Alzheimer’s Drug Therapy Initiative (ADTI): Research Report UNIVERSITY OF VICTORIA Co-Principal Investigators Neena L. Chappell, Overall PI, PhD, FRSC, FCAHS, Canada Research Chair in Social Gerontology and Professor, Centre on Aging and Department of Sociology, University of Victoria B. Lynn Beattie, Clinical PI, MD, FRCPC, Professor Emeritus, Department of Medicine and Division of Geriatric Medicine, University of British Columbia Co-Investigators Ging-Yuek Robin Hsiung, MD, MHSc, FRCPC, FACP, Assistant Professor, Division of Neurology, Department of Medicine, UBC Clinic for Alzheimer Disease & Related Dementias, University of British Columbia Colin Dormuth, ScD Assistant Professor, Department of Anesthesiology, Pharmacology & Therapeutics; Chair, PharmacoEpidemiology (PEG) Working Group, Therapeutics Initiative, University of British Columbia K. Malcolm Maclure, ScD, Professor and B.C. Academic Chair in Patient Safety, Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia TABLE OF CONTENTS Table of Contents ........................................................................................................................................ 1 List of Tables .............................................................................................................................................. 2 List of Figures ............................................................................................................................................. 3 Glossary of Acronyms ................................................................................................................................ 4 Key Points ................................................................................................................................................... 7 Executive Summary .................................................................................................................................... 9 Introduction ............................................................................................................................................... 19 Seniors’ Medication Study (SMS) ............................................................................................................ 33 Clinical Epidemiological Project (Clin Epi) ............................................................................................. 51 Utilization and Cost Project (U & C) ........................................................................................................ 74 Caregiver Appraisal Study (CAS) .......................................................................................................... 100 Gaps and Future Directions .................................................................................................................... 114 Policy Relevance .................................................................................................................................... 116 Recommendations ................................................................................................................................... 118 References ............................................................................................................................................... 120 Appendix 1: Special Authority Forms (Initial and Renewal) ................................................................. 128 Appendix 2: ADTI Publications Report ................................................................................................. 132 ADTI Final Report (August 12, 2015) 1 LIST OF TABLES Table 1. Distribution of Gender at 6, 12, 18, and 24 Months, n (%) .......................................... 36 Table 2. Drug Status at 6-Month Assessment Intervals, n (%) ................................................... 37 Table 3. Type of Cholinesterase Inhibitor, n (%) ....................................................................... 37 Table 4. Definition of “Treatment Response” for the SMMSE, Global Deterioration Scale (GDS), and OPAR Outcome Measures ...................................................................................... 38 Table 5. Frequency of Treatment Response within SMMSE Categories, n (%) ........................ 40 Table 6. Frequency of Treatment Response within GDS Categories, n (%) .............................. 40 Table 7. Frequency of Treatment Response within OPAR Categories1, n (%) .......................... 41 Table 8. Mean SMMSE, GDS, and OPAR Values at the 6 and 12 Months for Indeterminate Responders .................................................................................................................................. 42 Table 9. Demographic Description of Patients in Clin Epi ........................................................ 53 Table 10. Baseline Characteristics - ADRD Patients.................................................................. 81 Table 11. Baseline Characteristics - ADRD Patients and Controls ............................................ 81 Table 12. ADRD Cohort: Association between ADTI on Utilization and Cost ......................... 82 Table 13. ADRD Patients Compared with Cohort: Association of ADTI with Utilization and Costs of Health Services ............................................................................................................. 83 Table 14. Patients Included in Analysis of Switching Rates ...................................................... 87 Table 15. Baseline Characteristics – Study 3.............................................................................. 89 Table 16. Sample Characteristics, T1 ........................................................................................ 101 ADTI Final Report (August 12, 2015) 2 LIST OF FIGURES Figure 1. Number of Completed Assessment Forms for the SMS Participants at Each Time Period .......................................................................................................................................... 34 Figure 2. Flowchart of Seniors’ Medication Study (SMS) Enrollment ...................................... 35 Figure 3. SA Renewal Time Intervals Used in the Analyses ...................................................... 53 Figure 4. Persistence of Response to ChEI from First (5-7 Months) to Second (10-14 months) Renewal....................................................................................................................................... 58 Figure 5. Persistence of Response to ChEI from Second (10-14 Months) to Third (15-20 months) Renewal ........................................................................................................................ 59 Figure 6. Average SMMSE Scores across Time for Naïve Patients Who Were 65 to 74 Years Old when Initially Approved for a ChEI (top graph), 75 to 84 Years Old (middle graph), and 85 Years Old or Older (bottom graph) ............................................................................................. 67 Figure 7. ChEI Users: Time to Discontinuation or Death .......................................................... 86 Figure 8. ChEI Discontinuation: Cumulative Incidence Plot ..................................................... 86 Figure 9. Switching between ChEI Discontinuation: Crude Rates and Adjusted Rate Ratios per Period .......................................................................................................................................... 87 Figure 10. Survival Curve for ChEI Users and Non-users ......................................................... 89 Figure 11. Mortality by Duration of Follow-up .......................................................................... 90 Figure 12. Hazard Ratios for Mortality Comparing ChEI Users and Non-users, by Year since First Diagnosis ............................................................................................................................ 91 Figure 13. LTC Entrance in ADRD Patients by ChEI Use: Cumulative Incidence Plot ............ 92 Figure 14. LTC Entrance Rates by Duration of Follow-up ........................................................ 92 Figure 15. Hazard Ratios for LTC Entrance Comparing ChEI Users and Non-users, by Year since First Diagnosis ................................................................................................................... 93 Figure 16. Results of Quantile Regression, Quarter 3, Total Cost ............................................. 94 ADTI Final Report (August 12, 2015) 3 GLOSSARY OF ACRONYMS AD Alzheimer’s disease ADRD Alzheimer’s disease and related dementias ADS Adult Day Services ADTI Alzheimer’s Drug Therapy Initiative AL Assisted Living B.C. British Columbia CAS Caregiver Appraisal Study CCD Continuing Care Data CCIMS Continuing Care Information Management System CDMI Chronic Disease Management Initiative CDT Clock-Drawing Test CER Clinical Evidence Review CG/P Caregiver and patient ChEI Cholinesterase inhibitors (donepezil/Aricept, galantamine/Reminyl, rivastigmine/Exelon) CIHI Canadian Institute for Health Information Clin Epi Clinical Epidemiology Project CRS Community Rehab Services DAD Hospital Discharge Abstract Database DSM-IV Diagnostic and statistical manual of mental disorders GDS Global Deterioration Scale GEE Generalized Estimating Equation HAs Health Authorities HCC Home and Continuing Care HCCMRR Home and Community Care Minimum Reporting Requirements HDPS High dimensional propensity scores HNS Home Nursing Services HSS Home Support Services LTC Long-term care MoH B.C. Ministry of Health MSP Medical Services Plan OPAR Overall Patient Assessment Rating OT Occupational therapy PHNs Personal Health Numbers PNet PharmaNet PSD Pharmaceutical Services Division ADTI Final Report (August 12, 2015) 4 PT Physiotherapy RC Respite Care RCR Respite Care - Residential RCT Randomized Control Trials SA Special Authority form(s) SMMSE Standardized Mini-Mental State Examination SMS Seniors’ Medication Study TICS Telephone Interview for Cognitive Status U&C Utilization and Cost Project UBC University of British Columbia UVic University of Victoria ADTI Final Report (August 12, 2015) 5 ADTI Final Report (August 12, 2015) 6 KEY POINTS The Seniors’ Medication Study showed Standardized Mini-Mental State Examination (SMMSE) scores submitted by physicians on Special Authority forms (SA) correlated quite well (~0.65) with the Clock-Drawing Test (CDT) and Telephone Interview for Cognitive Status (TICS), similar to correlations for the reliability of blood pressure measurements. The Clinical Epidemiology Project showed SMMSE scores and other cognitive function measures fluctuated considerably between enrolment and first SA renewal, even among ‘non- naïve’ patients. After various adjustments, the average change in SMMSE score among naïve patients (new to a cholinesterase inhibitor [ChEI]), by 6 months was +1.6 points, consistent with observations in randomized clinical trials (e.g., +0.8 in the AD2000 trial). This average change is small compared to the natural fluctuation between first and second SMMSE in individual patients (standard deviation of +3.5 points; 95% of fluctuations falling within +7 points). SMMSE response could not be predicted from available data nor were there differences in outcomes for different types of ChEIs. There was indirect evidence that a drop in SA- measured cognitive function was associated with early stopping of ChEIs. These findings are limited by lack of a valid comparison group and large loss to follow-up (approximately 40%). The Utilization and Cost Project revealed no change in trends of utilization or costs of health services after ADTI introduction, except for a shift in drug costs to PharmaCare from other payers, and a small increase in costs of services by general practitioners ($3.70/patient). Direct comparisons of ChEI users with non-users, among patients with Alzheimer’s disease and related dementias (ADRD) demonstrated increased costs of health services in patients with low- moderate costs (up to $1.50/day) but decreased costs in those with heavy costs (up to $10/day). ChEI users had longer survival in the first 2 years, then similar survival, dropping to shorter survival in patients alive at the beginning of the 5th years since diagnosis. When examining monthly trends, ChEI use was associated with a growth in mortality rates from month to month during the 7 years following diagnosis compared with a slow decline in non-users. ChEI use was associated with increased long-term care entrance compared to non-use. Due to the nature of the data and the observational study design, the results are inconclusive; causation cannot be imputed. They are suggestive only, and additional research is warranted. The Caregiver Appraisal Study revealed differential findings depending on the measure used. The benefit perceived was small and inconsistent. Caregivers thought patients were calmer and disease progression slowed but saw little improvement in abilities or behaviour. Caregivers were unblinded, and a placebo effect could not be calculated. Caregivers’ appraisals of patients’ improvement or deterioration did not correlate well with clinicians’ assessments on SA. Summary. There is insufficient evidence to support coverage of ChEIs based on the findings from these 4 studies. The indication of possible increased mortality among ChEI users is uncertain and warrants further research. If coverage of ChEIs continues, the SA process should be maintained to ensure standardized clinical assessments over time, allowing clinicians to recommend stopping the medications in patients who are deteriorating. If coverage of ChEIs is stopped or restricted, the impact should be measured by delaying the policy change in some areas and comparing patients’ rates of entry into long-term care between comparable areas. ADTI Final Report (August 12, 2015) 7 ADTI Final Report (August 12, 2015) 8