Transcript Nursing home care paris

Clinical Issues in Moderate Severe Dementia
Dr. William Dalziel
Chief, Ottawa Regional Geriatric Assessment Program
Associate Professor, University of Ottawa
April, 2005
SITTING
WORLD
MAN
campus
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
AD
VaD
Post-stroke dementia
Infarcts, white matter
lesions, vascular risk
factors
Amyloid 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
AD in the Community
Moderate
44%
Mild
46%
Severe
10%
AD within Institutions
Moderate
34%
Mild
11%
Severe
55%
CSHA Working Group, CMAJ, 1994.
CSHA Working Group, Can J Aging, 1994.
How would you differentiate
mild dementia from
moderate/severe dementia?
Severity of Dementia
1.
2.
3.
4.
5.
6.
7.
8.
Cognition: Memory vs executive function.
Function: IADLs vs PADLs
Interval of Need: 24 hr vs 8 hr
Behaviour: AD vs non Alzheimer’s
dementias
Safety
Caregiver Impression/ Burden
Cost
Institutionalization
Diagnosing Severe AD:
Mini-Mental State Examination (MMSE)
Severity
MMSE Score Stage
Level of autonomy
27-30
Normal
Independent living
18-26
Mild AD
Independent living
10-17
Moderate AD Supervision required
<10
Severe AD
Total dependence
Gauthier S. CMAJ, 2002.
Severity
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
7 Severe AD
Requires assistance dressing, bathing, and toileting.
Experiences urinary and fecal incontinence.
Speech ability declines to about a half-dozen
intelligible words. Progressive loss of abilities to
walk, sit up, smile, and hold head up.
Reisberg B et al. Psychopharmacol Bull, 1988.
Hours per month spent caring for AD patients
AD Caregiver Time by Disease
Severity
140
120.0
113.4
120
100.5
100
80
68.8
60
40
20
0
Mild
Mild-to-moderate
Moderate
Severe
Hux et al. CMAJ, 1998.
Mean Annual Cost of AD by
Disease Severity
$35,000
Nursing home stay
$30,000
Community services
$25,000
Medications, physician
fees
Unpaid net supervision
time
Unpaid direct care time
$20,000
$15,000
$10,000
$5,000
e
ev
er
S
er
at
e
M
od
at
e
-t
om
od
er
M
ild
$0
M
ild
Canadian dollars (1996)
$40,000
Hux et al. CMAJ, 1998.
Outcome measures used in
Alzheimer’s Disease
Cognition
(ADAS-Cog)
Function
(DAD/ADCSADL)
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
Behaviour
(NPI)
ADCS-ADL
Alzheimer's Disease CoOperative Study – Activities of
Daily Living
NPI *
Neuropsychiatric Inventory
Caregiver burden
SCGB
Screen for Caregiver Burden
*Contains subscale NPI-D, which measures caregiver distres
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 status
AND
Inattention/fluctuation
PLUS
Disorganized thinking
OR
Altered level of consciousness


Sensitivity 94-100%
Specificity 90-95%
Ann Intern Med. 1990; 113:941
Arch 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:
E:
M:
E:
N:
T:
I:
A:
Drugs
anticholinergics, ETOH
Endocrine BS, Na, Ca, Mg, cortisol, etc.
Metabolic organ failure, hypoxia, etc.
Epilepsy or seizures postictal status
Neoplasm especially SIADH, CNS
Trauma
concussion, surgery
Infection any
“Apoplexy” any vascular event MI, PE, CVA
Medications Associated with
Delirium


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



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
Steroids
Metoclopramide
– Lithium
– Anticonvulsants
– 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 and
Slowing of Disease Progression
2
Change from baseline
in functioning
1
0
-1
-2
-3
-4
-5
-6
Gauthier S: Brain Aging 2002; 2(3):9-22.
Farlow MR: Int J Clin Pract 2001; Suppl. 127:37-44.
Baseline
Mini-Mental State Examination (MMSE)
Natural history of AD
30
Early diagnosis
Severe
Mild-to-moderate
Symptoms
25
20
Diagnosis
Loss of functional
independence
15
Behavioural
problems
Nursing home
placement
10
5
Death
0
1
2
3
Time4(years)
5
6
7
8
Feldman & Grundman. From Clinical Diagnosis & Management of Alzheimer’s Disease (2 nd Edition); (Ed) Gauthier, 1999
Time to NH Placement by Treatment Duration
n=596
Feldman et al. Poster presentation at the European Federation of Neurological Societies, Paris,
France, 2004
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.
Donepezil in Advanced AD (sMMSE 5-12):
Global Function
CIBIC-plus
3.4
p=0.0017 p=0.0007
p=0.0004
LS mean score ± SE
3.6
p=0.0006
3.8
p=0.002
Clinical
improvement
p=0.0002
No change
4.0
4.2
Clinical
decline
4.4
4.6
4.8
Donepezil
Placebo
5.0
 = 0.7
5.2
0
4
8
12
18
24
Week 24
LOCF
62
63
(72)
(73)
Study week
Donepezil
Placebo
n=69
n=70
61
61
68
62
64
64
Gauthier S et al. Neurology, 2003.
Donepezil in Advanced AD
(sMMSE 5-12): Cognition
SIB
8
LS mean change from
baseline ± SE
6
p=0.0005
p=0.0091
p=0.007
p=0.0099
4
p=0.0033 p=0.0017 Clinical
improvement
2
Baseline
0
-2
Clinical
decline
-4
-6
Donepezil
Placebo
-8
 = 7.4
-10
0
4
8
Donepezil n= 71
Placebo
n= 73
67
70
61
61
12
18
Study week
66
62
63
65
24
Week 24
LOCF
62
63
(71)
(73)
Gauthier S et al. Neurology, 2003.
Donepezil in Advanced AD
(sMMSE 5-12): ADLs
DAD
2
Clinical
improvement
p=0.0431
LS mean change from
baseline ± SE
0
p=0.0251
-2
p=0.0082
Baseline
Clinical
decline
-4
-6
-8
-10
Donepezil
Placebo
-12
 = 7.2
-14
0
Donepezil n= 72
Placebo
n= 69
12
Study week
68
63
24
Week 24
LOCF
63
63
(72)
(69)
Gauthier S et al. Neurology, 2003.
Donepezil in Advanced AD
(sMMSE 5-12): Behaviour
NPI 12-item total
LS mean change from
baseline ± SE
-8
p=0.0314
p=0.0198 p=0.0062
p=0.0252
-6
-4
Clinical
improvement
-2
Baseline
0
2
Clinical
decline
4
Donepezil
Placebo
6
 = 6.9
8
0
4
8
Donepezil n= 71
Placebo
n= 72
67
69
61
59
12
18
24
Week 24
LOCF
67
62
63
65
62
62
(71)
(72)
Study week
Gauthier S et al. Neurology, 2003.
Donepezil in Advanced AD (sMMSE
5-12): Behaviour
-2.0
item score at Week 24 (LOCF)
LS mean change from baseline
NPI individual item analysis
-1.5
Donepezil (n=72)
Placebo (n=73)
p=0.0275
p=0.036
-1.0
-0.5
p=0.0159
Clinical
improvement
0.0
0.5
1.0
Clinical decline
1.5
Gauthier S et al. Neurology, 2003.
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
Design
 A post hoc analysis of patients with advanced AD (GDS 5) from a 26week, 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

Doraiswamy et al. Prog Neuropsychopharmacol Biol Psychiatry, 2002.
Rivastigmine in Advanced AD:
Summary
The 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.
Galantamine in Advanced AD:
Study Design
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
Wilkinson DG et al. Int J Clin Pract, 2002.
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 2004
JAMA 2004;291:pg
317-24
Study objectives



Tariot et al 2004
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
Study design

Randomised, double-blind, placebo-controlled study

37 investigator sites in the US

24-week, double-blind treatment period

Tariot et al 2004
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)
Summary of key efficacy results
(mean change from baseline)
LOCF analysis
(last observation carried forward)
Week 24 OC analysis
(observed cases)
Memantine#
Placebo#
p-value*
Memantine#
SIB
0.9
(n=198)
-2.5
(n=196)
<0.001
1.0
(n=171)
-2.4
(n=153)
<0.001
ADCSADLsev
-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-Care
0.8
(n=185)
2.3
(n=179)
0.001
0.6
(n=172)
2.2
(n=151)
0.001
*p-values are two-way analysis of covariance
Tariot et al 2004
Placebo#
p-value*
Cognition: SIB
Mean change from baseline,
OC analysis
n=190
n=197
2
***
n=181
*
n=171
**
***
Improvement
n=185
n=198
0
n=180
n=197
n=194
Worsening
SIB score difference (± SEM)
4
n=169
-2
n=164
n=153
Memantine
-4
0
Tariot et al 2004
4
8
12
Week
16
20
24
Placebo
*p<0.05
**p<0.01
***p<0.001
Function: ADCS-ADLsev
Improvement
Mean change from baseline,
OC analysis
1
n=198
0.5
*
0
n=197
*
*
n=185
*
-0.5
n=181
n=172
-1
*
n=195
-1.5
*
n=182
-2
n=170
-2.5
-3
n=163
-3.5
n=152
-4
0
Tariot et al 2004
Worsening
ADCS-ADLsev score
difference (± SEM)
n=198
n=190
4
8
12
Week
16
20
24
Memantine
Placebo
*p<0.05
Memantine treatment in patients with
moderate to severe AD already receiving
donepezil – summary



Tariot et al 2004
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
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)
LOCF analysis
(last observation carried forward)
OC analysis
(observed cases)
Memantine#
Placebo#
p-value*
Memantine#
Placebo#
CIBIC-plus
4.5
(n=118)
4.8
(n=118)
0.06
4.4
(n=97)
4.7
(n=84)
0.03
ADCSADLsev
-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
*p-values are based on Wilcoxon rank-sum test for between treatment comparison
#Numbers in parentheses represent patient numbers
Reisberg et al 2003
p-value*
Global change: CIBIC-plus
Improvement
Mean change from baseline,
OC analysis
3.8
n=126
4.0
n=107
n=126
4.2
n=97
*
4.4
n=105
4.6
4.8
n=84
5.0
0
Reisberg et al 2003
4
8
12
16
20
Week
24
28
Worsening
CIBIC-plus global score
3.6
Memantine
(20 mg/day)
Placebo
*p=0.03
Assessment of functional
improvement
DCS-ADL inventory customised to severe dementia
List of selected items
1. Eating
8. Watches TV
2. Walking
9. MAKES CONVERSATION*
3. TOILETING*
10. CLEARS A TABLE*
4. Bathes
11. FINDS BELONGINGS*
5. Grooms
12. Obtains a beverage
6. Gets dressed
13. DISPOSES OF LITTER*
7. USES A
TELEPHONE*
14. Travels outside home
Galasko et al 1997, Galasko et al 2000; H. Lundbeck A/S, Data on file
15. Can be left alone
16. Turns faucet on
17. Turns faucet off
18. Turns light on
19. Turns light off
Function: ADCS-ADLsev
Improvement
n=119
1
n=126
n=107
0
n=126
-1
n=117
n=97
-2
*
n=106
-3
Worsening
ADCS-ADLsev score difference
Mean change from baseline,
OC analysis
-4
-5
-6
n=84
-7
0
Reisberg et al 2003
4
8
12
16
Week
20
24
28
Memantine
(20 mg/day)
Placebo
*p=0.003
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 1999
Int. 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 change:
CGI-C response

Global endpoint:
CGI-C
1. ‘very much
improved’
2. ‘much improved’
3. ‘minimally improved’
4. ‘no change’
5. ‘minimally worse’
6. ‘much worse’
7. ‘very much worse’
Winblad & Poritis 1999
Regarded as a
response to treatment
Classified as a
non-response
Global change:
CGI-C, ITT population
Percentage of responders
80
**
70
60
*
50
59
73
40
45
40
30
Memantine
(10 mg/day)
Placebo
20
10
0
Week 4
Week 12
*p=0.006; **p<0.001, stratified Wilcoxon test
(n=166)
Winblad & Poritis 1999
Function:
BGP care dependency,
ITT population
Mean (± SEM) BGP
care dependency score
30
Worsening
25
20
Improvement
*
15
Memantine
(10 mg/day)
10
Placebo
0
2
4
6
8
Week
Winblad & Poritis 1999; H. Lundbeck A/S, Data on file
10
12
14
*p=0.016, stratified
Wilcoxon test
Behaviour and function:
D-test items
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 stand up 2
Ability to move 3
Ability to wash 4
Ability to take a shower 5
or bath
Ability to dress 6
Ability to use the toilet 9
Group activities 13
Memantine
Hobbies/interests 14
Winblad & Poritis 1999
Placebo
0
10
20
30
40
Frequency of improvement (%)
50
60
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
Memantine
Precautions/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 aggressively
2. Care for caregivers aggressively
3. The Dementia Cocktail:
• AChEI
• Vitamin E
• ASA
• Vitamin B6/B12/Folate
• Memantine
• Statin