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Amyloid PET Scans: Another Expensive Imaging Test We Don’t Need? Susan Molchan, Peter Whitehouse, Brian Gran and Cory Cronin Preventing Overdiagnosis, Barcelona September 21 World Alzheimer Day Our context- A Changing Story of Alzheimers • The Mythical Monster • Heterogeneity • Age-relatedness • Alzheimer's Disease Cooperative Study uncooperative (law suits) • Alzheimer Association fragmenting (chapters leaving) • Dementia replacing Alzheimer's e.g. WHO Dementia Summit • Perhaps we are curing ourselves of “cure” Stopping Alzheimers • Public health in the ascendancy – “brain health” Monster in the Mind: The Convenient UnTruth about Alzheimer’s - Jean Carper Responsible Research and Innovation • Technology in a cultural and moral context • Broader moral scope than American bioethics – European origins • Starting with social need – grand challenges and wicked problems • Engaging the whole system, especially citizens and end users • Taking the long view – e.g. the precautionary principle • Examining opportunity costs Changing Trajectory report– save trillions with free magic drug Institutional Corruption case study Leon Flicker Cochran Dementia Group 21st birthday Oxford September 16, 2016 field still making the same mistakes Florbetapir (Amyvid) Authors’ conclusions Although the good sensitivity achieved in some included studies is promising for the value of 11C-PIB-PET, given the heterogeneity in the conduct and interpretation of the test and the lack of defined thresholds for determination of test positivity, we cannot recommend its routine use in clinical practice.11C-PIB-PET biomarker is a high cost investigation, therefore it is important to clearly demonstrate its accuracy and standardise the process of the 11C-PIB diagnostic modality prior to it being widely used. History of Amyloid Imaging Commercialization Strategy (US) 2012 – FDA approves florbetapir (Amyvid) - estimates amyloid neuritic plaque density 2013 – CMS – Coverage denied – Insufficient evidence The CMS standard: “reasonable and necessary for the diagnosis or treatment of illness” - Exceptions: CMS will pay for scans to (1) to rule out Alzheimer’s in difficult diagnoses; (2) to enrich clinical trials 2013 Alzheimer’s Assoc Int’l Conference 2015 IDEAS study design approved by CMS 2016, March: IDEAS begins enrollment –will continue 24 months http://www.ideas-study.org/ An Accurate “Definitive” Diagnosis of Alzheimer’s Disease From the protocol “Helps direct rational pharmacologic therapy” “ . . . leads to a care plan that improves safety and minimizes the risk of preventable complications” “Establishing the diagnosis in the early stages . . . Enables patients to participate in care planning while they are still able . . .” “Receiving a definitive diagnosis has a positive psychological impact on most patients who are experiencing symptoms and their caregivers.” Evidence for these benefits????? The definition of dementia expert – no conflicts of interest ? IDEAS Objectives/Aims Open-label longitudinal cohort to assess the impact of amyloid PET scans on: Aim 1 - patient management pre- and post- PET scan N= 11,050 PET scanned (40% dementia, 60% mild cognitive impairment (MCI) Aim 2 – economic outcomes as assessed by hospital admission & ER visits as per CMS claims database (as compared with an unscanned cohort over 12 months) N= 18,488 PET scanned IDEAS Outcome Measures Aim #1 Impact of amyloid PET on patient management Case report forms w/ intended management before PET compared with Case report forms w/ actual management 90 days post PET Hypothesis: Amyloid PET info will lead to a ≥ 30% change between intended & actual management, as measured by a cumulative (composite) endpoint of: AD drug therapy Other drug therapy Counseling (about safety, future planning) - A one-sided analysis planned for dementia & MCI groups separately Potential impact of amyloid imaging on diagnosis and intended management in patients with progressive cognitive decline. Grundman M1, Pontecorvo MJ, Salloway SP, Doraiswamy PM, Fleisher AS, Sadowsky CH, Nair AK, Siderowf A, Lu M, Arora AK, Agbulos A, Flitter ML,Krautkramer MJ, Sarsour K, Skovronsky DM, Mintun MA; 45-A17 Study Group. Collaborators (39) Author information Abstract Changes in clinician behavior • After receiving the results of the florbetapir scan, diagnosis changed in 125/229, or 54.6% [95% confidence intervals (CI), 48.1%-60.9%], of cases, and diagnostic confidence increased by an average of 21.6% (95% CI, 18.3%-24.8%). A total of 199/229 or 86.9% (95% CI, 81.9%-90.7%) of cases had at least 1 change in their management plan. Intended cholinesterase inhibitor or memantine treatment increased by 17.7% (95% CI, 11.8%-25.8%) of all cases with positive scans and decreased by 23.3% (95% CI, 16.5%-31.8%) of all those with negative scans. Among subjects who had not yet undergone a completed work up, planned brain structural imaging (computed tomographic/magnetic resonance imaging) decreased by 24.4% (95% CI, 17.5%-32.8%) and planned neuropsychological testing decreased by 32.8% (95% CI, 25.0%-41.6%). In summary, amyloid imaging results altered physician's diagnostic thinking, intended testing, and management of patients undergoing evaluation for cognitive decline. IDEAS Outcome Measures Aim #2 Hypothesis: Amyloid PET is associated w/ ≥ 10% reduction in hospitalizations & ER visits These outcomes will be compared over 12 months between those who were scanned and a cohort that were never scanned, w/ data coming from Medicare claims data An algorithm will be used to match those w/ PET scans to those who will not be scanned, by diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions REVEAL Phase 4 Combining risk factors ApO 4 and amyloid imaging • Background problems • Pleotropic gene (cardiovascular plus) • Ethnicity – self identified African-americans • Current problems • Risk curves with or without standard errors • Amyloid scans – either positive or negative but a continuum also with error • Is knowledge power? – whose power and is it wisdom? My conclusion – if you have memory loss do not see an “expert”. See a primary care physician and if he/she gives you general health advice like diet and exercise then that is the best for your brain health too Opportunity costs •Brain health with purpose and in community •Arts and music •Community development and public health The Intergenerational School Freeway Fighter 1960’s environmental activist Dementia Friendly Communities Biomarkers – CSF and Blood Tests ApoE The major cholesterol transporter in the brain ApoE4 – 1 copy: increase risk 2-3X; 2 copies 10X; reduces onset age, increases risk for vascular disease, Lewy body dementia ApoE3 No impact on risk ApoE2 Decreased risk 40% of AD patients carry at least one Apo4 . . . So over 50% do not CSF – low levels of Ab 1-42 CSF high levels of phospho tau, total tau Sensitivity & specificity of 85-95% for incipient AD in MCI populations (Mattson N & Zetterberg H Euro Neurol 2009) “While this is of interest to researchers, public health policy makers and the diagnostics industry, they are of little use to clinicians.” The Model for IDEAS: National Oncologic PET Registry “A collaboration of the American College of Radiology Imaging Network, the American College of Radiology, and the Academy of Molecular Imaging, to ensure access to Medicare reimbursement for certain types of PET scans” Start up funding: Academy of Molecular Imaging, sustained from fees from participating PET facilities Chair: Dr. Bruce Hillner Co-Chair: Dr. Barry Siegel Data management and statistical analyses by the American College of Radiology and Brown University (Dr. C. Gatsonis) CMS Decision Memo for Positron Emission Tomography (FDG) for Solid Tumors June 11, 2013 -Reimbursement for many solid tumors despite no outcome advantage. Documented change in management Aim 2: A Twisted Rationale To compare hospitalizations, ER visits to an unscanned, cohort matched for age, cognitive impairment comorbidities Protocol (p.15-16) twists the rationale: Cites (unpublished) data showing dementia patients seen in a multidisciplinary dementia program w/ their caregivers had fewer hospitalizations, ER visits No specific diagnoses such as AD noted Yet the investigators state: “Per these data, we propose that these elements of care, resulting from a more accurate diagnosis, are some of the mechanisms that will improve outcomes and reduce risk of emergency room visits and hospitalizations.” A different conclusion: All dementia patients and caregivers should be referred to a multidisciplinary dementia program IDEAS: Eligibility/Inclusion Criteria Medicare beneficiaries referred by “qualified dementia specialists” who: Cognitive complaint verified by objectively confirmed cognitive impairment Etiologic cause of cognitive impairment is uncertain after a comprehensive evaluation by a dementia expert Alzheimer’s disease (AD) is a diagnostic consideration Knowledge of amyloid PET status is expected to alter diagnosis and management Recruitment into 1 of 2 cohorts: Cohort 1 Progressive Mild cognitive impairment (MCI) Cohort 2 Dementia of uncertain etiology IDEAS - Coalition Alzheimer’s Association (many pharma sponsors including Lilly, GE Healthcare) American College of Radiology -Dr. Barry Siegel Wash U (consultant GE Healthcare, Siemens; stock: Radiology Corp of America) (J Clin Onc 2016) -Dr. Bruce Hillner VCU Center for Statistical Sciences, Brown U School of Public Health - Dr. Constantine Gatsonis Medical Imaging and Technology Alliance (MITA) - 18F- florbetabir (Amyvid) (Lilly) - 18F-flutemetamol (Vizamyl) (GE Healthcare) - 18F-florbetaben (Neuraceq) (Piramal Life Sciences) Study chair: Dr. Gil Rabinovici (UCSF) (speaking fees GE Healthcare) (Ann Neur 2015) Study Co-chair: Dr. Rachel Whitmer (Kaiser Permanente) Operations Center: American College of Radiology Clinical Research Center, Philadelphia IDEAS Funding The IDEAS Study is sponsored by the American College of Radiology and the American College of Radiology Imaging Network (NCI, industry also fund this), with funding that is being provided by the Alzheimer’s Association, the American College of Radiology, and the manufacturers of the FDA-approved radiopharmaceuticals for amyloid imaging. Of the $100 million cost of the study, $8o million will be paid by Medicare to reimburse for PET scans - For 18,488 enrolled = $4,327/scan From the protocol . . . “Accurate Diagnosis of Dementia” (True or False?) “ . . . The majority of eligible patients do not receive cholinesterase inhibitors or memantine, drugs that have been shown to slow cognitive and functional decline . . . “ “ . . . AD drugs are often used off-label in patients with nonAD causes of dementia such as frontotemporal dementia (FTD) . . . Use of these medications is associated with adverse outcomes . . . “ “ . . . The lack of diagnostic accuracy also represents a barrier to developing and testing biologically specific therapies.” IDEAS Intended Management Plan 1) Watchful waiting 2) Intended changes in AD therapy (cholinesterase inhibitors and/or memantine) 3) Intended changes in other medications 4) Guidance about safety and planning 5) Referral to family support systems (Alzheimer’s Association for care plans, legal and safety education) 6) Additional diagnostic procedures 7) Referral to non-pharmacologic interventions 8) Plans to refer individuals to clinical trials (for AD or non-AD dementia) New Insights into the Dementia Epidemic Larson EB et al NEJM 2013 “the vast majority of dementia cases, especially those occurring late in life, tend to involve a mixture of Alzheimer’s disease, vascular disease, and other degenerative factors.” Dementia (Including Alzheimer’s Disease) Can be Prevented: Statement Supported by International Experts Smith AD and Yaffe K, J of Alz Dis 2014 “About half of the large decline in deaths from heart disease and stroke over the past 50 years has been the result of public health measures to modify risk factors. We are confident that the same approach will work for dementia.” Incidence of Dementia over Three Decades in the Framingham Heart Study Satizabal CL, et al, NEJM 2016. 5000 people over 60 1970s 3.6% 1980s 1990s 2.8% 2000s 2.2% 2.0% 44% fewer . . . Mostly vascular; AD just missed stat significance Average age of diagnosis: 80 to 85 Categories of therapy • Biological • Symptomatic • Cognitive e.g nicotinic receptors • Behavioral e.g. prazosin • Prevention e.g. amyloid vaccines • Primary – asymptomatic, preclinical Alzheimer's • Secondary – MCI • Psychosocial • • • • • • Physical activity Diet Educational interventions Brain games Arts and music, esepfcially dance Community-based – intergenerational school and dementia friendly communities Results Qualitative results Web-Based Resource Brain Imaging MRI: Atrophy of hippocampus & entorhinal cortex – best established. Overlap with Lewy body, hippocampal sclerosis, Frontotemporal dementia PET – FDG – Hypometabolism temporal, parietal Amyloid PET – 1/3 of people without dementia can have positive scans, although these are more likely to go on to develop MCI or AD compared to those with negative scans - Also positive in many with Lewy body dementia - Can be useful to rule out Alzheimer’s disease, especially in a younger person; or perhaps to differentiate from FTD