: i) exercise and ii) cognitive and social enrichment interventions versus iii) stretching and tone program (control group). The economic evaluation utilized a 6-month and 12-month time horizon using a Canadian health care system perspective. The specific research questions are: ▪ Is exercise training more cost-effective compared with a stretching and toning program at 6 months and 12 months? ▪ Is a cognitive and social enrichment activities program more cost-effective compared with a stretching and tone program at 6 months and 12 months? 14 Chapter 3: Research design and methods 3.1 Study design An economic evaluation conducted alongside a six-month three-arm randomized controlled trial with a 6-month follow-up aimed to improve cognitive function among individuals with chronic stroke (i.e., individuals who had a stroke at least 12 months prior to enrollment).117 3.2 The Vitality study The Vitality study was a 6-month single-blinded randomized controlled trial that compared the effects of two interventions with an active control group to improve cognitive function in older adults with chronic stroke. The Vitality study was designed to examine the independent effects of exercise training or social and cognitive enrichment activities versus a stretching and tone program among older adults with chronic stroke by looking at cognition as the primary outcome. This study also included a 6-month follow-up. Participants aged 55 years and older who had sustained an ischemic or hemorrhagic stroke were randomized into 1) multi-component exercise training (EX); 2) cognitive and social enrichment activities (ENRICH); or 3) an active control group consisting of stretching and toning exercises (BAT) with an allocation ratio of 2:2:3 (EX: ENRICH: BAT, respectively). The study was a single-site randomized control trial conducted at the Centre for Hip Health and Mobility in Vancouver, British Columbia from November 2013 to February 2020. The trial was registered at clinicaltrials.gov (NCT01027858) and further details of the study are outlined in the study protocol and primary clinical paper.117,139 3.2.1 Participants Study participants were recruited through advertisements in community centers, stroke support groups, and newspapers. The sample consisted of community-dwelling adults in Metro Vancouver, Canada, who had an ischemic or hemorrhagic stroke (confirmed by a previous Magnetic Resonance Imaging or Computerized Topography scan) at least one year before study enrollment. Participants were included if they were 1) 55 years and older; 2) had a Mini-Mental State Examination score greater than 20/30 at screening140; (3) able to comply with the intervention plan and other activities required for the trial; (4) able to write, speak and read English; (5) not planning to start or currently on a fixed dose of cognitive medication for study duration; (6) able to walk for at least 6 metres with rest intervals with or without assistive 15 devices; (7) able to participate in an activity tolerance for 60 minutes with rest intervals; and (8) not currently involved in regular therapy or progressive exercise. Participants were excluded if they have been: (1) diagnosed with any type of dementia; (2) diagnosed with any form of neurogenerative disease that affects cognition and mobility; (3) shown to have a high risk of cardiac complication during an exercise; (4) have a condition that impairs mobility as determined by a family physician; (5) taking medication that will negatively impact cognition; or (6) have aphasia, deemed by an inability to communicate by phone. All participants signed written and informed consent to participate in the study. Ethics approval was obtained from the University of British Columbia’s Clinical Research Ethics Board (H07-01160) and the Vancouver Coastal Health Research Institute (V13-00715). 3.2.2 Sample size The required sample size for the study was calculated based on the assessment of statistical significance between intervention groups on the primary measure of cognitive function, the ADAS-Cog-Plus. A mean change of 3 points on the ADAS-Cog was assumed for both the EX and ENRICH groups at 6 months, and a mean change of 1 point was assumed for the BAT group at 6 months. Using an alpha level of p<0.05, 39 participants per intervention group ensured a power greater than 0.80. The Vitality study randomized 120 participants into one of the three groups: (a) an exercise (EX), (b) cognitive and social enrichment activities program (ENRICH), and (c) a stretching and toning program (BAT). All classes for the three groups were 60 minutes long and ran twice weekly over 26 weeks. The classes were run by trained instructors with an instructor-to-participant ratio of 1:4. 3.2.3 Exercise intervention The exercise group (EX) consisted of 34 participants. The exercise program was adapted from a community-based Fitness and Mobility Exercise (FAME) program to improve fitness.141 The exercise program consisted of a combination of strength, aerobic, and balance training. This aligns with current evidence on the efficacy of combined exercise intervention to improve the quality of life among stroke survivors and older adults in general.115 Furthermore, the exercise 16 program was community-based which promotes adherence and encourages social engagement among older adults.142,143 Each class was structured to involve 10 minutes of warm-up, 20 minutes of strength training, 20 minutes of aerobic/ agility training, 5 minutes of balance training, and 5 minutes of cooldown period. These exercises consisted of intentional movement of the lower body and limbs including calf raises, an extension of triceps, high and low knee marches, and forward and backward walking, as well as arm movements including hitting balloons and throwing a ball. The program provided objective progression in the guided exercise of each participant by adding weight or altering movement tempo. 3.2.4 Cognitive and social enrichment activities intervention The cognitive and social enrichment group (ENRICH) consisted of 34 participants. The program engaged participants in activities promoting cognitive function and socialization that could be implemented with minimum resources in the community. Each class began with learning and memorization of a seven-item word list. This was followed by 15 minutes of the Lumosity brain training programme which consists of various short games that target various aspects of cognition. Participants completed a variety of social and mental activities in pairs or as a class for the remaining 30 minutes. At the end of the class, participants recalled words from the word list and recorded them on the Notes program on their iPad. 3.2.5 Active control The stretching and tone group (BAT) consisted of 52 participants. The program consisted of stretches, deep breathing and relaxation techniques, general posture education, and general core control exercises in the sitting position. This group served to control for any confounding variables including exercise received by going to the community center, as well as lifestyle changes not resulting from participation in the study. 3.3 Measures 3.3.1 Descriptive variables The Vitality study collected descriptive and demographic variables including age, weight, height, body mass index, gender, and educational status. Participants were also assessed on the type of stroke and level of cognitive functioning using the Mini-Mental State Examination,140 Montreal 17 Cognitive Assessment,144 and the Alzheimer’s Disease Assessment Scale – Cognitive Plus questionnaires.145 The study also assessed the impact of comorbidity using the Functional Comorbidity Index,146 as well as the level of motor impairment using the Fugl Meyer Total Motor score.147 3.3.2 Health resource utilization To track health resource utilization, we used a self-report questionnaire administered at 3, 6 and 12 months during the study period.148 The main resource use categories were visits to healthcare professionals, hospital admissions, and laboratory and diagnostic procedures. A unit cost was assigned for each of the cost components of health resource utilization from the British Columbia Medical Services Commission Payment Schedule 2021 price list.149 For the cost of specialized services, such as physiotherapy, or naturopathic medicine, prices were derived from the related British Columbia Association website. Where this was not available, the price was estimated as the average price from at least three practices in that specialty. The cost of delivering the exercise training, cognitive and social enrichment activities, and stretch and tone (comparator group) interventions was estimated from the costs of resources required for program delivery and implementations such as trainee salary and overhead costs minus any costs for a research protocol. For the base case analysis, cost included the cost of delivering the program, as well as healthcare resource use. All costs were inflated to 2022 Canadian dollars using Statistics Canada’s report on the consumer price index.150 Discounting was not used since the time horizon for the economic evaluation was less than 12 months. All costs are reported in 2022 Canadian dollars. A Kruskal-Wallis H test was used to determine if there exists a statistically significant difference in the mean healthcare resource use between the three groups. 3.3.3 Primary outcome measure for cognitive function The primary measure of cognitive function in the study was the Alzheimer’s Disease Assessment Scale – Cognitive-Plus (ADAS-Cog-Plus).145 The ADAS-Cog-Plus is a is a global measure of cognitive function that summarizes scores from the 13-item ADAS-Cog together with additional standard cognitive measures. The ADAS-Cog is a 13-item scale that assesses cognitive functioning in the domains of memory, language, orientation, and executive function.145 The 18 ADAS-Cog, together with the Trail making test A and B, Digit Span Forward and Backward, and Animal and Vegetable Fluency were used as inputs in the scoring algorithm for the ADAS-Cog-Plus. Scores on the ADAS-Cog-Plus range from -1 to 1, with a higher score indicating greater cognitive impairment; -1 indicates healthy cognitive function, 0 indicates minimal cognitive impairment (MCI), and 1 indicates dementia. The incremental effectiveness was calculated based on changes in ADAS-Cog-Plus at the end of the 6-month intervention and 6-month follow-up periods for the intervention versus the control group. While there is no established minimal clinically important difference (MCID) for the ADAS-Cog-Plus, an MCID of 3 points on the 13-item ADAS-Cog has been suggested as appropriate for patients with early dementia,151 with a change ≥ 4 recommended by a consensus committee of the Food and Drugs Administration for Alzheimer’s disease.63 3.3.4 Secondary clinical measures The study also assessed secondary outcomes measures including the presence of depressive symptoms using the Center for Epidemiological Studies Depression scale,153 an evaluation of general mobility and balance using the Short Physical Performance Battery,154,155 and Instrumental Activities of Daily Living.156 3.3.5 Quality-adjusted life years QALYs were assessed using the area under the curve analysis of health state utility values estimated from the European Quality of Life Five Domains three levels (EQ-5D-3L).157 The EQ-5D-3L is a 3-level patient-reported measure of quality of life comprising five domains: mobility, self-care, usual activities, pain, and depression.126 Each domain has three levels of responses of i) no problems, ii) some problems, or iii) extreme problems. Participant responses are converted to a utility score representing an individual’s health state using the Canadian valuation of EQ-5D health states.158 Scores range from -0.34 to 1, with 1 representing perfect health, 0 representing worst health/ death, and less than 0 representing a state worse than death. The utility score is then used to derive the quality-adjusted life years (QALYs) gained from the intervention. Incremental QALYs represent the difference in the mean QALY of the EX-intervention group compared with the mean QALY of the control group. QALYs gained or lost at the end of the 6-19 month intervention and 6-month follow-up period were calculated for the intervention versus the control group. A change of 0.03 QALYs based on the EQ-5D-3L is considered the minimum clinically important difference.159 3.4 Overview of economic evaluation A health economics analysis plan outlined in Appendix A was developed and outlined in the study protocol to examine the incremental costs and outcomes of EX and ENRICH programmes compared with BAT among community-dwelling adults with chronic stroke.117,139 Using a Canadian healthcare system perspective, I conducted a cost-effectiveness and cost-utility analysis within a 6-month time horizon for the intervention period and a 6-month follow-up period. Data were analyzed from the Vitality study using an intention-to-treat basis. I conducted all analyses for this economic evaluation using STATA version 17. 3.4.1 Cost-effectiveness analysis The outcome of the cost-effectiveness analysis was the incremental cost-effectiveness ratio (ICER). The ICER was estimated by dividing the difference in the mean cost of providing the intervention compared to the control by the difference in mean effectiveness. The ∆ Cost / ∆ Effectiveness was calculated for two scenarios: 1) EX versus control and 2) ENRICH versus control. The ICER was based on changes in cognitive function measured using the Alzheimer’s Disease Assessment Scale Cognitive Plus (ADAS-Cog-Plus).64 An analysis of the EX group versus the ENRICH group was not conducted because the sample size for the Vitality study was not powered apriori for a group comparison. 3.4.2 Cost-utility analysis The outcome of the cost-utility analysis was the incremental cost-utility ratio (ICUR). The ICUR was calculated by ascertaining the mean difference in cost of providing the interventions compared with the control and dividing that by the mean difference in health outcomes. The ∆ Cost / ∆ Utility was again calculated for the three scenarios: 1) EX versus control and 2) ENRICH versus control. The ICUR was based on changes in QALYs. 20 The ICER/ ICUR estimates involved 5,000 iterations of bootstrapping to calculate confidence intervals of the costs and effectiveness outcomes for each group. The bootstrapped dataset was used to plot the mean costs and effectiveness on a cost-effectiveness plane. From this, the probability that the intervention is cost-effective was determined based on which quadrant the results lie on the cost-effectiveness plane.160 For the cost-utility analysis, a value of 50,000 CAD/QALY was selected as the cost-effectiveness threshold.161 The cost-effectiveness threshold represents the maximum value a decision-maker is willing to pay for one QALY gained.162 There are three approaches for defining a cost-effectiveness threshold, the willingness-to-pay method, the precedent method, and the opportunity cost method.163 The willingness to pay method measures how much a person is willing to pay to enhance their health by a specific amount derived from preference data gathered through population surveys or consumer behavior.163 The precedent method infers a threshold based on an approved cost-effectiveness threshold for prior treatment.163 The opportunity costs method accounts for health benefits gained from treatment and forgone from displaced interventions.163 While there is no explicit cost-effectiveness threshold in Canada, a value of 50,000 CAD/ QALY is commonly cited based on the precedent of treatments already assessed by decision-makers.161,163,164 A cost-effectiveness acceptability curve (CEAC) was used to describe uncertainty around the ICER/ICUR estimates.165,166 The CEAC provides a graphical representation of the probability that the interventions were cost-effective compared to the comparator, over a range of willingness-to-pay thresholds.167 3.4.3 Base case analysis The complete case dataset was used for the primary analysis to estimate the incremental cost-effectiveness and cost-utility ratio. The complete case set consisted of two datasets: i) participants with complete costs and ADAS-Cog-Plus score data only for the cost-effectiveness analysis, and ii) participants with complete costs and QALY data only for the cost-utility analysis. This was to ensure consistency with the analysis for the primary clinical effectiveness study.139 3.4.4 Sensitivity analysis A probabilistic sensitivity analysis was used to estimate the uncertainty around the point estimate for the incremental cost-effectiveness and cost-utility ratios.168,169 A probabilistic sensitivity 21 analysis acknowledges that the input parameters used to estimate the ICER are random and hence associate a probability distribution for the parameters.170 Sensitivity analysis to assess uncertainty based on how missing data were handled was conducted on the following scenarios: i. An imputed dataset: Missing costs and outcome data in cost-effectiveness analysis can bias the results of the analysis as participants with complete data may be consistently different from those with incomplete data.171 Multiple imputations were used to predict estimates for missing costs and effectiveness data.171–174 Five-thousand iterations of bootstrapping were used to quantify uncertainty and determine which values were more likely.175 Using Multiple Imputation by Chained Equation (MICE), one imputation model for each variable of interest was specified. The imputation model included auxiliary variables informed by evidence from the literature that can predict variables with missing data. Predictive mean matching was used to ensure that the imputed values for missing costs and effectiveness outcomes were in an acceptable range.171 ii. Mean imputation where missing ADAS-Cog-Plus was replaced with the mean value from each treatment group estimated using the maximum likelihood approach. This was done to mirror the statistical analysis conducted for the primary clinical study.139 Maximum likelihood estimation was used to address missing data in the primary clinical trial by using observed data and the likelihood of observing the data (i.e., likelihood function) to estimate unknown parameters.176 The use of all available information improves the statistical power of the analysis and provides less biased estimates.177 3.4.5 Subgroup analysis Decisions on cost-effectiveness may differ for patient subsets with varying characteristics, hence there is the potential for inaccurate recommendations based on mean cost-effectiveness measures.178,179 A subgroup analysis was conducted to ascertain whether cost-effectiveness varies for a subgroup of participants. Participant subgroups were determined based on participants' characteristics that may influence their measure of cognitive function. Based on evidence from the literature that suggests varying costs and cost-effectiveness for different subgroups, the following subgroup of participants was selected for analysis: i) participants with a baseline ADAS-Cog-Plus score greater than 0, indicating some level of cognitive impairment,145 ii) participants 80 years and older,180 and ii) participants who had a hemorrhagic stroke.21,181 22 Chapter 4: Results 4.1 Baseline characteristics Baseline characteristics for 120 participants in the Vitality study are detailed in Table 1. The mean age for all participants was 71 years (SD = 9) with about 46% female participants. The mean Mini-Mental State Examination (MMSE) score for participants was 27.3 (SD = 2.5), 21.9 (SD = 4.1) for the Montreal Cognitive Assessment (MoCA), and 0.22 (SD = 0.80) for the Alzheimer’s Disease Assessment Scale-Cognitive Plus (ADAS-Cog-Plus) scores. The study participants exhibited mild cognitive impairment as indicated by the mean scores falling within the range of mild cognitive impairment on both the MoCA and ADAS-Cog-Plus assessments.144,145 Table 1. Baseline characteristics of Vitality randomized clinical trial participants Variable All participants N=120 EX (n=34) ENRICH (n=34) BAT (n=52) Mean (standard deviation) Median (Interquartile range) Frequency (Percentage) Age, years 70 (9) 71 (9) 71 (9) 70 (8) Weight(kg) 77.8 (16.0) 75.9 (13.2) 79.9 (18.0) 77.6 (16.5) Height(cm) 167.4 (9.8) 166.3 (10.5) 170.2 (9.6) 166.2 (9.3) Body Mass Index (kgm^2) 27.6 (4.5) 27.4 (3.7) 27.3 (4.4) 28.0 (5.1) Biological Sex: Female 46 (38%) 13 (38%) 11 (32%) 22 (42%) Type of stroke: Hemorrhagic Ischemic Ischemic & Lacunar Lacunar Unknown 33 (28%) 73 (61%) 1 (1%) 7 (6%) 6 (5%) 8 (24%) 22 (65%) 0 (0%) 3 (9%) 1 (3%) 10 (29%) 18 (53%) 0 (0%) 3 (9%) 3 (9%) 15 (29%) 33 (63%) 1 (2%) 1 (2%) 2 (4%) Education: High School Diploma or less Some College or University University Degree or Higher 9 (8%) 27 (23%) 84 (70%) 2 (6%) 8 (24%) 24 (71%) 2 (6%) 3 (9%) 29 (85%) 5 (10%) 16 (31%) 31 (60%) Montreal Cognitive Assessmenta 21.9 (4.1) 21.3 (3.7) 22.8 (4.0) 21.7 (4.5) Mini-Mental State Examinationb 27.3 (2.5) 28.0 (3.0) 27.1 (2.6) 28.0 (4.0) 27.6 (2.5) 29.0 (2.5) 27.2 (2.4) 28.0 (3.0) a The Montreal Cognitive Assessment (MoCA) ranges from 0 (worst) to 30 (best); scores between 26 and 30 are considered normal. b The Mini-Mental State Examination (MMSE) ranges from 0 (worst) to 30 (best); scores between 24 and 30 are considered normal. 23 Variable All participants N=120 EX (n=34) ENRICH (n=34) BAT (n=52) Functional Comorbidity Indexc 3.4 (1.8) 3.0 (2.0) 3.4 (2.0) 2.0 (3.0) 3.0 (1.5) 3.0 (1.0) 3.7 (1.8) 3.0 (2.0) Center for Epidemiological Studies - Depression Scaled 9.4 (8.2) 8.0 (10.0) 9.6 (6.4) 9.0 (10.0) 8.4 (10.3) 5.0 (5.5) 9.9 (7.8) 8.5 (12.0) Fugl Meyer Total Motor Scoree 92.0 (25.0) 79.0 (40.0) 92.5 (24.0) 94.0 (9.5) Alzheimer’s Disease Assessment Scale-Cognitive Plusf 0.22 (0.80) 0.39 (0.80) 0.12 (0.71) 0.17 (0.88) Economic outcome measure EQ-5D-3Lg 0.776 (0.118) 0.808 (0.163) 0.769 (0.125) 0.798 (0.118) 0.791 (0.130) 0.844 (0.163) 0.770 (0.106) 0.798 (0.135) Secondary Clinical measures Six Minute Walk Test, m 327.1 (139.9) 291.1 (147.8) 342.5 (143.4) 340.8 (131.9) Gait speed m/s 0.8 (0.4) 0.6 (0.4) 0.8 (0.4) 0.8 (0.4) Instrumental Activities of Daily Livingh 6.8 1.7) 8.0 (2.0) 6.8 (1.8) 8.0 (2.0) 7.0 (1.3) 8.0 (2.0) 6.8 (1.8) 8.0 (1.5) Short Physical Performance Batteryi 8.3 (2.6) 9.0 (3.0) 7.6 (2.5) 8.0 (4.0) 8.2 (2.3) 9.0 (3.0) 8.8 (2.7) 9.0 (3.0) Self-efficacy 1240.0 (490.0) 1210.0 (485.0) 1270.0 (357.5) 1290.0 (497.0) Physical Activity (caloric expenditure/wk in all exercise-related activities) 3457.7 (2446.1) 3077.4 (3121.5) 3262.2 (2499.6) 2819.4 (3245.2) 3535.4 (2718.0) 3354.3 (3064.4) 3536.3 (2255.0) 2905.9 (3120.1) c The Functional Comorbidity Index represents the number of comorbid illnesses and ranges from 0 (best) to 18 (worst); higher scores are associated with lower physical function. d The Center for Epidemiological Studies depression scale ranges from 0 (best) to 60 (worst) e The Fugl Meyer Total Motor Score ranges from 0 (worst) to 100 (best); scores > 79 indicate mild motor impairment, 56-79 indicate moderate impairment, 36-55 indicate severe impairment and 0-35 indicate severe impairment. f The Alzheimer’s Disease Assessment Scale-Cognitive Plus is a measure of cognitive function ranging from −3.46 (best) to 4.31(worst). Scores approximately of −1 imply healthy cognitive functioning, of 0 imply mild cognitive impairment, and 1 imply dementia. g The EQ-5D-3L is the EuroQol 5-domains, three-level version ranging from -0.34 (worst) to 1 (best) and was used to estimate health utility values. h The Instrumental Activities of Daily Living range from 0 (worst) to 8 (best). i The Short Physical Performance Battery range from 0 (worst) to 12 (best); scores < 9 indicates increased risk for disability. 24 4.2 Results for cost-effectiveness analysis (CEA): Intervention cessation (at 6 months) Of the 120 participants in the study, 99 (82.5%) participants had complete healthcare resource utilization and ADAS-Cog-Plus score at the end of the intervention and formed the dataset for complete case analysis for the cost-effectiveness analysis. A full breakdown of the proportion of missing data by treatment group for all participants in the study is provided in Appendix B. Figure 1. Consort flow diagram for cost-effectiveness analysis, adapted from the Vitality primary paper.139 25 4.2.1 Health care resource use and costs Unit costs for healthcare cost items are presented in Table 2. The mean healthcare cost was $1,261 (SD = 1,188) for the EX-group, $1,728 (SD = 1,973) for ENRICH, and $1,386 (SD = 1,150) for BAT. Participants in ENRICH had a higher mean healthcare resource cost per person compared to EX or BAT. However, a Kruskal-Wallis H test showed that the difference in mean healthcare resource use between the three groups was not statistically significant, χ2 (2) = 1.209, p = 0.546. The cost of health professional visits was the largest healthcare resource cost for all the groups. Table 2. Unit cost items for Vitality study at 6 months for cost-effectiveness analysis, cost per person, CAD$ 2022 Item EX (n=27) ENRICH (n=28) BAT (n=44) Reference Mean (Standard deviation) Personnel cost per person 780 780 740 Equipment cost per person 310 712 37 Total program cost per person 1090 1492 777 Vitality study expense records Healthcare professional visit 1032 (1016) 1455 (1760) 1079 (965) 2021 British Columbia Medical services plan Hospital admission 96 (157) 84 (235) 142 (197) Vancouver General Hospital fully allocated cost model a Laboratory tests and investigations 137 (217) 196 (362) 162 (183) 2021 British Columbia Medical services plan Total healthcare resource use 1261 (1188) 1728 (1973) 1386 (1150) Total costs b 2351 (1188) 3220 (1973) 2163 (1150) Abbreviation: CAD$ (Canadian dollars) a Taken for the fully allocated cost model at Vancouver General Hospital b Total cost is calculated as the sum of the cost of delivering the program and the total healthcare resource use. 26 4.2.2 ADAS-Cog-Plus As shown in Table 3, at the end of the 6-month intervention, the ADAS-Cog-Plus score was -0.192 (SD = 0.811) for the EX-group, -0.184 (SD = 0.638) for the ENRICH group and -0.171 (SD = 0.982) for the BAT group. Negative scores imply better cognitive function; therefore, participants in the EX-group had better cognitive performance at the end of the intervention, followed by the ENRICH group, then by the BAT group. Table 3. Cost-effectiveness analysis for Vitality study at 6 months. Variable Exercise (n=27) Social Cognitive Enrichment (n=28) Stretching and Toning (n=44) Mean (Standard deviation) Mean total cost per person 2351 (1188) 3220 (1973) 2163 (1150) Incremental costs 188 (285) 1057 (368) Reference a ADAS-Cog-Plus score -0.192 (0.811) -0.184 (0.638) -0.171 (0.982) Incremental ADAS-Cog-Plus score -0.021 (0.225) -0.013 (0.209) Reference a Incremental cost per change in ADAS-Cog Plus score -8823 b -79610 [95% CI: 1509, -2208]c Reference a Reference indicates that the comparator is the stretching and toning (control) group. b There is no WTP for which we can be 95% confident that the two therapies differ in value. c Confidence interval written as [lower limit, upper limit] and interpreted as: for WTP ≥ 0 & ≤ 1509, we can be 95% confident that the therapy with the larger point estimate for effect represents good value compared with the alternative. 27 Figure 2. Cost-effectiveness plane for cost-effectiveness analysis at 6 months.j 2a. Cost-effectiveness plane for EX vs BAT (time-horizon, 6-months; complete case analysis) for cost-effectiveness analysis showing the 95% confidence ellipse of incremental cost and effectiveness for comparison between the exercise training group and the stretching and toning control group (comparator). 2b. Cost-effectiveness plane for ENRICH vs BAT (time-horizon, 6-months; complete case analysis) for cost-effectiveness analysis showing the 95% confidence ellipse of incremental cost and effectiveness for comparison between the social/ cognitive enrichment group and the stretching and toning control group (comparator). Figure 3. Cost-effective acceptability curve for cost-effectiveness analysis at 6 months.k 3a. Cost-effective acceptability curve for comparison between the exercise training group and the stretching and toning control group (comparator) for 6 months intervention period. 3b. Cost-effective acceptability curve for comparison between the social/ cognitive enrichment group and the stretching and toning control group (comparator) for 6 months intervention period. j The vertical axis represents healthcare costs, and the horizontal axis represents the measure of effectiveness: ADAS-Cog Plus score. k The vertical axis represents the probability the ICER is in the cost-effective region and the horizontal axis represents the willingness to pay threshold. 28 4.2.3 Cost-effectiveness analysis Based on the point estimates for the total costs and the ADAS-Cog-Plus score for the base case analysis, the exercise program was more costly and more effective than the stretching and toning program with an ICER of $CAD -8823 per mean change in ADAS-Cog-Plus score. The social/ cognitive intervention program was more costly and more effective compared to the stretching and toning program with an ICER of $CAD -79610 [95% CI: 1509, -2208] per mean change in ADAS-Cog-Plus score. Figure 2a demonstrates that for exercise compared with the stretching and toning group, about 49% of 5,000 bootstrapped cycles were represented in the northwest quadrant. For the ADAS-Cog-Plus, a negative score represents better cognitive function. Hence, this indicates that the exercise intervention was more costly and more effective than the stretching and toning program. Figure 2b demonstrates that for the social/ cognitive enrichment group, about 75% of 5,000 bootstrapped cycles were represented in the northwest quadrant. This shows that the social/ cognitive intervention program was more costly and more effective compared to the stretching and toning program. As no willingness to pay threshold (WTP) exists for the ADAS-Cog-Plus, it is difficult to interpret the cost-effectiveness results. Figure 3a demonstrates that the probability of ICER -($CAD 8823) acceptance for exercise group compared to the control stretching and toning program is 40% for WTP value between CAD 15,000 and 60,000. The probability of ICER -($CAD 79610) for the social/ cognitive enrichment compared to the control stretching and toning program is also 40% above WTP value of CAD 30,000. 29 4.3 Results for cost-utility analysis: Intervention cessation (at 6 months) Of the 120 participants in the study, 91 (75.8%) participants had complete healthcare resource utilization and QALY score at the end of the intervention and formed the dataset set for complete case analysis for the cost-effectiveness analysis. A full breakdown of the proportion of missing data by treatment group for all participants in the study is provided in Appendix B. Figure 4. Consort flow diagram for cost-utility analysis, adapted from the Vitality primary paper.139 30 4.3.1 Health care resource use and costs Unit costs for healthcare cost items are presented in Table 4. The mean healthcare cost was $1,071 (SD = 742) for the EX-group, $1,719 (SD = 1,908) for ENRICH, and $1,416 (SD = 1,162) for BAT. Participants in ENRICH had a higher mean healthcare resource cost per person compared to EX or BAT. However, a Kruskal-Wallis H test showed that the difference in mean healthcare resource use between the three groups was not statistically significant, χ2 (2) = 1.675, p = 0.4328. The cost of health professional visits was the largest healthcare resource cost for all the groups. Table 4. Unit cost items for Vitality study at 6 months for cost-utility analysis, cost per person, CAD$ 2022 Item EX (n = 24) ENRICH (n=23) BAT (n=43) Reference Mean (Standard deviation) Personnel cost per person 780 780 740 Equipment cost per person 310 712 37 Program cost per person 1090 1492 777 Vitality study expense records Healthcare professional visit 865 (641) 1403 (1644) 1081 (975) 2021 British Columbia Medical services plan Hospital admission 81 (131) 96 (259) 151 (197) Vancouver General Hospital fully allocated cost model a Laboratory tests and investigations 129 (219) 220 (388) 182 (210) 2021 British Columbia Medical services plan Total healthcare resource use 1071 (742) 1719 (1908) 1416 (1162) Total costs b 2161 (742) 3211 (1908) 2193 (1162) Abbreviation: CAD$ (Canadian dollars) a Taken for the fully allocated cost model at Vancouver General Hospital b Total cost is calculated as the sum of the cost of delivering the program and the total healthcare resource use. 4.3.2 Quality-adjusted life years The incremental adjusted QALY (adjusted for baseline EQ-5D-3L score) after 6 months was 0.009 (SD=0.008) for EX compared with the BAT group, and 0.010 (SD=0.009) for ENRICH compared with BAT group. Adjusted QALY was calculated using a regression model which 31 included baseline utility and group. A minimal clinically important difference for QALYs is a change of 0.03.159 Table 5. Cost-utility analysis for the Vitality study at 6 months. Variable Exercise, (n=25) Social Cognitive Enrichment, (n=23) Stretching and Toning, (n=43) Mean (Standard deviation) Mean total costs per person 2161 (742) 3211 (1908) 2193 (1162) Incremental costs -32 (258) 1018 (378) Reference a QALY 0.378 (0.043) 0.389 (0.055) 0.370 (0.049) Adjusted QALY 0.381 (0.033) 0.382 (0.042) 0.372 (0.030) Adjusted Incremental QALY a 0.009 (0.008) 0.010 (0.009) Reference a Incremental costs per adjusted QALY -3381c 101687 [95% CI:14589, -140938]d Reference a a Reference indicates that the comparator is the stretching and toning (control) group. b Incremental QALYs are adjusted for baseline utility using a linear regression model. c There is no WTP for which we can be 95% confident that the two therapies differ in value. d Confidence interval is written as [lower limit, upper limit] and interpreted as: for WTP ≥ 0 & ≤ 14589: We can be 95% confident that the therapy with the larger point estimate for effect represents good value compared with the alternative. 32 Figure 5. Cost-effectiveness plane for cost-utility analysis at 6 months.l 5a. Cost-effectiveness plane (time-horizon, 6-months; complete case analysis) for cost-utility analysis showing the 95% confidence ellipse of increment cost and effectiveness (QALY) for comparison between the exercise training group and the stretching and toning control group (comparator). 5b. Cost-effectiveness plane (time-horizon, 6 months; imputed case analysis) for cost-utility analysis showing the 95% confidence ellipse of increment cost and effectiveness (QALY) for comparison between the social/ cognitive enrichment group and the stretching and toning control group (comparator). Figure 6. Cost-effective acceptability curve for cost-utility analysis at 6 months.m 6a. Cost-effective acceptability curve for comparison between the exercise training group and the stretching and toning control group (comparator) for 6 months intervention. 6b. Cost-effective acceptability curve for comparison between the social/ cognitive enrichment group and the stretching and toning control group (comparator) for 6 months intervention. l The vertical axis represents healthcare costs, and the horizontal axis represents the measure of effectiveness, quality-adjusted life year (QALY) using the EQ-5D-3L. m The vertical axis represents the probability the ICER is in the cost-effective region and the horizontal axis represents the willingness to pay threshold. 33 4.3.3 Cost-utility analysis Based on the point estimates for the total healthcare resource utilization and QALYs, for the base case analysis, the exercise program was cost-saving (i.e., less costly and more effective) than the stretching and toning program with an ICER of $CAD -3381 per QALY gained. The social/ cognitive intervention program was more costly and more effective compared to the stretching and toning program with an ICER of $CAD 101687 [95% CI:14589, -140938] per QALY gained. Figure 5a demonstrates that for exercise compared with the stretching and toning group, 77% of 5,000 bootstrapped cycles were represented in the southeast quadrant. This indicates that the exercise intervention was less costly than the stretching and toning program. However, incremental effectiveness was negligible, hence exercise did not lead to any meaningful change in quality of life compared to the stretching and toning program. Figure 5b demonstrates that for the social/ cognitive enrichment group, about 99% of 5,000 bootstrapped cycles were represented in the northeast quadrant. This shows that the social/ cognitive intervention program was more costly compared to the stretching and toning program. However, incremental effectiveness was negligible, hence the social/ cognitive intervention program did not lead to any meaningful change in quality of life compared to the stretching and toning program. Figures 6a and 6b both demonstrate that for both the exercise and social/ cognitive interventions compared to the stretching and toning program, the probability of ICUR acceptance was 100% using the Canadian willingness to pay threshold of CAD$50,000 per QALY gained. 4.4 Sensitivity analysis: Intervention cessation (at 6 months) 4.4.1 Cost-effectiveness analysis The sensitivity analysis for the cost-effectiveness analysis revealed similar results for the imputed dataset and mean imputation with the base case analysis. The incremental cost per mean change in ADAS-Cog-Plus showed that both the exercise and social/ cognitive interventions were more costly and more effective than the stretching and toning program. However, compared to the base case analysis, the ADAS-Cog-Plus score for the imputed dataset and mean imputation at the end of the intervention suggest that participants in ENRICH group had better cognitive performance at the end of the intervention, followed by the EX-group, then the BAT group. 34 4.4.2 Cost-utility analysis The sensitivity analysis for the cost-utility analysis revealed similar results for the imputed dataset, and mean imputation with my base case analysis. The incremental cost per QALY gained showed that both the exercise and social/ cognitive interventions were more costly and more effective than the stretching and toning program. Similar to the base case analysis, incremental QALY suggests that both EX and ENRICH led to negligible improvement in health-related quality of life compared to the BAT group. Table 6. Results of sensitivity analyses at 6 months. Scenario Outcomes EX ENRICH BAT Imputed dataset # of participants 34 34 52 Mean (SD) cost 2250 (192) 3310 (347) 2130 (152) Incremental cost 120 (33) 1178 (45) Reference ADAS-Cog-Plus score -0.080 (0.146) -0.212 (0.116) -0.043 (0.138) Incremental ADAS-Cog-Plus -0.036 (0.233) -0.168 (0.027) Reference Cost/ ADAS-Cog-Plus -3308 [95% CI: -1122, 5038] -7014 [95% CI: -10048, -5386] Reference QALY 0.381 (0.005) 0.380 (0.006) 0.376 (0.004) Incremental QALY 0.005 (0.001) 0.005 (0.001) Reference Cost/ QALY 24300 [95% CI:10519, 44122] 255253 [95% CI: 179888, 421361] Reference Mean imputation using MLE for ADAS-Cog # of participants 34 34 34 Mean (SD) cost 2250 (192) 3310 (347) 2130 (152) Incremental cost 120 (33) 1178 (45) Reference ADAS-Cog-Plus score -0.142 (0.777) -0.212 (0.599) -0.148 (0.905) Incremental ADAS-Cog-Plus 0.056 (0.026) -0.064 (0.024) Reference Cost/ ADAS-Cog-Plus 21233 [95% CI: 1499, -2592] -18366 [95% CI: -70970, -10631] Reference 35 4.5 Subgroup analysis: Intervention cessation (at 6 months) 4.5.1 Cost-effectiveness analysis The results of a subgroup analysis for the cost-effectiveness analysis are presented in Table 7. Exploratory analysis revealed that the exercise intervention compared to the stretching and tone program was cost-saving (i.e., less costly and more effective) for a subgroup of participants 80 years and older. The exercise group was less effective compared to the stretching and toning program for participants with better cognitive function at baseline (i.e., score < 0) and those with hemorrhagic stroke. The social/ cognitive intervention was always more costly than the stretching and toning program for all the subgroups in the exploratory analyses; it was more effective for participants with better cognitive function at baseline (i.e., score < 0), those with ischemic and lacunar stroke and participants 80 years and older. 4.5.2 Cost-utility analysis Exploratory analyses for a subgroup of participants for the cost-utility analysis in Table 8 revealed that the exercise intervention compared to the stretching and tone program was cost-saving (i.e., less costly and more effective) for a subgroup of participants 80 years and older, those who has better cognitive function at baseline (i.e., score < 0), as well as participants with hemorrhagic stroke. The analyses for the social/ cognitive intervention compared with the stretching and toning program revealed a similar result as the base case analysis (i.e., more costly and more effective) for all subgroups, except for participants with better cognitive performance at baseline where a negative incremental QALY was observed. 36 Table 7. Results of subgroup analyses for cost-effectiveness analysis at 6 months Category Subgroup Outcomes EX vs BAT ENRICH vs BAT ADAS-Cog-Plus at baseline Greater than or equal to 0 (n=56) Mean Incremental costs (2022 CAD$) 147 (184) 301 (154) Mean Incremental ADAS-Cog-Plus -0.20 (0.22) -0.265 (0.212) ICER -738 -1136 [1471, 42] Less than 0 (n=43) Mean Incremental costs (2022 CAD$) 320 (593) 2104 (692) Mean Incremental ADAS-Cog-Plus 0.076 (0.218) 0.237 (0.201) ICER 4204 8861 [2074, -10406] Age Greater than or equal to 80 (n=17) Mean Incremental costs (2022 CAD$) -173 (212) 142 (290) Mean Incremental ADAS-Cog-Plus -0.059 (0.528) -0.500 (0.488) ICER 2929 -284 Less than 80 (n=82) Mean Incremental costs (2022 CAD$) 279 (341) 1296 (431) Mean Incremental ADAS-Cog-Plus -0.120 (0.240) 0.019 (0.229) ICER -2321 69195 [1580, -2817] Type of stroke Hemorrhagic stroke (n=27) Mean Incremental costs (2022 CAD$) -185 (329) 705 (393) Mean Incremental ADAS-Cog-Plus 0.497 (0.453) 0.113 (0.402) ICER -372 6258 Ischemic & Lacunar stroke (n= 72) Mean Incremental costs (2022 CAD$) 312 (362) 1204 (483) Mean Incremental ADAS-Cog-Plus -0.207 (0.260) -0.059 (0.248) ICER -1507 -20280 [1237, -1680] 37 Table 8. Results of subgroup analyses for cost-utility analyses at 6 months. Category Subgroup Outcomes EX vs BAT ENRICH vs BAT ADAS-Cog-Plus score at baseline Greater than or equal to 0 (n=54) Mean Incremental costs (2022 CAD$) 91 (191) 311 (166) Mean adjusted Incremental QALY 0.015 (0.011) 0.030 (0.009) ICER 6232 10237 Less than 0 (n=37) Mean Incremental costs (2022 CAD$) -185.53 (552.52) 2166.33 (763.22) Mean adjusted Incremental QALY 0.002 (0.011) -0.021 (0.016) ICER -86039 -103149 [132327, -24205] Age Greater than or equal to 80 (n=16) Mean Incremental costs (2022 CAD$) -310 (221) 184 (271) Mean adjusted Incremental QALY 0.025 (0.013) 0.023 (0.017) ICER -12449 8010 (-10515, -33519] Less than 80 (n=75) Mean Incremental costs (2022 CAD$) 26 (310) 1236 (453) Mean adjusted Incremental QALY 0.006 (0.009) 0.007 (0.011) ICER 4375 179491 [19586, -90053] Type of stroke Hemorrhagic stroke (n=28) Mean Incremental costs (2022 CAD$) -247 (326) 6423 (385) Mean adjusted Incremental QALY 0.001 (0.020) 0.024 (0.014) ICER -369564 26828 Ischemic & Lacunar stroke (n= 63) Mean Incremental costs (2022 CAD$) 42 (336) 1241 (523) Mean adjusted Incremental QALY 0.013 (0.008) 0.002 (0.116) ICER 3213 498712 (14683, -53848] 38 4.6 Results for cost-effectiveness analysis: End of follow-up (at 12 months) Of the 120 participants in the study, 93 (77.5%) participants had complete healthcare resource utilization and ADAS-Cog-Plus score at the end of follow-up and formed the dataset for complete case analysis for the cost-effectiveness analysis. A full breakdown of the proportion of missing data by treatment group for all participants in the study is provided in Appendix B. 4.6.1 Health care resource use and costs Unit costs for healthcare cost items are presented in Table 9. The mean healthcare cost was $2,439 (SD = 2,260) for the EX-group, $3,138 (SD = 3,253) for ENRICH, and $2,496 (SD = 1,826) for BAT. Participants in ENRICH group had a higher mean healthcare resource cost per person compared to EX or BAT. However, a Kruskal-Wallis H test showed that the difference in mean healthcare resource use between the three groups was not statistically significant, χ2 (2) = 0.671 p = 0.7151. The cost of health professional visits was the largest healthcare resource cost for all the groups. Table 9. Unit cost items for Vitality study at 12 months for cost-effectiveness analysis, cost per person, CAD$ 2022 Item EX (n = 24) ENRICH (n=27) BAT (n=42) Reference Mean (standard deviation) Cost of delivering the program 1090 1492 777 Vitality study expense records Healthcare professional visit 2047 (2015) 2696 (2960) 1999 (1539) 2021 British Columbia Medical services plan Hospital admission 154 (236) 152 (310) 224 (285) Vancouver General Hospital fully allocated cost model a Laboratory tests and investigations 245 (351) 309 (485) 268 (314) 2021 British Columbia Medical services plan Total healthcare resource use 2439 (2260) 3138 (3253) 2496 (1826) Total costs b 3529 (2260) 4630 (3253) 3273 (1826) Abbreviation: CAD$ (Canadian dollars) a Taken for the fully allocated cost model at Vancouver General Hospital b Total cost is calculated as the sum of the cost of delivering the program and the total healthcare resource use. 39 4.6.2 ADAS-Cog-Plus As shown in Table 10, at the end of the 12-month follow-up period, that ADAS-Cog-Plus score was -0.1 (SD = 0.805) for the EX-group, -0.192 (SD = 0.738) for the ENRICH group and -0.254 (SD = 0.951) for the BAT group. As negative scores imply better cognitive function, this suggests that participants in the BAT-group had better cognitive performance at the end of the follow-up period, followed by the ENRICH group, then by the EX-group. Table 10. Cost-effectiveness analysis for Vitality study at 12 months. Variable Exercise (n=24) Social Cognitive Enrichment (n=27) Stretching and Toning (n=42) Mean (Standard deviation) Mean total cost per person 3529 (2260) 4630 (3253) 3273 (1826) Incremental costs 256 (510) 1357 (612) Reference a ADAS-Cog-Plus score -0.100 (0.805) -0.192 (0.738) -0.254 (0.951) Incremental ADAS-Cog-Plus score 0.154 (0.231) 0.063 (0.216) Reference a Incremental cost per change in ADAS-Cog Plus score 1664n 21668 [95% CI: 587, -3305]o Reference a a Reference indicates that the comparator is the stretching and toning (control) group n There is no WTP for which we can be 95% confident that the two therapies differ in value. o Confidence interval written as [lower limit, upper limit] and interpreted as: for WTP ≥ 0 & ≤ 587: We can be 95% confident that the therapy with the larger point estimate for effect represents bad value compared with the alternative. 40 Figure 7. Cost-effectiveness plane for cost-effectiveness analysis at 12 months.p 7a. Cost-effectiveness plane (time-horizon, 12-months; complete case analysis) for cost-effectiveness analysis showing the 95% confidence ellipse of incremental cost and effectiveness (ADAS-Cog-Plus score) for comparison between the exercise training group and the stretching and toning control group (comparator). 7b. Cost-effectiveness plane (time-horizon, 12-months; complete case analysis) for cost-effectiveness analysis showing the 95% confidence ellipse of increment cost and effectiveness (ADAS-Cog-Plus score) for comparison between the social/ cognitive enrichment group and the stretching and toning control group (comparator) Figure 8. Cost-effective acceptability curve for cost-effectiveness analysis at 12 months.q 8a. Cost-effective acceptability curve for comparison between the exercise training group and the stretching and toning control group (comparator) for the end of the 6-month follow-up period. 8b. Cost-effective acceptability curve for comparison between the social/ cognitive enrichment group and the stretching and toning control group (comparator) for the end of the 6-month follow-up period. p The vertical axis represents healthcare costs, and the horizontal axis represents the measure of effectiveness: ADAS-Cog Plus score. q The vertical axis represents the probability the ICER is in the cost-effective region and the horizontal axis represents the willingness to pay threshold. 41 4.6.3 Cost-effectiveness analysis Based on the point estimates for the total costs and the ADAS-Cog-Plus score for the base case analysis, the exercise program was more costly and less effective than the stretching and toning program with an ICER of $CAD 1664 per mean change in ADAS-Cog-Plus score. The social/ cognitive intervention program was more costly and less effective compared to the stretching and toning program with an ICER of $CAD 21668 [95% CI: 587, -3305] per mean change in ADAS-Cog-Plus score. Figure 7a demonstrates that for exercise compared with the stretching and toning group, about 66% of 5,000 bootstrapped cycles were represented in the northeast quadrant. For the ADAS-Cog-Plus, a positive score represents a worse cognitive function. Hence, this indicates that the exercise intervention was more costly and less effective than the stretching and toning program. Figure 7b demonstrates that for the social/ cognitive enrichment group, about 86% of 5,000 bootstrapped cycles were represented in the northeast quadrant. This shows that the social/ cognitive intervention program was more costly and less effective compared to the stretching and toning program. Figure 8a demonstrates that the probability of ICER $CAD 1,664 for the exercise group compared with the balance and tome group is 35% for WTP value $CAD 30,000 and above. The probability of ICER $CAD 21,668 for the social/ cognitive enrichment group compared with the stretching and toning group is 35% for a WTP value of $CAD 35,000 and above. As noted earlier, as no WTP exists for the ADAS-Cog-Plus, it is challenging to interpret this result. 4.7 Results for cost-utility analysis: End of follow-up (at 12 months) Of the 120 participants in the study, 73 (60.8%) participants had complete healthcare resource utilization and QALY score at the end of the intervention and formed the dataset set for complete case analysis for the cost-effectiveness analysis. A full breakdown of the proportion of missing data by treatment group for all participants in the study is provided in Appendix B. 42 4.7.1 Health care resource use and costs Unit costs for healthcare cost items are presented in Table 11. The mean healthcare cost was $2,059 (SD = 1,448) for the EX-group, $3,356 (SD = 3,438) for ENRICH, and $2,705 (SD = 1,984) for BAT. Participants in ENRICH had a higher mean healthcare resource cost per person compared to EX or BAT. However, a Kruskal-Wallis H test showed that the difference in mean healthcare resource use between the three groups was not statistically significant, χ2 (2) = 1.644, p = 0.4396. The cost of health professional visit was the largest healthcare resource cost for all the groups. Table 11. Unit cost items for Vitality study at 12 months for cost-utility analysis, cost per person, CAD$ 2022 Item EX (n = 20) ENRICH (n=20) BAT (n=33) Reference Mean (standard deviation) Cost of delivering the program 1090 1492 777 Vitality study expense records Healthcare professional visit 1685 (1185) 2810 (3114) 2170 (1685) 2021 British Columbia Medical services plan Hospital admission 155 (239) 180 (351) 245 (293) Vancouver General Hospital fully allocated cost model a Laboratory tests and investigations 227 (374) 366 (525) 290 (336) 2021 British Columbia Medical services plan Total healthcare resource use 2059 (1448) 3356 (3438) 2705 (1984) Total costs b 3149 (1448) 4848 (3438) 3482 (1984) Abbreviation: CAD$ (Canadian dollars) a Taken for the fully allocated cost model at Vancouver General Hospital b Total cost is calculated as the sum of the cost of delivering the program and the total healthcare resource use. 4.7.2 Quality-adjusted life years The incremental adjusted QALY (adjusted for baseline EQ-5D-3L score) after follow-up was 0.002 (SD=0.008) for EX compared with the BAT group, and 0.004 (SD=0.01) for COG compared with BAT group. Adjusted QALY was calculated using a regression model which included baseline utility and group. A minimal clinically important difference for QALYs is a change of 0.03.159 43 Table 12. Cost-utility analysis for the Vitality study at 12 months. Variable Exercise (n=20) Social Cognitive Enrichment, (n=20) Stretching and Toning, (n=33) Mean (Standard deviation) Mean total cost per person 3149 (1448) 4847 (3438) 3481 (1984) Incremental costs -333 (511) 1366 (743) Reference b QALY 0.374 (0.050) 0.384 (0.061) 0.373 (0.056) Adjusted QALY 0.376 (0.030) 0.379 (0.045) 0.374 (0.028) Adjusted Incremental QALY b 0.002 (0.008) 0.004 (0.010) Reference b Incremental costs per adjusted QALY -154198c 331306 [95% CI: -11551, -78678] d Reference b a Reference indicates that the comparator is the stretching and toning (control) group. b Incremental QALYs are adjusted for baseline utility using a linear regression model. c There is no WTP for which we can be 95% confident that the two therapies differ in value. d Confidence interval is written as [lower limit, upper limit] and interpreted as: there is no WTP for which we can be 95% confident that the 2 therapies differ in value. 44 Figure 9. Cost-effectiveness plane for cost-utility analysis at 12 months.r 9a. Cost-effectiveness plane (time-horizon, 12-months; complete case analysis) for cost-utility analysis showing the 95% confidence ellipse of increment cost and effectiveness (QALY) for comparison between the exercise training group and the stretching and toning control group (comparator). 9b. Cost-effectiveness plane (time-horizon, 12-months; imputed case analysis) for cost-utility analysis showing the 95% confidence ellipse of increment cost and effectiveness (QALY) for comparison between the social/ cognitive enrichment group and the stretching and toning control group (comparator). Figure 10. Cost-effective acceptability curve for cost-utility analysis at 12 months.s 10a. Cost-effective acceptability curve for comparison between the exercise training group and the stretching and toning control group (comparator) for the 6-month follow-up period. 10b. Cost-effective acceptability curve for comparison between the social/ cognitive enrichment group and the stretching and toning control group (comparator) for the 6-month follow-up period. r The vertical axis represents healthcare costs, and the horizontal axis represents the measure of effectiveness, quality-adjusted life year (QALY) using the EQ-5D-3L. s The vertical axis represents the probability the ICER is in the cost-effective region and the horizontal axis represents the willingness to pay threshold. 45 4.7.3 Cost-utility analysis Based on the point estimates for the total healthcare resource utilization and QALYs, for the base case analysis, the exercise program was less costly and more effective than the stretching and toning program with an ICER of $CAD -154198 per QALY gained. The social/ cognitive intervention program was more costly and more effective compared to the stretching and toning program with an ICER of $CAD 331306 [95% CI: -11551, -78678] per QALY gained. Figure 9a demonstrates that for exercise compared with the stretching and toning group, 50% of 5,000 bootstrapped cycles were represented in the southeast quadrant. This indicates that the exercise intervention was less costly than the stretching and toning program. However, incremental effectiveness was negligible, hence exercise did not lead to any meaningful change in quality of life compared to the stretching and toning program. Figure 9b demonstrates that for the social/ cognitive enrichment group, about 99% of 5,000 bootstrapped cycles were represented in the northeast quadrant. This shows that the social/ cognitive intervention program was more costly compared to the stretching and toning program. However, incremental effectiveness was negligible, hence the social/ cognitive intervention program did not lead to any meaningful change in quality of life compared to the stretching and toning program. Figures 10a and 10b both demonstrate that for both the exercise and social/ cognitive interventions compared to the stretching and toning program, the probability of ICUR acceptance was 100% using the Canadian willingness to pay threshold of CAD$50,000 per QALY gained. 4.8 Sensitivity analysis: End of follow-up (at 12 months) 4.8.1 Cost-effectiveness analysis The sensitivity analysis for the cost-effectiveness analysis revealed similar results for the imputed dataset and mean imputation with the base case analysis for exercise compared with the stretching and toning program. The incremental cost per mean change in ADAS-Cog-Plus showed exercise was more costly and less effective than the stretching and toning program. Compared to the base case analysis, the ADAS-Cog-Plus score for the imputed dataset and mean imputation suggest that social/ cognitive enrichment was more effective compared to the stretching and toning group. 46 4.8.2 Cost-utility analysis The sensitivity analysis for the cost-utility analysis revealed that both exercise and social/cognitive enrichment interventions was more costly and less effective compared to the stretching and toning program. Similar to the base case analysis, incremental QALY suggests that both EX and ENRICH led to negligible improvement in health-related quality of life compared to the BAT group. Table 13. Results of sensitivity analyses at 12 months Scenario Outcomes EX ENRICH BAT Imputed dataset # of participants 34 34 52 Mean (SD) cost 3283 (352) 4685 (568) 3253 (245) Incremental cost 32 (56) 1429 (73) Reference ADAS-Cog-Plus score -0.014 (0.145) -0.233 (0.132) -0.109 (0.140) Incremental ADAS-Cog-Plus 0.095 (0.028) -0.122 (0.027) Reference Cost/ ADAS-Cog-Plus 339 [95% CI: -790, 2340] -11677 [95% CI: -20390, -8199] Reference QALY 0.372 (0.004) 0.377 (0.005) 0.379 (0.003) Incremental QALY -0.007 (0.001) -0.002 (0.001) Reference Cost/ QALY -4409 [95% CI: -19632, 10934] -804739 [95% CI: -5914400, -438911] Reference Mean imputation using MLE for ADAS-Cog # of participants 34 34 34 Mean (SD) cost 3283 (352) 4685 (568) 3253 (245) Incremental cost 32.26 (56.126) 1429.47 (72.84) Reference ADAS-Cog-Plus score -0.155 (0.118) -0.230 (0.117) -0.222 (0.119) Incremental ADAS-Cog-Plus 0.067 (0.024) -0.001 (0.024) Reference Cost/ ADAS-Cog-Plus 482 [95% CI: -1169, 4270] -188074 [95% CI: 34674, -26489] Reference 4.9 Subgroup analysis: End of follow-up (at 12 months) 4.9.1 Cost-effectiveness analysis The results of a subgroup analysis for the cost-utility analysis are presented in Table 14. Exploratory analysis revealed that the exercise intervention compared to the stretching and tone program was more effective and more costly for participants with worse cognitive function at baseline (i.e., score ≥ 0). The exercise group was less costly but less effective compared to the 47 stretching and toning program for a subgroup of participants 80 years and older and those with hemorrhagic stroke. The social/ cognitive intervention was more costly but more effective compared with the stretching and toning program for subgroups of participants with worse cognitive function at baseline (i.e., score ≥ 0), those with ischemic and lacunar stroke, and participants 80 years and older. 4.9.2 Cost-utility analysis Exploratory analyses for a subgroup of participants for the cost-utility analysis revealed that the exercise intervention compared to the stretching and tone program was more costly for a subgroup of participants those who had worse cognitive functioning at baseline (i.e., score ≥ 0), as well as participants with ischemic or lacunar stroke. Exercise was also less effective compared to the stretching and tone program participants less than 80 years and those with hemorrhagic stroke. The analyses for the social/ cognitive intervention compared with the stretching and toning program revealed a similar result as the base case analysis (i.e., more costly and more effective) for all subgroups, except for participants with better cognitive performance at baseline and those with ischemic and lacunar stroke, where a negative incremental QALY was observed. 48 Table 14. Results of subgroup analyses for cost-utility analysis at 12 months. Category Subgroup Outcomes EX vs BAT ENRICH vs BAT ADAS-Cog-Plus at baseline Greater than or equal to 0 (n=54) Mean Incremental costs (2022 CAD$) 166 (378) 120 (324) Mean Incremental ADAS -0.044 (0.253) -0.080 (0.225) ICER -3749 -1502 Less than 0 (n=39) Mean Incremental costs (2022 CAD$) 621 (1075) 3272 (1130) Mean Incremental ADAS 0.216 (0.217) 0.126 (0.205) ICER 2875 25943 [4231, -7854] Age Greater than or equal to 80 (n=15) Mean Incremental costs (2022 CAD$) -243 (650) 374 (788) Mean Incremental ADAS 0.494 (0.397) -0.049 (0.429) ICER -493 -7669 Less than 80 (n=78) Mean Incremental costs (2022 CAD$) 404 (593) 1657 (712) Mean Incremental ADAS -0.003 (0.254) 0.017 (0.245) ICER -133819 95319 Type of stroke Hemorrhagic stroke (n=26) Mean Incremental costs (2022 CAD$) -1092 (704) 525 (864) Mean Incremental ADAS 0.260 (0.431) 0.348 (0.368) ICER -4205 1511 Ischemic & Lacunar stroke (n= 67) Mean Incremental costs (2022 CAD$) 710 (636) 1630 (772) Mean Incremental ADAS 0.057 (0.270) -0.052 (0.266) ICER 12396 -31138 [518, -1680] 49 Table 15. Results of subgroup analyses for cost-utility at 12 months. Category Subgroup Outcomes EX vs BAT ENRICH vs BAT ADAS-Cog-Plus score at baseline Greater than or equal to 0 (n=42) Mean Incremental costs (2022 CAD$) 88.41 (453.52) 2.82 (420.30) Mean adjusted Incremental QALY 0.003 (0.012) 0.022 (0.001) ICER 28424 126 [-28066, 291012] Less than 0 (n=31) Mean Incremental costs (2022 CAD$) -707.07 (1055.27) 3634.96 (1312.89) Mean adjusted Incremental QALY 0.001 (0.012) -0.023 (0.018) ICER -495827 -159149 [192103, -35481] Age Greater than or equal to 80 (n=15) Mean Incremental costs (2022 CAD$) -243.47 (649.57) 374.32 (788.38) Mean adjusted Incremental QALY 0.006 (0.01) 0.01 (0.16) ICER -38160 37054 Less than 80 (n=58) Mean Incremental costs (2022 CAD$) -300.84 (617.79) 1882.38 (914.24) Mean adjusted Incremental QALY -0.0001 (0.01) 0.0001 (0.012) ICER 1507353 12600429 [3665, -58851] Type of stroke Hemorrhagic stroke (n=21) Mean Incremental costs (2022 CAD$) -1223.94 (784.57) 132.95 (1002.84) Mean adjusted Incremental QALY -0.003 (0.023) 0.022 (0.016) ICER 351469 5933 Ischemic & Lacunar stroke (n= 52) Mean Incremental costs (2022 CAD$) 49.90 (639.23) 1894.89 (954.95) Mean adjusted Incremental QALY 0.005 (0.008) -0.004 (0.0126) ICER 10851 -513843 [-7863, -32059] 50 Chapter 5: Discussion 5.1 Summary of results The results for the cost-effectiveness analysis (i.e., ICER per mean change in the ADAS-Cog-Plus score) indicate that at the end of the 6-month intervention, both exercise and cognitive and social enrichment were more costly and more effective compared to the control stretching and toning program, with exercise experiencing the greatest benefits in health outcome. Incremental cost for participants in the cognitive and social enrichment group was 5.6 times the incremental costs of participants in the exercise group. Incremental health gain for participants in the exercise group was -0.021 (SD = 0.225) and greater than that for participants in the cognitive and social enrichment program, -0.013 (SD = 0.209). This finding was consistent with results from the primary clinical trial that exercise resulted in the most substantial gains in cognitive function.139 The primary clinical trial specifically demonstrated that participants in the exercise group observed clinically important improvement in cognitive function, while those in cognitive and social enrichment activities did not.139 This thesis presents further evidence to support the cost-effectiveness of exercise intervention in improving health outcomes while reducing healthcare resource utilization, despite a slightly higher implementation cost. The results for the cost-effectiveness analysis at the end of the 6-month follow-up period (at 12 months) indicate that the improvements in cognitive function were not sustained for both exercise and cognitive and social enrichment programs with ICERs of 0.154 (SD = 0.231) and (SD = 0.216) respectively. Again, this was consistent with findings from the primary clinical analysis which found non-significant differences in cognitive performance between the intervention groups and the comparator at 12 months.139 This study provides additional evidence to suggest that while exercise reduced healthcare resource utilization, it was associated with a higher implementation cost and did not lead to improvement in cognitive function at follow-up. Similarly, cognitive, and social enrichment activities did not improve health outcomes and had higher implementation and healthcare resource utilization costs. It is challenging to interpret the confidence interval representing uncertainty in the incremental cost-effectiveness ratio which depends on both incremental cost and incremental effectiveness.182,183 For instance, a negative ICER may be due to lower costs with better 51 outcomes or higher costs with worse outcomes. Specifically, for the ADAS-Cog-Plus, negative scores represent better cognitive functioning, hence a positive ICER could represent lower costs with better outcomes (i.e., cost-saving region), or higher costs with worse outcomes. Hence utilizing a cost-effectiveness plane can be beneficial in identifying which intervention provides better value for money by illustrating the position of their ICER on the cost-effectiveness plane.184 The results for the cost-utility analysis (i.e., ICER per QALY gained) indicate that at the end of the 6-month intervention period, both exercise and cognitive and social enrichment did not change health-related quality of life compared to the stretching and toning program. Participants in the exercise group had a negative incremental cost of $32 (SD = 259), whereas participants in the cognitive and social enrichment group had a higher incremental cost of $1,018 (SD = 378). Incremental QALY gained was 0.009 (SD = 0.008) and 0.01 (SD = 0.009) for exercise and cognitive and social enrichment activities respectively compared to the stretching and toning program, both below the meaningful clinical difference of 0.03.159 This finding suggests that while the exercise intervention reduced healthcare resource utilization costs, it did not improve health-related quality of life. The cognitive and social enrichment intervention was associated with higher costs and little to no improvement in health-related quality of life. The cost per QALY gained for the interventions exceeded the accepted cost-effectiveness threshold of CAD $50,000. The results for the cost-utility analysis at the end of the 6-month follow-up period (at 12 months), incremental QALYs gained from the interventions reduced to 0.002 (0.008) for exercise, and 0.004 (0.010) for cognitive and social enrichment activities compared to the control. Again, participants in the exercise group had a negative incremental cost of $333 (SD = 511), whereas participants in the cognitive and social enrichment group had a higher incremental cost of $1,366 (SD = 743). This suggests that while exercise further reduced healthcare resource utilization costs at the end of the 6-month follow-up period, it did not improve health-related quality of life. Overall, the social and cognitive enrichment intervention was more costly to deliver, and participants had a higher mean healthcare resource utilization per person. While the exercise was 52 more costly to deliver compared to the stretching and toning group, participants in the exercise group had the lowest mean healthcare resource use at the end of intervention and follow-up for all the groups. This finding suggests that although a stretching and toning program is a cheaper intervention, exercise is more effective in reducing healthcare resource utilization than stretching and toning or cognitive and social enrichment activities. Sensitivity analyses provided consistent findings that multicomponent exercise and cognitive and social enrichment activities were cost-effective solutions to improve cognitive function, but not health-related quality of life. Exploratory subgroup analyses found that exercise was cost-saving for participants 80 years and older. This emphasizes the significance of implementing interventions specifically aimed at older adults who are at a greater risk of experiencing cognitive decline. 5. 2 Comparison with other studies To my knowledge, there are no published trial-based economic evaluations that assess the efficiency of lifestyle interventions to improve post-stroke cognitive impairment. Efficacy studies show that exercise and/or cognitive training can be effective to improve cognition.109,110 Additionally, cost studies show that there are significant costs associated with stroke, however, evidence on which interventions can efficiently reduce the economic burden of stroke remains scarce.185 The findings from this study build on broader evidence demonstrating the cost-effectiveness of lifestyle interventions such as exercise and cognitive training to improve cognitive function among older adults.186,187 Despite approximately 20-80% of stroke survivors experiencing cognitive impairment, there is a lack of research on the efficiency of lifestyle interventions specifically for stroke patients, making it difficult to compare findings with existing research.188 A model-based economic evaluation found that a combined physical exercise and cognitive program was cost-effective among healthy community-dwelling older adults to prevent dementia compared to a ‘do nothing’ alternative.186 Among older adults with cognitive impairment, the findings on the cost-effectiveness of exercise and cognitive training to improve cognition are less consistent.187 Some research suggests that exercise can be a cost-effective intervention to improve cognitive function in people with cognitive impairment.187,189 For older adults with mild 53 cognitive impairment, a trial-based economic evaluation demonstrated that resistance training and aerobic training were cost-effective compared to stretching and toning exercises.73 The economic evaluation alongside the Vitality study provides novel evidence that multicomponent exercise can also be cost-effective to improve cognitive function among people with stroke. On the contrary, findings from other studies suggest that exercise may not be cost-effective.187 For individuals with mild to moderate dementia, a trial-based economic evaluation showed that high-intensity aerobic and strength exercise was not cost-effective compared to usual care.190 The study found that exercise had higher total costs including intervention cost, but did not lead to clinical improvement in cognitive function measured by the ADAS-Cog.190 Compared to the Vitality study which excluded patients with dementia, this study included individuals with a confirmed diagnosis of dementia. A possible explanation for a lack of cost-effectiveness could be that people with worse cognitive function or dementia are less likely to recover to a healthy state compared with participants who are healthy or have mild cognitive impairment.186 The Vitality study findings also provide evidence that cognitive training can be a cost-effective intervention for poststroke cognitive impairment. While this finding provides evidence of cost-effectiveness for people with mild cognitive impairment, results from other studies suggests that cognitive training is not cost-effective for people with dementia.187 A study suggested that among individuals with mild-to-moderate dementia, a maintenance cognitive stimulation therapy was not cost-effective compared to usual care to improve cognitive function.191 As the study relied on the 11-item ADAS-Cog to measure cognitive function, the lack of responsiveness in mild cognitive impairment compared to the ADAS-Cog-Plus may have contributed to this result.145 Another study found that among people with dementia, a home-based cognitive stimulation program was not cost-effective compared to usual care to improve cognitive function.192 The cost-utility analysis from this study found that, compared to stretching and toning, both exercise and cognitive training did not lead to changes in health-related quality of life. This finding is consistent with results from other research which found that individually tailored exercise was cost-effective to improve behavioral and psychological symptoms but not cost-effective for quality-adjusted life year gains.193 There are three possible explanations for this 54 finding. First, the Vitality study was powered to detect changes in cognitive function and not health-related quality of life.117 Generally, it is difficult to capture the full extent of costs and benefits of economic evaluation conducted alongside clinical trials as the trials are powered in terms of the primary outcomes and do not cover costs.194,195 This may lead to a lack of statistical power to detect a difference in quality of life even when one exists.196,197 Second, the instrument used to estimate the health-related quality of life in the study, the EQ-5D-3L is a generic measure that may not capture condition-specific changes.198 While the EQ-5D-3L has shown to be valid and reliable in the stroke population,199 it may not be sensitive enough to detect changes in health-related quality of life with patients with poststroke cognitive impairment. A study found that cognitive stimulation therapy compared to usual care was cost-effective to improve health-related quality of life using the Quality of Life-Alzheimer's Disease scale, but not the EQ-5D.191 Finally, the length of intervention can also influence its effectiveness.200,201 A systematic review of exercise interventions for older adults found that interventions lasting 3 months can be effective to improve quality of life outcomes.202 The 6-month intervention for the Vitality was within a timeframe to see an effect. Hence, it is unlikely that this contributed to the insignificant changes in health-related quality of life, especially since changes were observed in the primary clinical outcome for cognitive function.139 5.3 Strengths The primary strength of this study is the novel health economic data providing preliminary evidence for the efficiency of lifestyle interventions to improve poststroke cognitive impairment among older adults. Economic evaluations in stroke care have mainly focused on the functional consequences of stroke.127,203 Out of 232 studies included in a recent systematic review of model-based economic evaluations of post-stroke outcomes, only two studies included cognitive impairment as a health state, none of which included lifestyle interventions.136 This highlights the dearth of economic evidence for lifestyle interventions aimed at improving cognitive impairment after a stroke. This study offers new evidence regarding the cost-effectiveness of interventions for enhancing cognitive function in older adults with chronic stroke. Another strength of this study is that it is an economic evaluation conducted alongside a clinical trial. Trial-based economic evaluations ensure that both the intervention and control groups are subject to similar data collection procedures.204 The potential for bias in trial-based economic 55 evaluations is therefore reduced by elements of the trial design such as randomization and blinding.205 Furthermore, as cost and effectiveness outcomes are collected prospectively alongside the clinical trial, this reduces response and recall bias.183 Trial-based economic evaluations can inform policy decisions if they use a standard comparator with established cost-effectiveness, use final outcome measures such as QALYs, have an appropriate follow-up period, are adequately powered to assess cost and effects, and/or include a representative patient sample.206 The trial was adequately powered to detect changes in cognitive function, employed QALYs as the outcome measure, and recruited a broad sample of patients with chronic stroke, making the study findings relevant. 5.4 Limitations This thesis has limitations. Firstly, this study used a 6-month and 12-month time horizon for the economic evaluation. As the duration of interventions and their outcomes affects estimated costs and effects,207 it may be difficult to capture the full costs and benefits of the intervention within a shorter time. Secondly, it is difficult to interpret the results of cost-effectiveness analysis for cognitive function, due to a lack of an established minimal clinically important difference (MCID) for the ADAS-Cog-Plus.208 Although, an MCID of 3 points or more is recommended for the ADAS-Cog,63 an MCID for the ADAS-Cog-Plus remains unestablished. This makes it difficult to interpret the results of the cost-effectiveness analysis and ascertain what means a change in the ADAS-Cog-Plus is clinically relevant. Third, the sample size for the study was based on the primary outcome of the trial, not the variables for the economic evaluation. The correlation between costs and effects, as well as the standard deviation of expected costs which depends on detailed measurement of resource utilization, influences the sample size required.196 A small sample size leads to greater variation in cost outcomes which creates uncertainty in assessing cost-effectiveness. Additionally, the sample may not be generalizable to a broader population of chronic stroke patients. Furthermore, the comparator for the economic evaluation was not a “do nothing”. The Tri-council policy statement on ethical research (TCPS 2) requires the use of an active treatment comparator when evidence of its effectiveness exists for the population studied.209 With extensive evidence on the benefits of exercise especially among older adults, it is deemed 56 unethical to not offer any exercise for the control group.210 Participants in the control group received sham exercises involving stretching and toning classes.117 While there is no evidence that these exercises improve cognitive function, the program may have led to health gains for participants such as improvement in functional mobility.211,212 This yields a conservative estimate of effectiveness between the intervention and control group. Finally, healthcare resource utilization used to estimate incremental cost was self-reported by participants. Issues of recall bias may result in an underestimation of healthcare resource utilization costs. There are challenges associated with the accuracy of responses by participants with cognitive decline, as studies have shown that individuals with cognitive decline tend to overestimate their health-related quality of life.208 5.5 Uncertainty in findings Missing data is a common issue in cost-effectiveness analyses, as incomplete or non-responses on patient questionnaires and participant dropouts can lead to biased results.171,183 Missing data may be classified as Missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). MCAR describes a mechanism where neither the missing data is independent of observed nor unobserved factors.213 MAR describes a mechanism where missingness is unrelated to the unobserved values. 213 MNAR describes a mechanism where the unobserved variable itself predicts missingness.213 While it is difficult to determine whether MAR and MNAR hold for a particular dataset, it is possible to investigate whether the assumption of MCAR holds. Complete case analysis (CCA) with only participants with complete data on all variables assumes MCAR, but CCA can produce biased results and is inefficient when the MCAR assumption is not plausible.171,172,182 Maximum likelihood estimation (MLE) and multiple imputations (MI) are advanced methods that often provide unbiased estimates under the less restrictive MAR assumption.182,214 MLE involves using all available information in the observed data to estimate missing values.177 MI involves replacing missing values with plausible imputed datasets that are combined to account for uncertainty about the missing data.214 Sensitivity analyses are useful to test the robustness of results across different missing data assumptions.172,173 I conducted a probabilistic sensitivity analysis to explore uncertainty caused by how missing data were handled in the economic evaluation. Overall, the findings from the imputed data analysis were consistent with those of the base case analysis, but there were 57 differences in the magnitude of incremental costs and effectiveness. Multiple imputations is preferred to reduce bias in cost-effectiveness analysis, but it may not always lead to accurate results.215 The plausibility of missing at random assumption for multiple imputations requires that all variables that can predict the outcome of interest be included in the imputation model, and missing data in the predictive variables together with omission of any of these variables in the imputation model could lead to biased estimates.214,215 For example, in a recent study, multiple imputations (MI) analysis resulted in an unrelated association between cardiovascular risk and cholesterol, whereas a complete case analysis (CCA) resulted in an association between the two variables.216 The reason for the discrepancy was the omission of a cardiovascular disease outcome in the MI analysis.217 In this case, CCA provided a less biased estimate than MI. A high clinical variability from broad inclusion criteria and missing baseline variables in the Vitality study may have affected the accuracy of the imputation for the ADAS-Cog-Plus. Furthermore, the assumption of missing at random (MAR) is not always clinically plausible.218 5.6 Policy Implications Due to the significant burden associated with stroke and the increasing demand for scarce healthcare resources, it is important to determine the relative efficiency of different stroke interventions.185 At present, there are no approved pharmacological treatments for post-stroke cognitive impairment, and prospective medications have demonstrated limited efficacy.97 To guide resource allocation and implementation of lifestyle interventions that have shown efficacy to improve cognitive decline following a stroke, it is important to evaluate their efficiency.219 This study shows that a 6-month exercise or cognitive, and social enrichment intervention is cost-effective for poststroke cognitive impairment. Although the economic evaluation trial was not designed to compare exercise and cognitive and social enrichment, the results suggest that exercise led to better cognitive function without increasing healthcare resource use, while cognitive and social training had higher costs. This indicates that decision-makers may prefer multicomponent exercise over cognitive and social enrichment activities to improve cognitive function after a stroke in the absence of a willingness to pay threshold based on the ADAS-Cog-Plus. Based on the Canadian willingness to pay a threshold of CAD$50,000 per QALY gained, both exercise and cognitive and social enrichment activities had a high probability of being cost-effective even though the impacts on health-related quality of life were negligible. Exercise was 58 relatively inexpensive compared to the potential cost saving associated with its implementation while cognitive and social enrichment was more costly compared to stretching and toning but also did not improve quality of life. Furthermore, the improvement in cognitive function achieved at the end of the intervention was not sustained by the end of the six-month follow-up period. There was also no improvement in health-related quality of life from either exercise or cognitive and social enrichment activities. This emphasizes the need for ongoing implementation of exercise and/or cognitive and social enrichment activities to sustain the benefits obtained from these interventions. The findings of this study provide compelling evidence for further exploration of the effectiveness of multicomponent exercise interventions for poststroke cognitive impairment in larger clinical trials. By conducting these trials, we can gather more comprehensive data and insights into the effectiveness and cost-effectiveness of such interventions. This will contribute to a deeper understanding of their efficiency and guide future decision-making regarding the implementation of multicomponent exercise as an intervention for poststroke cognitive impairment in the community. Based on the existing evidence highlighting the effectiveness of exercise interventions among older adults, I recommend the incorporation of a multi-component exercise approach into the standard practice for post-stroke care. This comprehensive approach should encompass aerobic, strength, and balance components.115,220 Furthermore, these exercise components should be progressively structured, delivered by qualified exercise specialists, and tailored to individual needs, considering specific risk factors associated with post-stroke conditions.117,221 59 Chapter 6: Conclusion The study provides novel evidence that multicomponent exercise is cost-effective to improve cognitive function in older adults with chronic stroke and reduce the economic burden of stroke. Cognitive and social enrichment activities can be effective to improve poststroke cognitive impairment, however, it is associated with higher costs. Future studies should investigate ways to optimize the cost-effectiveness of cognitive and social enrichment activities for post-stroke cognitive impairment, such as identifying subgroups of patients who may benefit the most from these interventions or finding ways to reduce implementation costs. 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Stroke. 2014;45(8):2532-2553. doi:10.1161/STR.0000000000000022 78 Appendices Appendix A: Health Economics Analysis Plan for Vitality Study. This health economic plan outlines the process for the economic evaluation of the Vitality study, a 6-month, three-arm randomized controlled trial with the aim of enhancing cognitive function among stroke survivors - as detailed in the published study protocol(cite). All analyses will be performed in STATA version 28.0 and reported following the CHEERS 2022 guidelines. Overview The economic evaluation will estimate the incremental costs and effects of a 6-month targeted exercise program or cognitive and social enrichment program compared with a stretch and tone program (i.e., comparator) among community dwelling adults with chronic stroke. Cost-effectiveness will be based on the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR). The economic evaluation will use a 6-month and 12-month time horizons. Costs Healthcare resource use will be estimated from participant self-reported data administered at 3 months and 6 months. Unit costs will be assigned for each of the cost items based on the British Columbia Medical Services Commission Payment Schedule 2021 price list. Total costs for each participant will be calculated from costs associated with healthcare professional visits, hospital admissions, and laboratory and diagnostic procedures health. All unit costs will be valued and reported in 2022 Canadian prices. Outcomes The primary measure for cognitive function using the Alzheimer’s Disease Assessment Scale-Cognitive -Plus (ADAS-Cog-Plus) will be used as a measure of effectiveness for the cost-effectiveness analysis. Quality Adjusted Life Years (QALY), estimated from the European Quality of Life Five Domains three levels (EQ-5D-3L) will be used as a measure of effectiveness for the cost-utility analysis. Missing data We will combine imputations and bootstrapping to quantify any missing data. Data analysis The incremental cost-effectiveness/ utility ratio will be calculated as: 𝐼𝐶𝐸𝑅 𝑜𝑟 𝐼𝐶𝑈𝑅 = ∆𝐶𝑜𝑠𝑡𝑠∆ 𝐸𝑓𝑓𝑒𝑐𝑡𝑖𝑣𝑒𝑛𝑒𝑠𝑠 where ∆ Cost represents the represents the difference between the mean costs of providing the intervention compared with the control and, ∆ Effectiveness represents the difference in their mean effectiveness. Sensitivity analysis We will conduct one-way and probabilistic sensitivity analysis to estimate uncertainty around the ICER/ ICUR estimates. 79 Appendix B: Number and proportion of participants with complete data in Vitality study Variable All participants Exercise (n=34) Social/ Cognitive enrichment (n=34) Stretching and toning (n=52) Number (%) ADAS-COG-PLUS baseline 120 (100%) 34 (100%) 34 (100%) 52 (100%) ADAS-COG-PLUS endpoint 103 (86%) 29 (85%) 29 (85%) 45 (87%) ADAS-COG-PLUS follow-up 96 (80%) 25(74%) 28 (82%) 43 (83%) EQ-5D-3L at timepoint 1 - baseline 120 (100%) 34 (100%) 34 (100%) 52 (100%) EQ-5D-3L at timepoint 2 107 (89%) 30 (88%) 30 (88%) 47 (90%) EQ-5D-3L at timepoint 3 105 (88%) 30 (88%) 29 (85%) 46 (89%) EQ-5D-3L at timepoint 4 104 (87%) 29 (85%) 29 (85%) 46 (89%) EQ-5D-3L at timepoint 5 101 (84%) 29 (85%) 26 (77%) 46 (89%) EQ-5D-3L at timepoint 6 102 (85%) 29 (85%) 28 (82%) 45 (87%) EQ-5D-3L at timepoint 7 – 6 months 100 (83%) 27 (79%) 29 (85%) 44 (85%) EQ-5D-3L at timepoint 8 100 (83%) 29 (85%) 27 (79%) 44 (85%) EQ-5D-3L at timepoint 9 99 (83%) 28 (82%) 28 (82%) 43 (83%) EQ-5D-3L at timepoint 10 99 (83%) 29 (85%) 27 (79%) 43 (83%) EQ-5D-3L at timepoint 11 96 (80%) 28 (82%) 27 (79%) 41 (79%) EQ-5D-3L at timepoint 12 95 (79%) 27 (79%) 27 (79%) 41 (79%) EQ-5D-3L at timepoint 13 – follow up 87 (72%) 25 (74%) 24 (71%) 38 (73%) All 13 timepoints 73 (61%) 20 (59%) 19 (56%) 34 (65%) QALY at end of intervention 93 (78%) 25 (74%) 24 (71%) 44 (85%) QALY at follow up 77 (64%) 22 (65%) 21 (62%) 34 (65%) HRU- timepoint 1 baseline 119 (99%) 34 (100%) 34 (100%) 51 (98%) HRU- timepoint 4 midpoint 107 (89%) 30 (88%) 30 (88%) 47 (90%) HRU- timepoint 7 endpoint 101 (84%) 27 (79%) 28 (82%) 46 (89%) HRU- timepoint 13 follow up 98 (82%) 26 (77%) 29 (85%) 43 (83%) HRU- Total at end of intervention 100 (83%) 27 (79%) 28 (82%) 45 (87%) HRU- Total at follow up 95 (79%) 25 (74%) 28 (82%) 42 (81%)
Thesis/Dissertation
eng
Interdisciplinary Studies
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Davis, Jennifer Colleen
Liu-Ambrose, Teresa
Applied health economics : economic evaluation of lifestyle interventions to promote cognition in older adults with chronic stroke
Text