Download Peter Whitehouse – Amyloid PET Scans

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
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•
•
•
•
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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