Clinical Issues in Moderate - Severe Dementia Dr. William Dalziel Chief, Ottawa Regional Geriatric...

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


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


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


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


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


Donepezil in Advanced AD (sMMSE 5-12): ADLs

Clinicalimprovement

Clinicaldecline

Baseline

0

7269

24

6363


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


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


p=0.0252

p=0.0198 p=0.0062p=0.0314

= 6.9

NPI 12-item totalNPI 12-item total


-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


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


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*


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)



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


-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


Global change: CGI-C, ITT population


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


*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

Clinical Issues in Moderate - Severe Dementia Dr. William Dalziel Chief, Ottawa Regional Geriatric...

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