1 alireza atri, md, phd associate director, clinical programs, geriatric research education &...
TRANSCRIPT
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Alireza Atri, MD, PhDAssociate Director, Clinical Programs,
Geriatric Research Education & Clinical Center (GRECC)
ENRM VA Bedford Medical Center
Memory Disorders Unit & MA Alzheimer’s Disease Research Center
Dept. of Neurology, Massachusetts General Hospital
Harvard Medical School
Alzheimer’s Dementia: Overview of Evaluation and Care
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Disclosure/conflict of interestAlireza Atri – past 3 years
I am not/have not been part of any speakers bureau
Support: NIH, Veterans Administration (VA)
Institutional Research Grant: Forest Research Institute
Scientific Advisory Board, Consultation and/or lectures/CME programs: Alzheimer’s Association (MA/NH), Daiichi-Sankyo, Forest Research Institute, Harvard Medical School Continuing Education (HMS CE), Lundbeck, Merck, Merz, Veterans Health Administration Office of Research (ORD RRD)
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Human beings are members of a whole,In creation of one essence and soul,If one member is afflicted with painOther members uneasy will remain.If you have no sympathy for human pain,The name of human you cannot retain.
Saadi Shirazi (Persian/Iranian Poet, 1184–1283)
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Overview
Early detection of cognitive impairment and dementia is crucial: it allows for early education, and care and planning to minimize harm, establish practical and healthy habits, and to shore up existing functions before they are lost
Good evidence level for benefits of AD treatments (pharmacological and non-pharmacological)
Must balance risks and benefits on an individual patient-caregiver dyad basis
Best standard of care treatments combine behavioral and pharmacological treatments, education & care of the patient and caregivers
reduce long-term clinical decline and delay time to full-time disability
reduce caregiver burden
Provide cumulative and meaningful benefits
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No man is an island, entire of itself...
Any man’s death diminishes me, because I am involved in mankind; and therefore never send to know for whom the bell tolls; it tolls for thee
John Donne
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Costs of caring for individuals with Alzheimer’s disease:
Worldwide: $604 billion in 2010 (>1% of world GDP)U.S: 190-220 billion (direct costs)
Global impact of AD
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AD is the sixth leading cause of mortality in the U.S. and the only one that is increasing …
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Projected numbers of people with AD in the U.S.
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AD risk factors and the amyloid cascade hypothesis
AGE
30
40
50
60
70
80
90
Amyloid deposition Microglial
activation Neurofibrillarytangles Neuronal loss/
neurochemical changes
DEMENTIA
Risk factors:•Aging and gender (F>M)•Family history•Severe head injury•Altered cerebral perfusion•ApoE 4 (CLU, CR1, PICALM, SORL1, TOMM 40) genotype•Environmental stressors•Gene mutations•Cerebral amyloidosis
Age geneticsCardiovascular risk factors
Other age-related brain diseases
Amyloid-βaccumulation
Synaptic dysfunction; glial activation;
tangle formation;neuronal death
Cognitive decline
Brain and cognitive reserve? Environmental factors
Hypothetical model of AD pathophysiological cascade
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Concept of co-occurrence of Vascular Disease & AD pathology in Dementia
VaD AD
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Spectrum of CVD
MRI Infarction
Stroke
White Matter Hyperintensities
Brain Atrophy
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AD Spectrum occurs on a continuum of severity from No Mild Marked impairment
*MCI = mild cognitive impairment
% of end-stage AD100
60
20
0
80
40
40 50 7060 80
PRECLINICALphase
MCIphase
DEMENTIAphase
Onsetof MCI*
Clinical diagnosisof AD
Estimated start of amyloid deposition
Age (years)
Degree of cognitiveimpairment
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The basic dementia work-up
• Fallacy 1: “I can tell if there’s something wrong with them, and besides, if I start asking them these kinds of questions they’d be offended”
• Fact 1a: “Physician heal thyself” – we must disabuse ourselves of such false and damaging notions
• Fact 1b: normalize and explain rationale and benefits of screening you’d be delivering good care that is appreciated
The Fallacies & Facts regarding screening - Why & How To Screen?
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The basic dementia work-up
• Fallacy 2a: “I can simply rely on the information provided by my patients to make my decisions”
• Fallacy 2b: “Screening doesn’t make a difference – dementia declares itself, and catching it early makes no difference to my patient’s health or my practice”
The Fallacies & Facts regarding screening - Why & How To Screen?
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The basic dementia work-up
• Consider two typical cases:
• Case 1: Mrs. Smith 78 y.o. woman with difficult to control HTN, mild depression, anxiety and insomnia is admitted to the hospital for pneumonia, is started on antibiotics along with her outpatient anti-HTN medication regimen blood pressure falls from 169/88 to 76/43
• Case 2: Mr. Jones 74 y.o. recent widower with IDDM x20 yrs, HTN, CAD, s/p MI and h/o CHF, all previously well-controlled but now with escalating # of admissions in the last 2 years due to “out of control diabetes”, “hypoglycemia”, and “exacerbations of CHF”
The Fallacies & Facts regarding screening - Why & How To Screen?
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The basic dementia work-up
• Fallacy 2a: “I can simply rely on the information provided by my patients to make decisions”
• Fact 2a: Need to “Trust but verify” – need objective and reliable corroboration to form an informed impression and plan of care
The Fallacies & Facts regarding screening - Why & How To Screen?
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The basic dementia work-up
• Fallacy 2b: “Screening doesn’t make a difference – dementia declares itself, and catching it early makes no difference to my patient’s health or my practice”
• Fact 2b: Unrecognized cognitive impairments affect patient health and safety, and clinicians often contribute to poor patient medical and safety outcomes by violating “primumum non-nocere” when we form wrong impressions and plans and ask too much of patients who have unrecognized diminished capacity
The Fallacies & Facts regarding screening - Why & How To Screen?
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The basic dementia work-up
1. Normalize and explain
2. Reliable information
3. Sensitive measures of all domains1. Cognition (e.g. MoCA)
2. Function (ADL measure; e.g. FAQ)
3. Behavior & Neuropsychiatric symptoms (e.g. Neuropsychiatric Inventory)
Why & How To Screen?
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Suggestions for Dementia Screening and Tracking Instruments
1. Global Screen:1. AD8
2. Function - Activities of Daily Living:1. FAQ (Functional Assessment Questionnaire scale)2. IADLs3. PSMS
3. Neuropsychiatric/Behavioral (aka. Non-cognitive Behavioral Symptoms, NCBS): 1. NPI (Neuropsychiatric Inventory)
4. Cognitive Screen:1. MOCA (Montreal Cognitive Assessment) (screen MCI/mild dementia)2. Blessed Dementia Scale Information-Memory-Concentration (BDS-IMC scale,
aka. “Right side” of the Blessed) (Tracking)3. SLUMS (St. Lois Univ. Mental Status exam)4. Addenbrooke’s Cognitive Exam Revised (ACE-R)
5. Staging, Severity, “Global”:1. CDR (Clinical Dementia Rating Scale)2. FAST3. CIBIS-PLUS4. GDS
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ORIENTATION 10 ( )
Spatial: 5 ( ) What is the: (year) (season) (date) (day) (month)
Temporal: 5 ( ) Where are we: (state) (county) (town) (facility) (floor)
REGISTRATION 3 ( )
Name three objects and have person repeat them back. Give one point for each correct answer on the first trial. 1. _______ 2. _______ 3. _______
(e.g. Apple, Penny, Table) Then repeat them (up to 6x) until all three are learned. [Number of trials ____ ]
ATTENTION AND CALCULATION 5 ( )
Serial 7's. Count backwards from 100 by serial 7's. One point for each correct answer. Stop after 5 answers. [ 93 86 79 72 65 ]Alternatively spell "world" backwards. [ D - L - R - O - W ]
RECALL 3 ( ) Ask for the names of the three objects learned above. Give one point for each correct answer.
LANGUAGE 9( )
Name: a pen (1 point) and a watch (1 point)Repeat the following: "No ifs, ands, or buts" (1 point)Follow a three-stage command: "Take this paper in your [non-dominant] hand, fold it in half and put it on the floor". (3 points) [1 point for each part correctly performed]Read to self and then do: CLOSE YOUR EYES (1 point)Write a sentence [subject, verb and makes sense] (1 point)Copy design [ 5 sided geometric figure; 2 points must intersect] (1 point)
Score: /30
MMSE
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Cognitive Screening in Primary Care
Why is MMSE not sensitive to early cognitive changes or dementia in many populations?
not enough memory load only 3 items highly concrete and high frequency objects/words
delay period not long enough
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Suggestions for Dementia Screening Instruments
1. Global screening instrument:1. AD8
2. Function - Activities of Daily Living:1. FAQ (Functional Assessment Scale)
3. Neuropsychiatric/Behavioral: 1. NPI (Neuropsychiatric Inventory)
4. Cognitive screen:1. MOCA (Montreal Cognitive Assessment) 2. Blessed Dementia Scale Information-Memory-Concentration
(BDS-IMC scale, aka. “Right side” of the Blessed)3. Addenbrooke’s Cognitive Exam Revised (ACE-R)
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Scored out of 30
Cut off for Impairment:
<26* (100% specificity)
*Add 1 point if ≤ 12 yrs education
MOCA
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Neuropsychological Testing
When initial evaluation is borderline or in pts with unusual clinical profiles
To establish a baseline and track longitudinal change
To clarify patterns of cognitive impairment To consider percentile performance in each
test and domain Especially useful in pts with superior premorbid ability
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Neuropsychological Testing
To help distinguish between depression/mood disorders & dementia
To help determine competency To assist in the evaluation and counseling of
dementia in the early stages: Determination of disability Determine specific weaknesses Determine specific strengths Recommend strategies for safety and more
efficient functioning
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Minimum of TWO cognitive OR behavioral domains impaired
a. Memory dysfunction: anterograde; deficit in acquisition, storage or retrieval of new information
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b. Frontal systems dysfunction: executive dysfunction or poor judgment & reasoning
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c. Visuospatial dysfunction
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d. Language (communication) dysfunction
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e. Personality changes & Behavioral dysfunction
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AD DEMENTIA CLASSIFICATION
1. Probable AD dementia (clinical classification)
2. Possible AD dementia (clinical classification)
3. Probable or Possible AD dementia with evidence of the AD pathophysiological process (research classification)
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AD DEMENTIA CLASSIFICATION
1. Probable AD (PrAD) dementia with increased level of certainty
i. PrAD with documented decline
ii. PrAD in carrier of causative AD genetic mutation (APP, PSEN1, PSEN2) (but NOT ApoEe4)
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• strokes that are temporally related to onset or worsening of cognitive impairment
• multiple or extensive infarcts or severe white matter hyperintensity burden
• core features of Diffuse Lewy Body Dementia (DLB) other than dementia itself
• prominent features of Primary Progressive Aphasia(PPA)
• evidence of another concurrent, active neurological disease, or non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition
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AD DEMENTIA CLASSIFICATION
2. Possible AD dementia
1. Atypical course (sudden onset or insufficient historical detail or objective cognitive documentation of progressive decline)
2. Mixed Presentation (VaID, DLB features, medications or other illness)
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Basic Dementia Workup
Laboratory tests: - CBC w/ diff- Chem 20 w/ glucose & Liver function tests- Vitamin B12- TSH – thyroid function- ESR and hsCRP – screen for occult general (systemic)
infectious, inflammatory or neoplastic (cancer) process- Homocysteine- Lipid panel – cholesterol
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Atrophy of AD Brain
Atrophy of hippocampus & temporal lobe > frontal & parietal lobe >> occipital lobe & motor cortex
Pattern is characteristic, but not specific for AD
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Dynamic Biomarkers of the Alzheimer’s Spectrum Pathological Cascade
Jack CR et al. Lancet Neurol. 2010
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Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management
MRI is better at detecting: Atrophy (e.g. hippocampal atrophy, ventricular enlargement
““Normal”Normal” ““Moderate Atrophy”Moderate Atrophy”
Scheltens, P. Imaging in AD. Dialogues in Clinical Neuroscience (2009)
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MRI is better at detecting: Atrophy (e.g. hippocampal atrophy, ventricular enlargement Cerebrovascular disease burden: Leukoaraiosis (white matter
microangiopathic changes) and micro/lacunar infarcts
From: O’Brien, JT, et al. 2003. Vascular Cognitive Impairment. Lancet Neurology. Feb (2):89-98; and Scheltens, P. Imaging in AD. Dialogues in Clinical Neuroscience (2009)
Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management
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MRI is better at detecting: Atrophy (e.g. hippocampal atrophy, ventricular enlargement Cerebrovascular disease burden: Leukoaraiosis (white matter
microangiopathic changes) and micro/lacunar infarcts Microhemorrhages (non-acute)
Atri et al. Prevalence and effects of lobar microhemorrhages in early-stage dementia. Neurodeg Dis 2005
Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management
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MRI is better at detecting: Atrophy (e.g. hippocampal atrophy, ventricular enlargement Cerebrovascular disease burden: Leukoaraiosis (white matter
microangiopathic changes) and micro/lacunar infarcts Microhemorrhages (non-acute) Hydrocephalus
Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management
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Selective Use of Additional Tests Under Special Circumstances
CSF: Abeta/tau/phospho-tau profile Cerebral Metabolism or blood flow: FDG-PET >> SPECT Amyloid-PET Other tests for rare dementing conditions/mimics
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CSF Biomarkers for AD (and other neurodegenerative dementias);Abeta-42 and Tau Levels
Low Abeta-42 High Tau High Phospho-Tau Low ATI (A-beta to Tau+Phos-Tau index; <1.0) Sensitivity (88-95%) > specificity (83-87%) Predictive potential: longitudinal studies
“Conversion” from “normal control” (Latent AD) to “MCI” (Prodromal AD) (Tau/A-beta ratio > 2.4)
“Conversion” from MCI to AD (sens. 95%, spec. 83-87%)
Hansson et al. Lancet Neuro, 2006; Li et al. Neurology, 2007
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FDG and PIB PET in early AD (82 yo MMSE 27)
K. Johnson MGH
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MULTIFACTORIAL Treatment of Alzheimer’s disease
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Symptomatic treatment of AD– current status
FDA-approved indication/labels for AD: Disease specific
Cholinesterase inhibitors (ChEIs): donepezil*, rivastigmine, galantamine* NMDA antagonist: memantine
* Generic forms available in the U.S.
No FDA-Approval indication/label for AD: Non-specific
Antidepressants Antipsychotics** (**risperidone approved by EMA for short-term treatment of
refractory severe agitation & psychosis in AD dementia) Vitamin E, C
Other pharmacological agents taken Gingko biloba, cerebrovascular agents, antioxidants, statins, anti-inflammatories,
vitamins (B/C), antiepileptic agents, fish oil/omega-3 fatty acids, hormones, “nootropics”
None have proven efficacy in AD dementia RCTs
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Summary of Level I Evidence from pivotal studies in AD Dementia
Treatment Dosing Level I Evidence Side Effects Other
Donepezil 5mg or 10mg or 23mg
Multiple R DB PC trials 3-12 months. Mild, mod, severe
Low incidence GI esp diarrhea and nausea
ODT and Generic available for 5 and 10 mg doses
Rivastigmine Oral: 3mg-6mg BIDPatch: 9.5-13.3 mg/24h
Multiple R DB PC trials 6 months. Mild to moderate
Low-moderate GI incl anorexia, diarrhea & vomiting w/ oral; rash w/ TP
Start doses not effective. 13.3 mg/24h patch better when pt declines
Galantamine 8mg or 12mg BID Multiple R DB PC trials 6 months. Mild to moderate
Low incidence GI esp diarrhea and nausea
ER available for QD. Start dose not effective. Generic available
Memantine 10mg BID28 mg XR QD
Multiple R DB PC trials 6 months. Moderate to severe
Few AE’s; occ. mild transient confusion ~weeks3-5
4-step titration to max dose, one week apart
Combination Tx (Memantine added to stable donepezil)
10 mg BID or 28 mg XR QD memantine added to chronic ChEI therapy
Two R DB PC moderate to severe trials
Few AE’s; mild transient confusion ~weeks3-5
RTC data in mild AD lacking; observational studies support long-term benefits
Vitamin E 1000 IU BID Two R DB PC trials moderate to severe trial
Few AE’s More robust effects on slowing functional than on cognitive decline; “Controversy” re:Survival data
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AChEI & Memantine Combination Therapy
RATIONALE & BIOLOGICAL EFFECT
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Memantine + donepezil combination therapy – potential synergistic mode of action
M
M
D
Cholinergic neuron
MemantineGlutamatergic
neuron
Donepezil
AChr
M
M
M
D
D
D
M
Cortex
NBM
Hippocampus
Acetylcholine
Glutamate
AcetylcholinesteraseAChE
Acetylcholine receptor
NMDA receptor
AChE
AChE
AChE
D
D
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Memantine + donepezil synergistically affect ACh release in experimental rat model
Hippocampal levels of acetylcholine in rats
800
600
400
200
0
Per
cen
tag
e in
crea
se in
AC
h (S
E)
Memantine5 mg/kg (n=11)
Memantine + donepezil (n=11)
Donepezil0.5 mg/kg (n=11)
Sum
Ihalainen et al. Neuropharmacology 2011; 61 (5-6): 891–899
Experiment conducted in the presence of 5 M neostigmine*p<0.05 (t-test; t=2.6) versus sumSum=sum of increases elicited by each drug individually
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Memantine + donepezil has a potential synergistic effect
Memantine and donepezil, applied individually, each produce an increase in extracellular ACh in the hippocampus of anaesthetised rats – driven by different mechanisms
Combined treatment with both drugs produces an enhancement in ACh levels – greater than the sum of the parts
The action of memantine and donepezil together suggests a potential synergistic interaction on synaptic ACh release
Ihalainen et al. Neuropharmacology 2011; 61 (5-6): 891–899; Giovannini et al. J Neurosci 1994; 14: 1358–1365
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Combination Therapy (ChEI + memantine) in AD – Phase III, EFFICACY placebo‑controlled 24-week studies
Tariot PN, et al. JAMA 2004; Grossberg et al. CNS drugs 2013; Porsteinsson AP, et al. Curr Alzheimer Res 2008
Study Type of memantine therapy (20 mg/day)
Duration(weeks)
MMSE inclusio
n criteria
Number of patients
MMSE <20 + receiving donepezil
Tariot et al., 2004(MD-02)
10 mg BID Added to stable donepezil therapy (5–10 mg/day for ≥3 months)
24 5–14, inclusive
403(202 memantine + donepezil;
201 placebo + donepezil)
Grossberg et al.2013(MD-50)
28 mg XR to any approved ChEI therapy (5 or 10 mg/day donepezil: 6, 9 or 12 mg/day rivastigmine; 16 or 24 mg/day galantamine for ≥3 months)
24 3-14, inclusive
661(333 memantine XR + ChEI;
328 placebo + ChEI)
Porsteinsson et al., 2008(MD-12)
Added to any approved ChEI therapy (5 or 10 mg/day donepezil: 6, 9 or 12 mg/day rivastigmine; 16 or 24 mg/day galantamine for ≥3 months)
24 10–22, inclusive
202(105 memantine + donepezil;97 donepezil monotherapy)
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Combination therapy benefits cognition
Severe Impairment Battery (SIB)
*p<0.05; **p<0.01; ***p<0.001 versus donepezil monotherapy Tariot et al. JAMA 2004; 291 (3): 317–324
0
-2
Wo
rsenin
gIm
pro
vemen
t
Baseline 4 8 12 18 24
Study week
Endpoint (LOCF)
4
-4
Mea
n c
han
ge
fro
m b
asel
ine
2
Donepezil monotherapy
Combination therapy (DPZL+MEM)
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Post hoc analyses of cognitive effects
Cognitive subscales (SIB): Memory (p<0.05) Language (p<0.05) Praxis (p<0.05)
Post hoc-derived functional communication and language subscales: Naming capabilities (p<0.01) Functional communication (according to caregivers) (p<0.01)
Schmitt et al. Alzheimer Dis Assoc Disord 2006; 20 (4): 255–262;Saxton et al. 60th Annual Meeting of the American Academy of Neurology, 2008; Chicago, IL, USA
Benefits for memantine combination therapy (versus donepezil monotherapy) on:
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Combination therapy benefits function
Activities of Daily Living inventory (ADCS-ADL19)
*p<0.05 versus donepezil monotherapy Tariot et al. JAMA 2004; 291 (3): 317–324
Baseline 4 8 12 18 24
Study week
Wo
rsenin
gIm
pro
vemen
tM
ean
ch
ang
e fr
om
bas
elin
e
1
0
-1
-2
-3
-4Endpoint (LOCF)
Combination therapy (DPZL+MEM)Donepezil monotherapy
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Post hoc analyses of functional effects
Functional single items (ADCS-ADL19): Grooming (p<0.01) Watching TV (p<0.01) Finding belongings (p<0.01)
Functional subscales (ADCS-ADL19): Connectedness/autonomy (p<0.05) Higher level functions (p<0.05)
Statistically significant less decline in the total ADCS-ADL19 score
Feldman et al. Alzheimer Dis Assoc Disord 2006; 20 (4): 263–268
Benefits for memantine combination therapy(versus donepezil monotherapy) on:
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Donepezil monotherapy
Combination therapy benefits behavior
Neuropsychiatric Inventory (NPI)
**p<0.01; ***p<0.001 versus donepezil monotherapy Cummings et al. Neurology 2006; 67 (1): 57–63
Mea
n c
han
ge
fro
m b
asel
ine
4
2
0
-2
-4
Wo
rsenin
gIm
pro
vemen
t
Study week
Endpoint (LOCF)
0 12 24
Combination therapy (DPZL+MEM)
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Post hoc analyses of behavioral effects
Behavioral domains (NPI): Agitation (p<0.01) Irritability (p<0.01) Appetite/eating changes (p<0.05) Most other domains showed non-significant improvement This behavioral response was stable over time
Significantly less caregiver distress, due to the patient’s: Agitation/aggression Night-time behaviour Eating changes
Prevention of emergence of agitation, irritability, and night-time behavior (all p<0.05)
Cummings et al. Neurology 2006; 67 (1): 57–63
Benefits for memantine combination therapy (versus donepezil monotherapy)
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*Occurring in ≥5% of patients in either treatment group
Most frequent adverse events* (%)
Combination (n=202)
Donepezil monotherapy (n=201)
Total patients with AEs
Discontinuations due to AEs
78
7.4
72
12.4
Agitation
Confusion
Fall
Influenza-like symptoms
Dizziness
Headache
Urinary tract infection
Urinary incontinence
Accidental injury
Upper respiratory tract infection
Peripheral edema
Diarrhea
Fecal incontinence
9.4
7.9
7.4
7.4
6.9
6.4
5.9
5.4
5.0
5.0
5.0
4.5
2.0
11.9
2.0
7.0
6.5
8.0
2.5
5.0
3.0
8.0
6.5
4.0
8.5
5.0
Tariot et al. JAMA 2004; 291 (3): 317–324
Confusion was more common in patients receiving combination therapy, but this did not lead to more discontinuations
Gastrointestinal AEs possibly ameliorated by combination therapy
Fewer patients receiving combination therapy discontinued due to AEs
Agitation possibly ameliorated with combination therapy
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Combination Therapy (ChEI + memantine) in AD – Phase III, EFFICACY placebo‑controlled 24-week studies
Tariot PN, et al. JAMA 2004; Grossberg et al. CNS drugs 2013; Porsteinsson AP, et al. Curr Alzheimer Res 2008
Study Type of memantine therapy (20 mg/day)
Duration(weeks)
MMSE inclusio
n criteria
Number of patients
MMSE <20 + receiving donepezil
Tariot et al., 2004(MD-02)
10 mg BID Added to stable donepezil therapy (5–10 mg/day for ≥3 months)
24 5–14, inclusive
403(202 memantine + donepezil;
201 placebo + donepezil)
Grossberg et al.2013(MD-50)
28 mg XR to any approved ChEI therapy (5 or 10 mg/day donepezil: 6, 9 or 12 mg/day rivastigmine; 16 or 24 mg/day galantamine for ≥3 months)
24 3-14, inclusive
661(333 memantine XR + ChEI;
328 placebo + ChEI)
Porsteinsson et al., 2008(MD-12)
Added to any approved ChEI therapy (5 or 10 mg/day donepezil: 6, 9 or 12 mg/day rivastigmine; 16 or 24 mg/day galantamine for ≥3 months)
24 10–22, inclusive
202(105 memantine + donepezil;97 donepezil monotherapy)
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Evidence LevelCombination (ChEI with add-on memantine)
Efficacy RCTs
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Measuring Magnitude of Clinical Effects (clinical significance) - Effect Sizes
Source: Cohen J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.).Hillsdale, NJ: Lawrence Earlbaum Associates.
• Effect size is a name given to a family of indices that measure the magnitude of a treatment effect
• Cohen defined the effect size d as: = (difference between means)/(standard deviation)
Suggested as a guide that:
Small d = 0.2
16 yr. old 15 yr. old
Medium d = 0.5
18 yr. old 15 yr. old
Large d = 0.8
18 yr. old 13 yr. old
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Atri & Molinuevo, et al. Alzheimer Res Ther. 2013 Jan 21;5(1):6
Combination therapy (memantine + donepezil) is superior to placebo added to donepezil monotherapy in all three key domains of meta-analysis (MMSE < 20)
MMSE <20 (5-19)
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Combination Treatment has good safety profile (meta-analysis; MMSE<20)
Atri & Molinuevo, et al. Alzheimer Res Ther.
2013 Jan 21;5(1):6
71 *indeterminate (underpowered)
*
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DOMINO 52-week study: donepezil and memantine in moderate to severe AD
52-week, multicentre, double-blind, placebo-controlled, clinical trial in outpatients: With probable or possible AD
(SMMSE score 5–13) Stable on 10 mg/day donepezil Whose clinician was considering a
change in drug treatment
Participants were randomly assigned to one of: Continue donepezil Discontinue donepezil Continue donepezil and start
memantine Discontinue donepezil and start
memantine
Howard et al. N Engl J Med 2012; 366: 893–903SMMSE=Standardised Mini Mental State Examination
Start memantinen=73
Receiving drug at end of study
n=38 (52%)
Continue donepezil
Start placebon=73
Receiving drug at end of study
n=34 (47%)
Continue donepezil
Start memantinen=76
Receiving drug at end of study
n=27 (36%)
Discontinue donepezil for placebo
Start placebon=73
Receiving drug at end of study
n=20 (27%)
Discontinue donepezil for placebo
Randomised N=295
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“Whoa!!! That CAN’T be right!”
• A priori specified initial target: Ntarget1=800
• Revised target: Ntarget2=430
• Enrollment achieved: Nactual=295 (37% of initial target; 68% of revised target)
• Had high (72%) and disproportionate withdrawal rate over one year
Atri et al. Neurodeg Dis 2012; 10 (1–4): 170–174
Howard et al. N Engl J Med 2012; 366: 893–903
Neurology Today; April 19, 2012: 12-13
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DOMINO cumulative probability of study drug withdrawal: 28% of the adjusted target (n=430) completed 52 weeks, spread over 4 treatment arms
Howard et al. N Engl J Med 2012; 366: 893–903Kaplan–Meier actuarial plot of the cumulative probability of withdrawal from the assigned study drug
Days since randomisation3640 42 126 210
0.7
0.5
0.4
0.2
0.0
Pro
babi
lity
of w
ithdr
awal
from
st
udy
drug
0.1
0.3
0.6
0.8
n=38
n=72
n=34
n=73
n=27
n=74
n=20
n=72
Continue donepezil vs. discontinue donepezil
Hazard ratio: 0.5195% CI: 0.36 to 0.72
p<0.001
Start memantine vs. start placeboHazard ratio: 0.66
95% CI: 0.47 to 0.93p=0.02
Memantine + donepezil
Placebo + donepezil
Memantine + discontinue donepezil
Placebo + discontinue donepezil
WO
RS
E D
RO
P-O
UT
78
Memantine + donepezil
Visit week
6 18 30 520
42
36
32
28
BA
DLS
(±S
E) Im
provement
40
38
34
30
26
Placebo + discontinue donepezil
Memantine + discontinue donepezil
Multilevel modelling repeated-measures regression; SMMSE=Standardised Mini Mental State Examination; BADLS=Bristol Activities of Daily Living Scale Howard et al. N Engl J Med 2012; 366: 893–903
Visit week
6 18 30 520
10
8
6
4
2
0
SM
MS
E (
±SE
) Improvem
ent
9
7
5
3
1
Placebo + donepezil
*indeterminate (underpowered) by week 52
*
*
79
DOMINO-AD 52-week study: summary
Supports and extends the preponderance of clinical evidence and clinical wisdom that these anti-AD medications produce real benefits in slowing clinical decline, that:
Donepezil and memantine monotherapy are both superior to placebo for at least one year Stopping treatment was harmful Memantine resulted in much less behavioural worsening of NPI scores (p=0.002), with a benefit that was equivalent to 83% of the 12-month deterioration compared to placebo Graphical data suggest that combination therapy trajectory is superior to monotherapy in cognition, function and behavior for initial 30 weeks
80
Clinical effectiveness studies – Rationale for longitudinal naturalistic observational clinical cohort studies in AD
Inclusion of ‘real’ patients Significant comorbidities Concurrent medications Imperfect treatment adherence
Strengths: High validity; higher power (larger sample sizes and durations),
collect data over several stages of AD; better capacity to assess questions of practical importance; ethically & practically favorable
Limitations: Drug therapy is often not assigned randomly, Selection factors associated with long-term drug exposure
cannot be ruled out as alternative explanations for findings
81
Evidence LevelCombination (ChEI with add-on memantine) Long-Term
Observational Controlled Effectiveness Studies
82
Combination therapy slows long-term decline in cognition (BDS)
Years1 2 3 40
5
10
15
20
25
30
Pre
dic
ted
mea
n B
DS
sco
re
(err
ors
)
Worsening
*p<0.05, **p<0.01, ***p<0.001 versus no medication; #p<0.01, ###p<0.001 versus ChEI monotherapy
# of mistakes: 0–37 errors
0–3 errors (normal, MCI or very mild impairment)
4–10 errors (mild impairment/dementia)
11–16 errors (moderate impairment/dementia)
>16 errors (severe impairment/dementia)
No medication
ChEI monotherapy
Memantine combination therapy
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
83
Predictive cognitive scores and effect sizes
Cohen’s dBDS Years
1 2 3 4
Cohen defined effect sizes as:“small, d = 0.2”“medium, d = 0.5”“large, d = 0.8”
Worsening
30
20
10
0
1 2 3 4
Mo
del
pre
dic
ted
mea
ner
rors
(±
95%
CI)
Years
No treatmentChEI groupCOMBO
ChEI vs NO-RX 0.47*** 0.39** 0.32** 0.28*
COMBO vs NO-RX
0.56*** 0.73*** 0.76*** 0.77***
COMBO vs ChEI
0.10 0.34** 0.44*** 0.49***
*p<0.05, **p<0.01, ***p<0.001
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
84
No treatmentn=144
Average enrolment year
Average time in study
Cognition: Blessed Dementia Scale (BDS)
Function: Weintraub Activities of Daily Living (ADL)
1993
Mixed effects and GEE modeling analysis of 4-year trajectory of progression
•Are there differences long term?
•Are there benefits or detriments long term?
Study Aim: To compare long-term clinical trajectory of cognition and function between 3 treatment groups of AD patients (No-Tx=BSC, ChEI only, COMBO)
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
Outcomemeasures
BSC=best standard care
2 years
ChEI alonen=122
2000
2.2 years
Memantine + ChEI (COMBO) n=116
2002
3.3 years
Atri et al., 2008
382 patients at Mass General Memory Disorders Unit (1990–2006)
87
Combination therapy slows long-term decline in function (ADL)
Worsening
Years
1 2 3 40
20
30
40
60
70
80
Pre
dic
ted
mea
n le
vel o
f de
pen
denc
e (%
)
50
*p<0.05 versus no medication; ***p<0.001 versus no medication;
###p<0.001 versus ChEI monotherapyScored from 0% (normal) to 100% dependency
No medication
ChEI monotherapy
Memantine combination therapy
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
88
Cohen’s dADL Years
1 2 3 4
Predictive functional dependence and effect sizes
Significantly different from 0; *p<0.05; ***p<0.001
Worsening
Mo
del
pre
dic
ted
mea
n%
dep
end
ent
(± 9
5% C
I)
20
1 2 3 4Years
30
40
50
60
70
80
ChEI vs No-treatment
0.08 0.02 -0.03 -0.06
COMBO vs No-treatment
0.32* 0.48*** 0.60*** 0.67***
COMBO vs ChEI
0.23 0.46*** 0.62*** 0.73***
Cohen defined effect sizes as:“small, d = 0.2”“medium, d = 0.5”“large, d = 0.8”
No treatmentChEI groupCOMBO
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
89
Long-term study of time to institutionalisation – methods
Objectives To examine the effect of combination therapy on time to nursing
home admission and time to death
Methods A cohort of 429 patients with:
Probable AD (mean MMSE=18.7, SD=5.1) 1+ years of treatment
Subjects received: Annual physical/neuropsychological assessments in the clinic Biannual telephone interviews
Survival analysis was conducted with multivariable Cox proportional hazard models
Lopez et al. J Neurol Neurosurg Psychiatry 2009; 80 (6): 600–607
Lopez et al., 2009
Analysis 1No dementia treatment: n=416ChEI alone: n=387ChEI + memantine: n=140
ChEI alone: n=387ChEI + memantine: n=140
Analysis 2
90
• Patients taking combination therapy were 3–7 times less likely to be placed in a nursing home than patients receiving ChEI monotherapy
• No association was found with medication use and time to death
Combination therapy delays time to nursing home placement in AD; does not prolong life
Follow-up time (years)
70 1 2 3 4 5 6
1.00
0.75
0.50
0.25
0.00
Est
imat
ed p
ropo
rtio
n no
t ad
mitt
ed to
nur
sing
hom
e
Memantine combination therapy
ChEI monotherapy
Analysis 1No dementia treatment: n=416ChEI alone: n=387ChEI + memantine: n=140
ChEI alone: n=387ChEI + memantine: n=140
Analysis 2
Lopez et al. J Neurol Neurosurg Psychiatry 2009; 80 (6): 600–607
Follow-up time (years)
20.00.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5
0.00
1.00
0.75
0.50
0.25
Est
imat
ed p
rop
ort
ion
no
t ad
mit
ted
to
nu
rsin
g h
om
e
Memantine + ChEI
ChEI monotherapyNo dementiamedication
Lopez et al., 2009
91
Vitamin E
92
93
94 Dysken JAMA 2014
97
Antipsychotic use in AD
“YOUR REFLEXES SEEM FINEMR. HART”
98
Risperidone Efficacy: Meta-Analysis (BEHAVE-AD)
Targetsymptom
Meandifference
from placeboP-value 95% CI
Risperidone 1 mg Psychosis -0.79 P=0.03 -1.31, -0.27
Risperidone 1 mg Aggression -0.84 P=0.0002 -1.28, -0.40
Risperidone 2 mg Aggression -1.50 P<0.0001 -2.05, -0.95
Ballard & Howard. Nat Rev Neurosci . 2006; 7(6):492–500.
99
Adverse Events Dose/Day Risperidone Placebo Odds Ratio 95% CI P-value
Extrapyramidal symptoms
1 mg 32/500 20/571 1.78 1.00, 3.17 P<0.05
2 mg 35/165 12/163 3.39 1.69, 6.80 P=0.0006
Gait 1 mg 21/402 1/408 7.47 2.21, 25.28 P=0.001
Somnolence1 mg 138/665 72/685 2.36 1.71, 3.24 P<0.00001
2 mg 46 /165 13/163 2.36 2.30, 8.64 P<0.00001
Respiratory tract infection
1 mg 15/149 6/163 2.93 1.11, 7.76 P=0.03
Fever 2 mg 24/165 12/163 2.14 1.03, 4.44 P=0.04
Peripheral edema
0.5 mg 24/149 9/163 3.29 1.47, 7.32 P=0.004
1 mg 32/315 15/333 2.43 1.29, 4.59 P=0.006
2 mg 30/165 9/163 3.80 1.74, 8.29 P=0.0008
Ballard & Howard. Nat Rev Neurosci. 2006;7(6):492–500.
Adverse Events with Risperidone
100
Meta-Analysis: Negative Impact of Antipsychotic Treatment on Cognition (MMSE)
Schneider et al. Am J Geriatr Psychiatry. 2006;14(3): 191–210.
WMD: 0.73 [0.38, 1.09]
101Ballard et al. Cochrane Database of Systematic Reviews. 2006, Issue 1. Art. No.: CD003476. DOI: 10.1002/14651858.CD003476.pub2.
Meta-analysis: Risperidone Increases Risk of Cerebrovascular Events in AD
Number of cerebrovascular adverse events before end of treatment at 8–13 weeks
102
Mortality and Antipsychotics in People with Dementia
Wang et al. NEJM 2005:
mortality risk even higher with typical antipsychotics
Trial Information Summary of the Results
FDAMeta-analysis of 17 placebo-
controlled trials of atypical neuroleptics in AD
Significant 1.7-fold increase in mortality with neuroleptics
Schneider et al. JAMA 2005
Meta-analysis of 15 placebo-controlled trials of atypical
neuroleptics in AD
Significant 1.54-fold increased mortality risk, with
absolute increase of 1%
FDA Alert [6/16/2008]; Schneider et al. JAMA. 2005;294(15):1934–1943; Wang et al. N Engl J Med. 2005;353(22):2335–2341.
103
DART-AD differential survival: antipsychotics are associated with increased mortality risk
Ballard et al. Lancet Neurol 2009; 8 (2): 151–157
0
10
20
30
40
50
60
70
80
Number of months
Survival rate on placebo 71% 59% 53%
Survival rate on a antipsychotic 46% 30% 26%
24 36 42
Su
rviv
al r
ate
(%)
Relative risk= 1.8Log rank p=0.02
104
Antipsychotic treatment
Over short-term treatment periods atypical antipsychotics, particularly risperidone, shown to have modest efficacy (effect size, d~0.2)
Modest efficacy has to be balanced against potential risks/detrimental effects in estimating individualized risk-benefit calculus
With longer-term treatment, benefits are less clear-cut and the risks of severe adverse outcomes increase
105 Porsteinsson JAMA 2014
107 Atri A. Am J Manag Care. 2011.
Necessary • Early detection,
assessment & staging
• Sustained targeting& tailoring to patient, caregivers & environment
Practical Multifactorial Management of AD
108 Atri A. Am J Manag Care. 2011.
Necessary • Early detection,
assessment & staging
• Sustained targeting& tailoring to patient, caregivers & environment
Non-Pharmacological Interventions• Psycho-education
• Behavioral interventions
• Fostering support networks
• Monitoring health, safety & environment
• Caring for Caregivers
Practical Multifactorial Management of AD
109
Non-pharmacological Interventions & Behavioral Approaches:
• Psycho-education including:
• AD dementia in general and effects on cognition, function and behaviors
• Dementia care expectations
• The “progression and regression model of aging and dementia”
110
Non-pharmacological Interventions & Behavioral Approaches:
• Behavioral approaches – both general and targeted to the patient-caregiver dyad; these include:
• Simplification of environment• Establishing routines• Providing a safe, calm, and consistent care environment
• Utilizing strategies such as • interacting calmly• redirection to pleasurable activities and environment• reassurance• providing only necessary information in a manner that the patient can appreciate (i.e., in simple language and small chunks) and at the appropriate time• “benign therapeutic fibbing”• “Never saying No” to “allow the moment to pass”
111
Non-pharmacological Interventions & Behavioral Approaches:
• Establishing and fostering support networks for the patient and caregivers
• Identifying and monitoring health and safety risks for patient and others needs
• stove• weapon • driving safety• falling prey to fraud• poor work or financial decision making
• Advance planning for medical, legal and financial decision-making
• Caring for Caregivers, including caregiver support and respite care
112 Atri A. Am J Manag Care. 2011.
Necessary • Early detection,
assessment & staging
• Sustained targeting& tailoring to patient, caregivers & environment
Pharmacological• Eliminate inappropriate
medications
• Stage-appropriate combination therapy
• Cautious and judicious use of other medications when necessary
Non-Pharmacological Interventions• Psycho-education
• Behavioral interventions
• Fostering support networks
• Monitoring health, safety & environment
• Caring for Caregivers
Practical Multifactorial Management of AD
113
Elimination of redundant and inappropriate medicationssee Beers Criteria
Medications to avoid in older cognitively impaired individuals; adapted from Beers Criteria (AGS, 2012)
114
Medications to avoid in older cognitively impaired individuals; adapted from Beers Criteria (AGS, 2012)
Elimination of redundant and inappropriate medicationssee Beers Criteria
115
Treating Underlying Conditions that Exacerbate Dementia Symptoms
• “Treating” underlying medical and psychiatric conditions that can exacerbate dementia symptoms, including:
• dehydration• sleep problems/dysregulation• obstructive sleep apnea• pain• constipation• infections• electrolyte and metabolic derangements• anxiety • depression • psychosis• fear
116
• “Early”: start AChEIs (cholinesterase-inhibitors)*, stablize
• How early?
• Need to have an informed discussion with patient
When to Start?
FDA label indication: 1. ChEI’s:Donepezil: mild, moderate and severe ADGalantamine & Rivastigmine: mild to moderate AD2. Memantine (NMDA antagonist): moderate to severe AD
117
RCTs of ChEIs in MCI:RCTs of ChEIs in MCI:Failure to meet Failure to meet a priori a priori specified primary end points; a big caveat specified primary end points; a big caveat
for donepezil on other outcome measuresfor donepezil on other outcome measures
DonepezilDonepezil RivastigmineRivastigmine GalantamineGalantamine
Long-term Long-term ‘‘conversionconversion’’ trials trials
ADCSADCS
(3 years)(3 years)InDDEx InDDEx
(3-4 years) (3-4 years) Gal 11 and Gal 18 Gal 11 and Gal 18
(2 years)(2 years)
‘‘SSymptomaticymptomatic’’ trialstrials
401 (24 weeks)401 (24 weeks)
412 (52 weeks)412 (52 weeks)-- --
Primary outcomesPrimary outcomes NegativeNegative NegativeNegative NegativeNegative
Other outcomesOther outcomes
ADCSADCS: Significant delay : Significant delay in conversion all groups in conversion all groups for first 24 months (RR for first 24 months (RR reduction of 58% at 12 reduction of 58% at 12 months; 36% at 24 months; 36% at 24 months), and months), and throughout entire 36 throughout entire 36 month trial for APOE-e4 month trial for APOE-e4 carrierscarriers
401 & 402401 & 402: Positive : Positive outcomes on modified outcomes on modified ADAS-cogADAS-cog
-- --
Salloway S, et al. Neurology. 2004;63:651–657 Petersen RC, et al. N Engl J Med. 2005;352:2379-88Feldman HH, et al. Lancet Neurol. 2007;6:501-12; Winblad etal Neurology 2008;70:202402035
Doody R, et al.Neurology 2009;72:1555-61
118
119
120
• Early: start AChEIs (cholinesterase-inhibitors)*, stablize
* Unless severe/active/unstable GI bleed/PUD, arrhythmia/cardiac dz, seizure disorder, syncope
add memantine** (or vice-versa)
** unless poor kidney function (GFR<30 then cut dose in ½)
• Sustain multi-modal care and pharmacological Tx
When to Start?
FDA label indication: 1. ChEI’s:Donepezil: mild, moderate and severe ADGalantamine & Rivastigmine: mild to moderate AD2. Memantine (NMDA antagonist): moderate to severe AD
121
General Considerations
Remove deleterious medications; slowly start and maintain combination treatment with ChEI and memantine-add-on; treat exacerbating and comorbid conditions; promote quality sleep, life and health
Reduce stress
Reduce excessive EtOH intake
Promote restorative sleep (diagnose and treat sleep apnea)
Promote general physical, social & mental activity and health (and good diet and exercise)
Treat anxiety and depression that is not responsive to behavioral interventions and combination treatment with ChEI+memantine
Consider ECASA 81, Vitamin E* (*unless severe cardiovascular disease, on blood thinners, bleeding history/diathesis), Vitamin C, Vit B6/B12/folate
RESIST antipsychotics, NO BENZODIAZIPINESAtri, A. Effective Pharmacological Management of Alzheimer’s Disease. Am J Managed Care, 2011.
122
What else to screen for (cont.)
Screening for:
Home Safety
Public Safety - DRIVING
Medico-legal and legal issues
Stress, depression and support services for caregiver - CARE FOR THE CAREGIVER
123
124
125
Current Trends in Effective Multifactorial Management of AD
Atri A. Am J Manag Care. 2011.
Necessary • Early detection,
assessment & staging
• Sustained targeting& tailoring to patient, caregivers & environment
Pharmacological• Eliminate inappropriate
medications
• Stage-appropriate combination therapy
• Cautious and judicious use of other medications when necessary
Non-Pharmacological Interventions• Psycho-education
• Behavioral interventions
• Fostering support networks
• Monitoring health, safety & environment
• Caring for Caregivers
Caregivers are the glue• Sustained therapeutic alliance
• Tailored to patient & support environment
• Safety first
• Pragmatic: simplification of care routine where possible, consider preferences
126
When to Stop?
• End/Terminal-Stage Dementia/AD: non-verbal, no meaningful interaction or personhood, non-ambulatory
• No indication for ANY medications (except for comfort)
127
Multiple ways to define treatment benefits
Stabilisation
0
+
-
Assessing benefitsPlacebo Active
Less thanexpected decline
0
+
-
Improvement
0
+
-
Mean changes in symptom domains
Cognition
ADLsBehaviour
Inter-relationship between symptom domains
ADLsBehaviour
Cognition
128 Geldmacher et al. J Nutr Health Aging 2006; 10: 417–429
Time
Severe
Mild
Glo
ba
l sy
mp
tom
se
veri
ty
Untreated
Successful treatment
Treatment expectations versus expected decline
129
Ethically: Primum non nocere (“Above all, do no harm”) Nonmaleficence: proven safety Beneficence:
proven efficacy (decrease progression and delay emergence and severity of symptoms)
prevent harm from exploitation, promote safety Autonomy: patients and families should be masters of
their fate Justice: care should be available to all
Why Diagnose and Treat as Early as Possible?
130
Why Diagnose and Treat as Early as Possible?
Medically: Greater opportunity to care for patient and families Pathways are potentially most viable and function at its highest
(cognition, daily living functions, behavior, quality of life) Proven clinically significant benefits in populations of patients Allow patients to make own life decisions (medical, legal, financial,
social, psychological) and to make beneficial lifestyle changes Possibility of entering clinical trials for experimental medications Minimizes the potential of being exploited or abused
Economically: overall advantageous Depends on who is paying Delaying late-stage dementia makes economic sense
131
Effective Multifactorial Management of AD
Early detection, education,
communication,care coordination
& support
Non-Pharmacological:
behavioral strategies; ongoing
monitoring of health & safety and providing support
to patient & caregivers
Pharmacological: reduce potentialfor harm; slow clinical decline
using approved anti-AD medications;
judicial use of other Rx as needed
Provide meaningful benefits to patients, families &
caregivers
Atri A. Am J Manag Care. 2011.
132
Summary
Early diagnosis and management of AD is ethically, medically, scientifically and economically supported
Multifactorial AD care involves a combination of non-pharmacological and pharmacological approaches; it can: ameliorate current symptoms delay and reduce emerging problem behaviors reduce the pace of overall clinical decline delay nursing home placement lower the impact of illness on patients and caregiver provide palliation Provide cumulative and meaningful benefits over the
course of illness
133
To cure sometimesTo help oftenTo console always