Clinical Issues in Moderate -Severe
Dementia
Dr. William DalzielChief, Ottawa Regional Geriatric Assessment
ProgramAssociate Professor, University of Ottawa
April, 2005
SITTING
WORLD
MANcampus
1. Based on evidence and/or clinical experience, a trial with a cholinesterase inhibitor should be offered to all patients who have never had a trial even if their dementia is severe (MMSE <10) if there is some “perceived quality of life.”
A) Strongly disagree
B) Mildly disagree
C) Neutral
D) Mildly agree
E) Strongly agree
2. All patients with dementia on cholinesterase inhibitors (CI) regardless of MMSE (even if over 10) 1 month after admission to a Nursing Home should automatically have the CI discontinued
A) Strongly disagree
B) Mildly disagree
C) Neutral
D) Mildly agree
E) Strongly agree
The Continuum of Vascular Dementia and Alzheimer’s Disease
VaDAD
Mixed AD + Cerebrovasular
Disease
Infarcts, white matter lesions, vascular risk
factors
Post-stroke dementiaAmyloid plaques and neurofibrillary tangles
From the Nun Study
The presence of 1–2 lacunar infarcts in basal ganglia, thalamus or deep white matter increased odds ratio by 20.7 for those with AD lesions within neocortex
Fewer neuropathological lesions of AD appear to be needed to result in “clinical dementia” in those with lacunar infarcts . . or deep white matter infarcts than those without infarcts.
(Snowdon JAMA 1997; 277: 813-7)
It is now increasingly clear that risk factors should be treated in dementia whether the diagnosis is AD, VAD or mixed AD / VAD = 80% of dementia
STROKE PREVENTION = DEMENTIA PREVENTION
Atrial fibrillation
Hypertension especially systolic
Smoking
Diabetes
Hyperlipidemia
Distribution of AD in Different Settings
CSHA Working Group, CMAJ, 1994.CSHA Working Group, Can J Aging, 1994.
AD in the Community
Severe10%
Mild46%
Moderate44%
AD within Institutions
Severe55%Mild
11%
Moderate34%
How would you differentiate mild dementia from
moderate/severe dementia?
Severity of Dementia1. Cognition: Memory vs executive
function.2. Function: IADLs vs PADLs3. Interval of Need: 24 hr vs 8 hr4. Behaviour: AD vs non Alzheimer’s
dementias5. Safety6. Caregiver Impression/ Burden7. Cost 8. Institutionalization
Gauthier S. CMAJ, 2002.
MMSE Score
StageLevel of autonomy
27-30 Normal Independent living
18-26 Mild AD Independent living
10-17 Moderate AD
Supervision required
<10 Severe AD Total dependence
Se
veri
ty
Diagnosing Severe AD:Mini-Mental State Examination (MMSE)
Reisberg B et al. Psychopharmacol Bull, 1988.
Diagnosing Severe AD:Functional Assessment Staging (FAST)
FAST Scale Stage
Characteristics
1 Normal adult No functional decline.
2 Normal older adult Personal awareness of some functional decline.
3 Early AD Noticeable deficits in demanding job situations.
4 Mild AD Requires assistance in complicated tasks such as handling finances, planning parties, etc.
5 Moderate AD Requires assistance in choosing proper attire.
6 Moderately-severe AD
Requires assistance dressing, bathing, and toileting. Experiences urinary and fecal incontinence.
7 Severe AD Speech ability declines to about a half-dozen intelligible words. Progressive loss of abilities to walk, sit up, smile, and hold head up.
Se
veri
ty
68.8
100.5
113.4120.0
0
20
40
60
80
100
120
140
Mild Mild-to-moderate Moderate Severe
Ho
urs
pe
r m
on
th s
pe
nt
ca
rin
g f
or
AD
pa
tie
nts
AD Caregiver Time by Disease Severity
Hux et al. CMAJ, 1998.
$0
$5,000
$10,000
$15,000
$20,000
$25,000
$30,000
$35,000
$40,000
Ca
na
dia
n d
olla
rs (
19
96
)
Nursing home stay
Community services
Medications, physicianfees
Unpaid net supervisiontime
Unpaid direct care time
Mean Annual Cost of AD by Disease Severity
Hux et al. CMAJ, 1998.
Outcome measures used in Alzheimer’s Disease
Caregiver burdenCaregiver burden
Function(DAD/ADCS-
ADL)
Cognition(ADAS-Cog)
Behaviour(NPI)
Global(CIBIC-plus)
ADAS-Cog Alzheimer’s Disease Assessment Scale, Cognitive subscale
CIBIC-plus Clinician Interview-Based Impression of Change with Caregiver Input
DAD Disability Assessment in Dementia
ADCS-ADL Alzheimer's Disease Co-Operative Study – Activities of Daily Living
NPI *
Neuropsychiatric Inventory
SCGBScreen for Caregiver Burden
*Contains subscale NPI-D, which measures caregiver distress
Benefits Seen with AChEIs in RCTs
Global clinical impression Cognition Function (instrumental and personal activities of daily living:
ADLs) Behaviour (both delayed emergence and treatment effects) Decreased psychotropic use in long-term care. Direct caregiver time decreased one hour per day Delay to LTC placement (approximately 21-month delay) Reduced risk for nursing home placement RR .63 (p=0.004) Cost (studies show cost neutral to slightly cost beneficial)
Seek and Treat Comorbid Medical Conditions
1. The dementia patient is a TERRIBLE “historian”.
2. “Irreversible” dementia improves with “tuning up” morbid
conditions.
3. Dementia is a HUGE risk factor for delirium.
4. Quiet delirium is really dangerous. (Be watchful +++ in
patients with dementia).
5. MEDS, MEDS, MEDS, MEDS
Confusion Assessment Method
Acute change in mental statusAND
Inattention/fluctuationPLUS
Disorganized thinkingOR
Altered level of consciousness
Sensitivity 94-100% Specificity 90-95%
Ann Intern Med. 1990; 113:941Arch Intern Med. 1995; 155:301
Spectrum Of Delirium
Spectrum of Psychomotor Activity : HYPOACTIVE delirium (lethargy, excess
somnolence, sluggish) Individuals often not recognized as they
may not cause a disturbance so they don’t get ATTENTION
Spectrum Of Delirium
HYPERACTIVE delirium
(agitated, hallucinating,
inappropriateness)
MIXED - combination of both
Delirium: Signs Restlessness, agitation
“Picking” at the air/clothes...
Myoclonus (often multifocal)
Asterixis (suggests a metabolic cause)
Hallucinations (usually visual, tactile)
Causes of Delirium: A Checklist
D: Drugs anticholinergics, ETOHE: Endocrine BS, Na, Ca, Mg, cortisol, etc.M: Metabolic organ failure, hypoxia, etc.E: Epilepsy or seizures postictal statusN: Neoplasm especially SIADH, CNST: Trauma concussion, surgeryI: Infection anyA: “Apoplexy” any vascular event MI, PE, CVA
Any drug can potentially cause confusion
Take a careful history of any new drug STARTED or any old drug STOPPED recently
Medications Associated with Delirium
Medications Associated with Delirium
Sedatives - hypnotics; Benzodiazepines - toxicity or withdrawal Narcotics - especially Demerol Anticholinergics
Antihistamines eg. Gravol Tricyclic antidepressants eg. Amitriptyline
Antiparkinsonian agents Cardiac eg. Digitalis Miscellaneous
H2 blockers – Lithium Steroids – Anticonvulsants Metoclopramide – NSAIDs eg. Indocid
Miscellaneous Causes of Delirium Pain
Fecal Impaction
Urinary Retention
Alcohol Intoxication or withdrawal
Delirium: Etiology Good Physical Exam
Assess Hydration Status ? New localizing Neurological findings ? CHF/Pneumonia Rectal Exam to R/O Impaction ? Distended Bladder ? Infected Ulcer
Delirium: Search for Underlying Etiology
Review medication list Measurement of serum levels of
medications eg. Digoxin/phenytoin... Metabolic work up
CBC lytes/BUN/creat/glucose Ca, albumin liver function tests
R/O infection eg. CXR; urine C&S O2 saturation/ABG’s to R/O pCO2
Delirium: Search for Underlying Etiology
ECG to R/O silent MI
CXR to R/O pneumonia as physical exam
often difficult/inaccurate
CNS work-up (if indicated): ie. CT Head
Delirium: Search for Underlying Etiology
Positive urine cultures Common in the elderly Should only be used as the cause for a
delirium when patient has new urinary symptoms.
Delirium - Conclusions
A medical emergency!!
Common but under-recognized
Treatment: Address the underlying cause
Symptomatic Effect andSlowing of Disease Progression
Ch
ang
e fr
om
bas
elin
ein
fu
nct
ion
ing
2
1
0
-1
-2
-3
-4
-5
-6
Baseline
Gauthier S: Brain Aging 2002; 2(3):9-22.
Farlow MR: Int J Clin Pract 2001; Suppl. 127:37-44.
Natural history of AD
Time (years)Time (years)
SymptomsSymptoms
DiagnosisDiagnosis
Loss of functional Loss of functional independenceindependence
Behavioural Behavioural problemsproblems
Nursing home Nursing home placementplacement
DeathDeath
Min
i-M
enta
l Sta
te E
xam
inat
ion
(M
MS
E)
Min
i-M
enta
l Sta
te E
xam
inat
ion
(M
MS
E) Early diagnosisEarly diagnosis Mild-to-moderateMild-to-moderate SevereSevere
11 22 33 44 55 66 77 88
00
55
1010
1515
2020
2525
3030
Feldman & Grundman. From Clinical Diagnosis & Management of Alzheimer’s Disease (2nd Edition); (Ed) Gauthier, 1999
Time to NH Placement by Treatment Duration
Feldman et al. Poster presentation at the European Federation of Neurological Societies, Paris, France, 2004
n=596
Do not stop ACHEI because
The patient’s MMSE < 10
The patient develops behaviour problems
The patient changes address/moves to
Retirement or Nursing Home
Do Stop if
Quality of life is significantly diminished
What is the evidence of benefit for AChEIs in moderate to severe AD?
Aricept (donepezil) Exelon (rivastigmine) Reminyl (galantamine)
Donepezil in Advanced AD: MSAD Study Objectives
Examine the efficacy and safety of donepezil in patients with moderate to severe AD (sMMSE 5 to 17)
Assess the treatment effect of donepezil as a function of baseline dementia severity
Gauthier S et al. Neurology, 2003.
Donepezil in Advanced AD: MSAD Study Design
Design 24-week, randomized, double-blind, placebo-controlled study in
Canada, France and Australia 290 patients were randomized to receive donepezil (5 mg/d for
28 days, followed by 10 mg/d, as per clinician’s judgement) or placebo, 145 of which had severe AD
Subjects Patients residing in the community or in assisted living facilities,
but not receiving total nursing care
Outcome measures Primary: CIBIC-plus Secondary: sMMSE, SIB, DAD, IADL+, PSMS+, NPI, FRS Other: CSS, SF-36, CAUST
Gauthier S et al. Neurology, 2003.
Clinicalimprovement
Clinicaldecline
No change
0 Week 24 LOCF
(72)(73)
4
n=69n=70
12
6862
18
6464
8
6161
24
6263
DonepezilPlacebo
p=0.0004p=0.0017 p=0.0007
p=0.0006
p=0.002p=0.0002
= 0.7
CIBIC-plusCIBIC-plus
Donepezil in Advanced AD (sMMSE 5-12):Global Function
3.4
3.6
3.8
4.0
4.2
4.4
4.6
4.8
5.0
5.2
Study week
LS
mea
n s
core
± S
E
DonepezilPlacebo
Gauthier S et al. Neurology, 2003.
Donepezil in Advanced AD (sMMSE 5-12): Cognition
Clinicalimprovement
Clinicaldecline
Baseline
0
7173
Week 24LOCF
(71)(73)
4
6770
12
6662
18
6365
8
6161
24
6263
Donepezil n=Placebo n=
p=0.007
p=0.0091p=0.0005
p=0.0099 p=0.0033 p=0.0017
= 7.4-10
-8
-6
-4
-2
0
2
4
6
8
Study week
LS
mean
ch
an
ge f
rom
baseli
ne ±
SE
Donepezil
Placebo
SIBSIB
Gauthier S et al. Neurology, 2003.
Donepezil in Advanced AD (sMMSE 5-12): ADLs
Clinicalimprovement
Clinicaldecline
Baseline
0
7269
24
6363
Donepezil n=Placebo n=
Week 24LOCF
(72)(69)
12
6863
p=0.0431
p=0.0251p=0.0082
= 7.2-14
-12
-10
-8
-6
-4
-2
0
2
Study week
LS
mean
ch
an
ge f
rom
baseli
ne ±
SE
Donepezil
Placebo
DADDAD
Gauthier S et al. Neurology, 2003.
Donepezil in Advanced AD (sMMSE 5-12): Behaviour
Clinicalimprovement
Clinicaldecline
Baseline
0
7172
Week 24LOCF
(71)(72)
4
6769
12
6762
18
6365
8
6159
24
6262
Donepezil n=Placebo n=
p=0.0252
p=0.0198 p=0.0062p=0.0314
= 6.9
NPI 12-item totalNPI 12-item total
Gauthier S et al. Neurology, 2003.
-8
-6
-4
-2
0
2
4
6
8
Study week
LS
me
an
ch
an
ge
fro
m
ba
se
lin
e ±
SE
Donepezil
Placebo
Donepezil in Advanced AD (sMMSE 5-12): Behaviour
Gauthier S et al. Neurology, 2003.
Delusions
Hallucinatio
ns
Agitatio
n/aggression
Depression
Anxiety
Elation
Apathy
Disinhibition
Irritabilit
y
Aberrant m
otor behaviour
Night-time behaviour
Appetite/eatin
g
Clinicalimprovement
Clinical decline
p=0.0159
p=0.036p=0.0275
NPI individual item analysisNPI individual item analysis-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
LS
me
an
ch
an
ge
fro
m b
as
eli
ne
ite
m s
co
re a
t W
ee
k 2
4 (
LO
CF
) Donepezil (n=72)
Placebo (n=73)
Donepezil in Advanced AD (sMMSE 5-12): Summary
Donepezil-treated patients demonstrated benefits in: Global function, as shown by a clinician’s assessment
of change reflected by improved CIBIC-plus scores versus placebo
Cognition, as shown by improvement in scores on the MMSE and SIB scales versus placebo
Activities of daily living, as shown by a slower decline on the DAD scale versus placebo
Behaviour, as shown by improvement in overall NPI score, as well as on several individual NPI items, versus placebo
Gauthier S et al. Neurology, 2003.
Rivastigmine in Advanced AD: Study Design
Doraiswamy et al. Prog Neuropsychopharmacol Biol Psychiatry, 2002.
Design A post hoc analysis of patients with advanced AD (GDS 5) from a 26-
week, double-blind, randomized, placebo-controlled phase followed by a 26-week open-label phase
Double-blind phase: Patients were randomized to receive rivastigmine 1-4 mg/d,
6-12 mg/d or placebo for 26 weeks Open-label phase:
Patients all received rivastigmine 1-6 mg b.i.d. for 26 weeks
Subjects 158 patients diagnosed with AD with:
GDS 5 (moderately severe stage) Average MMSE score: Approx. 16
Outcome measures Primary efficacy measure: ADAS-cog
Rivastigmine in Advanced AD: SummaryThe moderately severe patient group was characterized by:
GDS score 5, and MMSE scores of ~16
Rivastigmine-treated moderately severe AD patients demonstrated benefits in:
Cognition, as shown by improvement in scores on the ADAS-cog scale versus placebo
Early treatment with rivastigmine leads to sustained benefits over a period of 1 year
Rivastigmine was safe and well tolerated in this patient cohort
Doraiswamy et al. Prog Neuropsychopharmacol Biol Psychiatry, 2002.
Wilkinson DG et al. Int J Clin Pract, 2002.
Design
Post hoc analysis of pooled data from 4 randomized, double-blind, placebo-controlled, multicenter trials
Subjects
502 patients diagnosed with AD with:• ADAS-cog >30
• Average MMSE: Approx. 15
Outcome measures
Primary: ADAS-cog, DAD, ADCS-ADL, NPI
Galantamine in Advanced AD: Study Design
Galantamine in Advanced AD: Summary
Galantamine-treated patients demonstrated benefits in:
Cognition, as shown by improvement in scores on the ADAS-cog scale versus placebo
Activities of daily living, as shown by stabilization on the ADCS-ADL scale versus placebo
Behaviour, as shown by stabilization in overall NPI score versus placebo
Galantamine was safe and well tolerated in this patient cohort
These data suggest that galantamine may be useful in patients with advanced AD
Wilkinson DG et al. Int J Clin Pract, 2002.
Neurotransmitter imbalance in AD In terms of treatment strategies in AD, two
neurotransmitters have been studied
Acetylcholine Levels of acetylcholine are abnormally low – the
basis for the use of acetylcholinesterase inhibitors
Glutamate Levels of the excitatory neurotransmitter,
glutamate, are elevated
Mechanism of action Memantine is a voltage-dependent, low to
moderate affinity, uncompetitive NMDA receptor antagonist
Memantine blocks the effects of tonic pathologically elevated levels of glutamate that may lead to neuronal dysfunction
However, it preserves physiological activation through the receptor required for learning and memory
Ebixa® Product Monograph
Memantine treatment in patients with moderate to severe AD already receiving donepezil
Tariot et al 2004JAMA 2004;291:pg 317-24
Study objectives To compare the efficacy and safety of
memantine versus placebo in patients with moderate to severe AD already receiving stable treatment with the AChEI, donepezil
Primary: SIB, modified ADCS-ADL 19 Secondary: CIBIC+, NPI, BGP
Tariot et al 2004
Study design Randomised, double-blind, placebo-controlled study
37 investigator sites in the US
24-week, double-blind treatment period
Memantine 20 mg/day (10 mg b.i.d. titrated over a 4-week period) or placebo, in patients already receiving stable doses of donepezil (5–10 mg/day)
Tariot et al 2004
Summary of key efficacy results(mean change from baseline)
Tariot et al 2004
*p-values are two-way analysis of covariance
LOCF analysis (last observation carried forward)
Week 24 OC analysis(observed cases)
Memantine# Placebo# p-value*
Memantine# Placebo# p-value*
SIB0.9
(n=198)-2.5
(n=196)<0.001
1.0(n=171)
-2.4 (n=153)
<0.001
ADCS-ADLsev
-2.0 (n=198)
-3.4 (n=197)
0.03-1.7
(n=172)-3.3
(n=152)0.02
CIBIC-plus 4.41
(n=198) 4.66
(n=196)0.03
4.38 (n=172)
4.64 (n=152)
0.03
NPI-0.1
(n=193)3.7
(n=189)0.002
-0.5(n=171)
2.9(n=152)
0.01
BGP-Care0.8
(n=185)2.3
(n=179)0.001
0.6(n=172)
2.2(n=151)
0.001
Cognition: SIBMean change from baseline, OC analysis
Tariot et al 2004
Memantine
Placebo
*p<0.05 **p<0.01***p<0.001
* **
***
*** Imp
rov
em
en
tW
ors
en
ing
n=198
n=197
n=197
n=194
n=190
n=180
n=185
n=169
n=181
n=164
n=171
n=153
-4
-2
0
2
4
0 4 8 12 16 20 24
Week
SIB
sco
re d
iffe
ren
ce
(± S
EM
)
Function: ADCS-ADLsevMean change from baseline,OC analysis
Tariot et al 2004
Memantine
Placebo
*p<0.05
* * Imp
rov
em
en
tW
ors
en
ing
*
*
n=198
n=197
n=198
n=195
n=190
n=182
n=185
n=170
n=181
n=163
n=172
n=152
*
*
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
0 4 8 12 16 20 24
Week
AD
CS
-AD
Lse
v s
co
re
dif
fere
nc
e (±
SE
M)
Memantine treatment in patients with moderate to severe AD already receiving donepezil – summary
First prospective, randomised, placebo-controlled study examining benefits of an NMDA receptor antagonist in patients with moderate to severe AD receiving stable treatment with an AChEI, donepezil
Memantine treatment compared with placebo, in AD outpatients, resulted in:
Significantly more patients completing the trial Significant improvements on global measures and
assessments of cognition, function in ADLs, and behaviour Sustained, improved cognitive performance relative to
baseline vs. progressive decline over the same duration of treatment
Memantine/AChEI treatment was safe and well tolerated
Tariot et al 2004
Efficacy in AD
Reisberg et al 2003 NEJM 2003;348:1333-
41
Study objectives and design
Objectives: Efficacy and long-term tolerability of memantine
in patients with moderate to severe Alzheimer’s disease
Design: Placebo-controlled, 28-week, double-blind,
randomised, parallel-group, fixed-dose, multicentre trial with optional 24-week, open-label extension
Reisberg et al 2003
Patient selection Male and postmenopausal female outpatients aged
50 years
Diagnosis of dementia: Alzheimer’s disease (DSM-IV) Probable Alzheimer’s disease (NINCDS-ADRDA)
Severity: MMSE score 3–14 GDS stage 5 or 6 FAST stage 6a CT or MRI scan, in last 12 months, consistent with
AD
Reisberg et al 2003
Efficacy measures
Efficacy measures were:Primary: Global endpoint (CIBIC-plus) Functional endpoint (ADCS-ADLsev inventory)
Secondary: Cognitive assessment (SIB) Behavioural assessment (NPI) MMSE, GDS, FAST Resource Utilisation in Dementia (RUD)
Reisberg et al 2003
Summary of key efficacy results(mean change from baseline)
Reisberg et al 2003
*p-values are based on Wilcoxon rank-sum test for between treatment comparison#Numbers in parentheses represent patient numbers
LOCF analysis (last observation carried forward)
OC analysis(observed cases)
Memantine# Placebo# p-value*
Memantine# Placebo# p-value*
CIBIC-plus 4.5
(n=118) 4.8
(n=118)0.06
4.4 (n=97)
4.7 (n=84)
0.03
ADCS-ADLsev
-3.1 (n=124)
-5.2 (n=123)
0.02-2.5
(n=97)-5.9
(n=84)0.003
SIB-4.0
(n=124)-10.1
(n=123)<0.001
-4.5(n=96)
-10.2 (n=83)
0.002
FAST 0.2
(n=121) 0.6
(n=118)0.02
0.1 (n=97)
0.5 (n=84)
0.007
Global change: CIBIC-plus Mean change from baseline, OC analysis
Reisberg et al 2003
Placebo
Memantine (20 mg/day)
*p=0.03
3.6
3.8
4.0
4.2
4.4
4.6
4.8
5.0
0 4 8 12 16 20 24 28Week
CIB
IC-p
lus
glo
bal
sco
re
Imp
rov
em
en
tW
ors
en
ing*
n=126
n=126
n=107
n=105
n=97
n=84
Assessment of functional improvement
DCS-ADL inventory customised to severe dementia
List of selected items
1. Eating
2. Walking
3. TOILETING*
4. Bathes
5. Grooms
6. Gets dressed
7. USES A TELEPHONE*
8. Watches TV
9. MAKES CONVERSATION*
10. CLEARS A TABLE*
11. FINDS BELONGINGS*
12. Obtains a beverage
13. DISPOSES OF LITTER*
14. Travels outside home
15. Can be left alone
16. Turns faucet on
17. Turns faucet off
18. Turns light on
19. Turns light off
Galasko et al 1997, Galasko et al 2000; H. Lundbeck A/S, Data on file
Function: ADCS-ADLsevMean change from baseline, OC analysis
Reisberg et al 2003
*p=0.003
Placebo
Memantine (20 mg/day)
-7
-6
-5
-4
-3
-2
-1
0
1
0 4 8 12 16 20 24 28
Week
AD
CS
-AD
Lse
v s
co
re d
iffe
ren
ce
Imp
rov
em
en
tW
ors
en
ing
*
n=126
n=119
n=107
n=117 n=97
n=84
n=126
n=106
CAREGIVING TIME
Memantine reduced caregiving time by 42 hr/month = 1.4 hr/day
Reisberg et al:Efficacy summary Treatment with memantine (20 mg/day) results in
significant improvement in core domains: global response, function, and cognition, in patients with moderate to severe AD
Memantine improves patients’ ability to carry out ADLs, thus helping them to maintain a degree of independence and reducing the burden to their carers
Memantine slows cognitive decline Behavioural improvements in agitation/aggression
and delusions (NPI) Memantine provides clinically meaningful benefits
to patients, carers and the community as a whole
Memantine in Severe Dementia
Winblad et al 1999Int. J of Ger Psych 1999; 14:pg
135-46
Patient selection Male and female inpatients aged 60–81 years
Diagnosis of dementia: Symptoms of dementia for at least 12 months DSM-III-R criteria GDS stages 5–7 MMSE score <10 Modified HIS and, in some patients, CT scan
used to identify VaD sub-group
Winblad & Poritis 1999; Rosen et al 1980
Efficacy measures
Efficacy variables: Global endpoint: CGI-C score Functional endpoint:
BGP ‘care dependency’ sub-scale score Items 1 and 3 of CGI score BGP total score and sub-scale scores Modified D-test score
Winblad & Poritis 1999
Global endpoint: CGI-C1. ‘very much improved’2. ‘much improved’3. ‘minimally improved’4. ‘no change’ 5. ‘minimally worse’ 6. ‘much worse’7. ‘very much worse’
Regarded as a response to treatment
Classified as a non-response
Global change: CGI-C response
Winblad & Poritis 1999
Global change: CGI-C, ITT population
Winblad & Poritis 1999
Percentage of responders
Memantine (10 mg/day)Placebo
*p=0.006; **p<0.001, stratified Wilcoxon test(n=166)
0
10
20
30
40
50
60
70
80
Week 4 Week 12
*
**
59
40
73
45
Function: BGP care dependency, ITT population
Winblad & Poritis 1999; H. Lundbeck A/S, Data on file
10
15
20
25
30
0 2 4 6 8 10 12 14
Mea
n (
± S
EM
) B
GP
ca
re d
epe
nd
en
cy s
co
re
*
Placebo
Memantine (10 mg/day)
*p=0.016, stratified Wilcoxon test
Week
Worsening
Improvement
Behaviour and function: D-test items
Winblad & Poritis 19990 10 20 30 40 50 60
2
3
4
5
6
9
13
14
Frequency of improvement (%)
Percentage of patients with dementia who improved in their ability to carry out D-test items, TPP dataset (n=151), p<0.05
Ability to take a shower or bath
Ability to dress
Ability to use the toilet
Group activities
Hobbies/interests
Ability to stand up
Ability to move
Ability to wash
Memantine
Placebo
Winblad et al:Efficacy summary
Patients with moderately-severe to severe dementia (AD and VaD) benefit from treatment with memantine, and statistically significant differences in core domains can be demonstrated already at 12 weeks
Treatment with memantine resulted in functional, cognitive and global improvement and reduced care dependence in AD patients as measured by BGP and CGI-C scores
This study provides solid evidence to support the use of memantine in patients with moderately-severe to severe dementia and clearly demonstrates that patients who receive memantine decline more slowly than they do without treatment
MemantinePrecautions/Tolerability
No cholinergic GI side effects Less CVS concern I.e. heart block/↓ HR Very low side effects Renally cleared
Mild – no dosage change Moderate – 10 mgm/day Severe – contraindicated
No hepatic clearance, cyt p450 problems
To The Future – Triple Therapy
1. Treat risk factors aggressively2. Care for caregivers aggressively3. The Dementia Cocktail:
• AChEI
• ASA
• Memantine
• Vitamin E
• Vitamin B6/B12/Folate
• Statin
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