Transcript Document

The Management of Alzheimer’s
Disease and Related Dementias
The Role of Cholinesterase Inhibitors
in the Treatment of Alzheimer’s
Disease and Related Dementias
Steven G. Potkin, MD
ABC: The Key Symptom Domains of AD
and Their Assessment Instruments
 Activities of daily living
– PDS
– ADFACS
– ADCS/ADL
 Behavior
– NPI
– BEHAVE-AD
 Cognition
– ADAS-Cog
– MMSE
Potential to Increase Diagnosis
and Treatment Across Disease Stages
Number of Patients
Number of patients1
Diagnosed2
Treated with AChE
inhibitor3
1,400,000
1,200,000
1,000,000
800,000
600,000
400,000
200,000
0
Mild4
Moderate4
Severe4
Disease Stages
Jack; 2MMI MDAD, 2001; 3On CHeI—midpoint of last year’s treatment by severity
rates and rates reported in Reminyl uptake 2001; 4Decision Resources.
1Mattson
Increased Probability of
Institutionalization by Disease Severity
Probability of
Institutionalization
1.0
0.867
0.8
0.6
0.345
0.4
0.2
0.017
0.0
Mild
Moderate
Severe
(MMSE: 21–30) (MMSE: 11–20) (MMSE: 0–10)
Severity of AD
Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):351-360
Effects of Disease Severity on
Impairment of ADL in Patients With AD
80
70
60
50
40
30
20
Adapted from Grossberg, 1999.
Moderate AD
(GDS 4)
Severe AD
(GDS 5 or 6)
More impairment
Mean PDS Score
Mild AD
(GDS 3)
Effects of Galantamine on ADL:
ADCS/ADL Scores Mean
(± SEM) Change from Baseline
ADCS/ADL Scores Mean Change from Baseline
Improvement
1
0
–1
–2
–3
–4
–5
–6
Baseline
Placebo (n = 234)
Galantamine 8 mg/day (n=106)
Galantamine 16 mg/day (n=211)
Galantamine 24 mg/day (n=212)
4
8
12
Deterioration
16
Time (Weeks)
AD Cooperative Study Activities of Daily Living Inventory; OC analysis
Tariot et al, 2000.
20
Effect of Donepezil on ADL at Endpoint:
Change in Assessment Scale Score from Baseline
Change from Baseline (%)
Assessment
scale
0
PDS
n=95
n = 97
ADFACS
n=181
n =196
DAD
n=121
n=126
**
MMSE=17.1
10
Clinical
decline
MMSE=12.05
20
*
Donepezil
30
*P<.05 vs placebo
**P<.01 vs placebo
OC analysis
MMSE=19.35
Placebo
Mohs et al, 2001; Feldman et al, 2001;
Winblad et al, 2001.
Mean Change from Baseline
Effects of Rivastigmine on ADL:
Progressive Deterioration Scale (PDS)
2
1
0
–1
–2
–3
–4
–5
–6
–7
Improvement
*
**
6–12 mg (n=231)
1–4 mg (n=233)
Placebo (n=235)
0
12
Weeks
*P<.05 vs placebo; **P<.001 vs placebo
Corey-Bloom et al, 1998.
Decline
18
26
Improvement in ADL: Rivastigmine
Treatment vs Placebo (PDS)
Item
Mild
(GDS ≤3)
Ability to handle money

Ability to tell time

Time spent on hobbies

Moderate
(GDS=4)
Severe
(GDS ≥5)
Participating in family finanaces

Ability to dress properly


Reduced forgetfulness


Time rearranging objects


Ability to use the phone

Comfort in different settings

Proper eating manners

Potkin et al, 2002.
Peak Frequency of Behavioral
Symptoms as AD Progresses
Frequency (% of Patients)
100
Agitation
80
60
40
Diurnal
rhythm
Depression
Irritability
Social
withdrawal
Aggression
Paranoia
Anxiety Mood
change
0
–40
–30
Accusatory
behavior
–20
–10
Hallucinations
Socially unacceptable behavior
Delusions
Sexually inappropriate behavior
20
Suicidal
ideation
Wandering
0
10
Months before/after Diagnosis
Jost and Grossberg, 1996.
20
30
Psychotic Symptom Frequency Increases
With Disease Severity
Patients Affected (%)
80
60
40
20
0
CDR 0.5
CDR 1
CDR 2
CDR 3
N=69; CDR=clinical dementia rating scale; most common psychotic symptoms: agitation,
wandering, irritability, withdrawal, physical assault
Farber NB, et al. Arch Gen Psychiatry. 2000(Dec):57(12):1165-1173
Effect of Galantamine on Behavioral
Symptoms: NPI Total Scores
Mean (± SEM) Change in NPI
Score from Baseline
Placebo
Galantamine 8 mg/d
–3
Improvement
–2
–1
0
1
2
3
4
Baseline
N=978
Galantamine 16 mg/d
Galantamine 24 mg/d
Deterioration
1
2
3
Time (Months)
NPI=neuropsychiatric inventory; Tariot et al, 2000.
4
5
Mean Change from Baseline NPI-NH
Individual Item Score at Week 24
Donepezil Behavioral Effects in Nursing Home
Patients at Week 24: Mean Change from
Baseline in NPI-NH Individual Items
–3
Placebo (n = 105)
Donepezil (n = 103)
Improvement
–2
–1
0
1
2
Baseline
3
4
ITT, LOCF analysis
NPI-NH=neuropsychiatric inventory-nursing home version
Decline
Tariot et al, 2001
Rivastigmine: Change on NPI-NH at Week 52
for Patients Who Had the Symptom at Baseline
Mean change from baseline
*
-2
*
*
*
-1
0
1
2
3
4
N=99
*P<.05 vs baseline; **P<.001 vs baseline; OC analysis
Cummings et al, 2002.
**
*
*
Improvement
*
-3
–3
–2
3
Baseline
Open-label
Rivastigmine
(3–12 mg/d)
n=119
Open-label
Rivastigmine
(3–12 mg/d)
2
n=125
Donepezil
(10 mg/d)
1
n=103
Placebo
0
Placebo
n=212
Galantamine
(24 mg/day
n=103
n=234
Donepezil
(10 mg/d)
–1
n=113
MMSE=17.7
NPI-101
MMSE=14.4
NPI-122
MMSE=11.8
NPI-123
MMSE=9.2
NPI-124
MMSE=10.8
NPI-125
OC analysis
Outpatients
ITT, LOCF analysis
Nursing home
OC analysis
Community/
assisted living
OC analysis
Nursing home
OC analysis
Nursing home
1
2
Adapted from Tariot et al, 2000; Tariot et al, 2001;
3
4
5
Feldman et al, 2001; Cummings et al, 2000; Bullock et al, 2001.
Improvement
n=98
Placebo
Mean Change from Baseline
NPI Improvement following AChE Inhibitors and Dual
AChE and BuChE Inhibitors Treatment in Five Studies
(Mean Change per Item after Approximately 6 Months)
Effects of Rivastigmine on Psychotropic
Medication Use
Patients Taking Psychotropic Drugs
During Rivastigmine Treatment (%)
Nursing Home AD Patients at Week 26
35
30
25
Antipsychotics (n=55)
Anxiolytics (n=33)
Antidepressants (n=57)
20
15
10
5
0
Increased
Dose
Anand R, et al. Neurobiol Aging. 2000;21:5220
Reduced
Dose
Terminated
Medication
Rivastigmine and Donepezil Administration
Increases Basal ACh Release in Aged Rats
14
Ach (fmol/µL)
12
Control
Donepezil
Rivastigmine
10
8
6
4
2
0
Cortex
Hippocampus
Chronic (21 Days)
18 hours after the last administration; N=4–8; *P<.005 vs controls
Scali et al. J Neural Transm. 2002;109(7-8):1067-1080
Most Frequent Adverse Events with
1-Week Dose Titration of ChE Inhibitors
Donepezil
Galantamine
Rivastigmine
Placebo
(n=315)
10 mg/Day
(n=315)
Placebo
(n=213)
24 mg/Day
(n=212)
Placebo
(n=868)
6–12
mg/Day
(n=1,189)
Nausea
6
19
13
37
12
47
Vomiting
3
8
8
21
6
31
Anorexia
2
7
6
14
3
17
Diarrhea
5
15
10
12
11
19
Adverse
Event (%)
Physicians’ Desk Reference, 2003; Raskind MA, et al. Neurology. 2000(June 27);54(12):2261-2268
Adverse Events with
1- vs 4-Week Titration of Galantamine
1-Week Titration (%)
Adverse
Event (%)
4-Week Titration (%)
Placebo
(n=213)
24 mg/Day
(n=212)
Placebo
(n=286)
24 mg/Day
(n=273)
Nausea
13
37
5
17
Vomiting
8
21
1
10
Diarrhea
10
12
6
6
Anorexia
6
14
3
9
Physicians’ Desk Reference, 2003; Raskind MA, et al. Neurology. 2000(June 27);54(12):2261-2268
Tolerability of Donepezil: Incidence of
Common Adverse Events by Titration Rate
No Titration
Adverse
Event (%)
1-wk Titration 6-wk Titration
Placebo
(n=315)
5 mg/Day
(n=311)
10 mg/Day
(n=315)
10 mg/Day
(n=269)
Nausea
6
5
19
6
Diarrhea
5
8
15
9
Insomnia
6
6
14
6
Fatigue
3
4
8
3
Vomiting
3
3
8
5
Muscle cramps
2
6
8
3
Anorexia
2
3
7
3
Physicians’ Desk Reference, 2003.
Slow (4 Weeks)-Dose Titration with
Rivastigmine Provides Low Potential for AEs
N=212
Adverse Event
Nausea/vomiting
N
8
%
3.8
Abdominal pain
Diarrhea
Agitation
1
5
7
0.5
2.4
3.3
Confusion
Hallucinations
Total
4
1
26
1.9
0.5
12.4
Shua-Haim et al, 2001.
Acute Titration-Related AEs with
ChE Inhibitor Therapy
 Cholinergically mediated AEs include nausea,




vomiting, abdominal pain, dizziness, diarrhea,
weight loss/anorexia
Tend to be transient, most frequent during dose
escalation and of mild to moderate intensity
Nausea and vomiting are centrally mediated, caused
by too rapid an increase in brain ACh levels
Slow-dose escalation and administration with food
are proven ways to reduce the incidence of these
AEs, especially with rivastigmine and galantamine
Go slowly; give with food with Exelon and Reminyl
Molecular Forms of AChE
CNS:
Brain
PNS:
Skeletal muscle
Erythrocyte
Globular
Tetramer
G4
Muscle:
Asymmetric
A12
Darvesh S. et al. Nature Reviews. 2003: 4:131-138.
Globular
Monomer
G1
Erythrocyte:
Globular
Dimer G2
Inhibitory Influence of ChE Inhibitors
on Molecular Forms
Human Control Cortex G1/G4
16.0S
11.4S
4.8S
Rivastigmine
Physostigmine
Heptylphysostigmine
Donepezil
7
50
6
25
Ratio G4/G1: 2.1
G4
G1
0
0
5
10 15 20 25 30 35
Human Alzheimer Cortex G1/G4
75
16.0S 11.0S
4.8S
50
5
4
3
Ratio G4/G1:
2.1
0
5
Enz et al, 1993.
G4
G1
10 15 20 25 30 35
Fraction Nr.
G1
preferring
2
1
25
0
Ratio IC G4/G1507
ChE Activity nmol x min–1 xml–1 Fraction
75
G4
preferring
0
Corte
Hippocampus
x Human Brain AChE
AChE Isoforms in Normal and AD Brains
AChE (µmol/Min. x mL Fraction)
Normal Adult Brain
G4
1.00
G1
Frontal
cortex
50
0
10
20
Nucleus
basalis
50
10
20
30
Caudate
nucleus
25
0
50
0
10
20
30
0
10
20
30
0
10
20
30
0
10
20
30
25
0
0
50
25
0
Number of Fraction
Enz, et al. Prog Brain Res. 1993;98:431-8.
G1
0.50
0.00
30
25
0
G4
1.00
0.50
0.00
AD
ChE Inhibitors: Tolerability
Donepezil Rivastigmine Galantamine
Cholinergically mediated
acute AEs
Yes
Yes
Yes
Yes*
None known
Yes*
++
+/–
+/–
CV problems
+
+/–
+
 EPS
++
+/–
+/–
Behavioral disturbances
+
+/–
+
Drug–drug interactions
Chronic AEs
Sleep disturbances
**Clinical significance is unclear; CV=cardiovascular; EPS=extrapyramidal symptoms; +/- little or none;
+ mild; ++ moderate
Inglis, 2002.
Adverse Events per 100,000 Prescriptions
for Rivastigmine and Donepezil
Adverse Events
per 100,000 Prescriptions
0.7
Rivastigmine
Donepezil
*
0.6
0.5
0.4
0.3
**
0.2
0.1
0
All Adverse
Reactions
*P<.05; **P<.01 vs rivastigmine
Rizzo et al, 2001.
Serious Adverse
Major Reactions
Reactions
from Clinical Trials
Significance of Drug-Drug Interaction
2C9/10/19
1A2
2D6
11%
4%
31%
54%
3A4
 5 CYP450 isoenzymes
account for ~99% of all drug
metabolism
 ~85% of drug metabolism is
mediated by 2 members of
the CYP450 system: CYP3A4
and CYP2D6
 Safety of rivastigmine:
no clinically relevant
interactions with 22
therapeutic classes of drugs
CYP450=cytochrome P450A
Anzenbacher P, Anzenbacherova E. Cell Mol Life Sci. 2001(May);58(5-6):737-747; Scordo MG,
Spina E. Pharmacogenomics. 2002(March);3(2):201-218; Grossberg GT, et al. Int J Geriatr
Psychiatry. 2000(March);15(3):242-247
ChE Inhibitors: Pharmacokinetic
Characteristics
AChE Inhibitors
Characteristic
Dual AChE/
BuChE Inhibitor
Donepezil
Galantamine
Rivastigmine
~70
70
~6
6
~1
12
Liver
50% kidney
50% liver
Kidney
Metabolism by
2D6/3A4 isoenzymes
Yes
Yes
Minimal
Administer with food?
No
Yes
Yes
Enhanced G1 inhibition
No
Unknown
Yes
Plasma half-life (hour)
Brain half-life
Elimination
pathway
Physicians’ Desk Reference, 2002; Nordberg and Svensson, 1998; Polinsky, 1998; Inglis, 2002.
Linear Dose Response of Rivastigmine in
ADAS-Cog, PDS, and MMSE Mean Change from
Baseline at Week 26
0.0
1.0
2.0
3.0
4.0
2
4
6
8
10
Last Prescribed Dose of
Rivastigmine (mg/d)
Mean change from
baseline on MMSE
0
2
4
6
8
10
12
Last Prescribed Dose (mg/day)
MMSE
1.5
Predicted response
Limits
1.0
0.5
0.0
–0.5
–1.0
–1.5
0
Anand, et al, 2000.
0
12
2
4
6
8
10
12
Last Prescribed Dose (mg/day)
Improvement
–1.0
Predicted response
Limits
2.0
1.0
0.0
–1.0
–2.0
–3.0
–4.0
–5.0
–6.0
–7.0
–8.0
Improvement
Limits
Predicted response
–2.0
Mean change from
baseline on PDS
PDS
Improvement
Mean Change from
Baseline on ADAS-Cog
ADAS-Cog
ADAS-Cog Score
Mean Change from Baseline
Effects of Rivastigmine on Cognition in
Patients With AD (MHIS score = 0) and AD with
Vascular Risk Factors (MHIS >0)
MHIS = 0
(n = 287)
–3
–2
MHIS >0
(n = 244)
***
Improvement
–1
0
1
**
2
*
3
4
Decline
5
6–12 mg/d
1–4 mg/d
Placebo
OC analysis, week 26
*P<.002 vs placebo; **P=.02 vs 6–12 mg/day (MHIS = 0); ***P<.001 vs placebo
MHIS=modified Hachinski ischemic scale
Adapted from Kumar, et al, 2000.
Effects of Rivastigmine on ADL in Patients with
AD (MHIS score=0) and AD With Vascular Risk
Factors (MHIS >0)
MHIS=0
(n=287)
MHIS >0
(n=244)
PDS Score Mean
Change from Baseline
0
**
-1
Improvement
-2
*
-3
-4
-5
Decline
-6
-7
6–12 mg/d
OC analysis, week 26
*P<.05 vs placebo; **P<.001 vs placebo
Adapted from Kumar, et al, 2000.
1–4 mg/d
Placebo
Evolution of VAD Syndrome
 Alzheimer: (1895) arteriosclerotic brain
degeneration
 Tomlinson: (1967) volume of brain infarction
 Hachinski: (1967) MID cumulative multiple
small strokes
 Roman: (1967) VAD
– Infarcts—size, location, and number
– Risk factors—DM, hypertension,
hyperlipidemia
VAD=vascular dementia
MID=multi-infarct dementia
Prevalence of Dementias:
European Study of 2346 Cases
Other 30.5%
VAD
15.8%
AD
53.7%
Other=(AD + CVD DLB, FTD, unknown); CVD=cerebrovascular disease; DLB=Lewy bodydementia
FTD=frontotemporal dementia
Lobo, et al, Neurology. 2000.
Vascular Risk Factors
 Hyperlipidemia
 TIA
 Hypertension
 FHx, Hx: Strokes,
 Diabetes
cardiac/periph vas
disease
 Coagulopathy
 EKG abnormalities
 Atrial fib or
arrhythmias
 Obesity
 Smoking history
 Alcohol history
VAD: MRI Required for Clinical Diagnosis
Scheltens, 2001.
Hippocampal ChAT Activity
Control
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
AD
AD/MID
MID
*
*
AD
AD/MID
MID
9
6
4
*
Control
n=
*P<0.01
Sakurada, et al, 1990.
9
Hippocampal Muscarinic Receptors
QNP (pmol/g protein)
350
300
*
250
200
150
100
50
0
Control
AD
AD/MID
MID
9
9
6
4
n=
*P<.05
Sakurada, et al, 1990.
Effects of Galantamine Treatment for 26 Weeks
on Cognition in VAD and AD Patients With CVD
ADAS-Cog Score
Mean Change from Baseline
3
Placebo
2
Galantamine 24 mg/d
1
0
–1
*
–2
Improvement
–3
–4
–5
*P<.05 vs placebo
Erkinjuntti, et al, 2002.
VAD
(n=188)
AD + CVD
(n=239)
Rivastigmine in Subcortical VAD: Efficacy
up to 22 Months in an Open-label Study
Change from Baseline in
NPI Score at 22 Months
-4.0
Rivastigmine (3–6 mg/d)
Cardioaspirin
-3.0
*
Improvement
-2.0
-1.0
0
1.0
0 1 3
8
12
Months
*P<.001 vs cardioaspirin and P<.05 vs baseline
Moretti, et al, 2002.
16
22
Decline
Change from baseline in
TPC score at 22 months
Rivastigmine in Subcortical VAD:
Efficacy up to 22 Months
4.0
Rivastigmine (3–6 mg/day)
Cardioaspirin
3.0
Improvement
*
2.0
1.0
0
-1.0
0 1 3
8
12
Months
*P<.001 improvement vs cardioaspirin and P<.01 vs baseline
TPC=ten point clock drawing
Moretti, et al, 2002.
16
22
Decline
Change from baseline in
RSS score at 22 months
Rivastigmine in Subcortical VAD:
Efficacy up to 22 Months
Rivastigmine (3–6 mg/day)
Cardioaspirin
-10.0
*
Improvement
22
Decline
-7.5
-5.0
-2.5
0
-2.5
0 1 3
8
12
Months
*P<.01 vs cardioaspirin and P<.05 vs baseline
RSS=relative stress scale
Moretti, et al, 2002.
16
Decreased Cholinergic Activity Associated
With Neuropathology of AD, DLB, and PD
ChAT (nmol/h/mgP)
15
10
Normal controls (NC)
AD
DLB
Parkinson’s disease (PD)
15
Parietal
cortex
10
Temporal
cortex
4
Occipital
cortex
3
5
5
2
1
0
0
NC AD DLB PD
*Lewy body variant of AD
Perry, et al, 1985, 1994.
0
NC AD DLB PD
NC AD DLB* PD
Brain Infarction and the Clinical Expression
of Alzheimer disease: The Nun Study (N=61)
 Participants with AD pathology and brain
infarcts had poorer cognitive function and a
higher prevalence of dementia than those
without infarcts (OR 20.7)
 Fewer neuropathologic lesions of AD appeared
to result in dementia in those with lacunar
infarcts in the basal ganglia, thalamus, or deep
white matter
 Cerebrovascular disease can play an important
role in determining the presence and severity of
the clinical symptoms of AD
Dementia With Lewy Bodies





15%–25% of all dementia in the elderly
Onset ~75–80 years
Duration ~3.5 years (<1–20)
Slight male predominance
Characterized by
–
–
–
–
–
–
Fluctuating cognitive impairment (~80%)
Persistent visual hallucinations (>60%)
Systematized delusions (~70%)
Depression (38%)
Parkinsonism (65%–70%)
Neuroleptic sensitivity (>50%)
Campbell, Stephens, Ballard, 2001.
Dementia With Lewy Bodies (cont’d)
Supportive Features
Transient loss of consciousness
40%
Falls and syncope
50%
Systematized delusions
70%
Neuroleptic sensitivity
50%
Depression
50%
REM sleep behavior disorder
25%
DLB is underdiagnosed and may constitute 15% of all dementias
Neuropsychiatric Symptoms in
DLB vs AD
Percentage of Patients
with Symptoms
80
DLB
AD
70
60
50
40
*
30
20
10
*
0
*P<.05
Ballard C, Walker M. Curr Psychiatry Rep. 1999(Oct);1(1):49-60
*
*
Behavioral Symptoms at
Baseline (NPI)
Ranked by Frequency of Occurrence (% of Patients)
Symptoms in >50% of Patients (%)
Symptoms in <50% of Patients (%)
Apathy/indifference
Anxiety
Depression/dysphoria
Delusions
Agitation/aggression
Irritability/lability
Aberrant motor behavior
Appetite; eating disorder 34.2
Elation/euphoria
18.3
Disinhibition
16.7
72.5
70.0
65.8
58.3
55.0
55.0
53.3
McKeith IG, Ballard CG, Perry RH, et al. Neurology. 2000(March 14);54(5):1050-1058
Behavioral and Cognitive Responses to Donepezil
in AD and DLB (Open-label, 5 mg/d for 6 Months)
Average
BEHAVE-AD
Score
2
AD (n=12)
DLB (n=4)
P=NS
1
0
P=NS
Baseline
6 months
P=NS
5
Increase in
MMSE Score
Baseline
4
3
2
1
P=NS
0
NS=nonsignificant
Samuel, et al, 2000.
AD
DLB
6 months
Effects of Rivastigmine on Behavioral
Symptoms in DLB (Double Blind)
NPI 10-Item Score—Percentage of
†
Patients Improving by 30% from Baseline
NPI 10-Item Score
70
*
–6
–5
Rivastigmine
–4
Placebo
–3
–2
–1
0
Baseline
Patients Improving (%)
–7
Improvement
Mean Change from Baseline
–8
60
**
50
40
30
20
10
0
12
Weeks
20
*P<.01 vs placebo; **P<.001 vs placebo
Responder definition recommended by NPI author (J Cummings)
†
Adapted from McKeith, et al, 2000.
Week 20
Rivastigmine
3–12 mg/d (n=59)
Placebo (n=61)
PD and Dementia
 At least one-third of PD patients develop
dementia
 Patients with PD have degeneration of the
nucleus basalis of Meynert and low brain
ChAT levels
 The dementia of PD is not improved by
dopaminomimetic drugs
 ChE inhibitor therapy in PD is indicated
Perry, et al, 1985; Korczyn, 2001.
NPI Hallucination and Sleep Scores
in PD Patients Receiving Rivastigmine
NPI Hallucination and
Sleep Scores
8
6
Baseline
Rivastigmine 3–12 mg/d
8
Increasing
Symptoms
N=12
6
N=12
4
4
**
2
*
2
0
0
Hallucination
Sleep
*P<.02; **P<.015; OC analysis
Reading PJ, Luce AK, McKeith IG. Mov Disord. 2001(Nov);16(6):1171-1174
Rivastigmine in PD: Cognition, Motor
Function, and Caregiver Burden
35
25
*
Improvement
Improvement
30
35
20
15
10
5
Improvement
MMSE
25
20
15
10
5
12
0
30
0
10
UPDRS
8
6
4
**
Baseline
Rivastigmine 3–12 mg/d
2
0
NPI Caregiver Distress
*P<.05; **P<.01 vs baseline; OC analysis;
Reading PJ, Luce AK, McKeith IG. Mov Disord. 2001(Nov);16(6):1171-1174
Effects of Rivastigmine Treatment on
ADAS-Cog and UPDRS Motor Scores in PDD
Baseline
Week 12
Mean rivastigmine dose (mg/d)
7.2
7.5
ADAS Cog total score
30.8
23.6
23.5*
UPDRS motor
43.9
42.9
43.6
ADAS-Cog Subscores Showing Statistically Significant
Improvement from Baseline at Week 26
Week 26
P
Naming
0.05
Recognition
0.007
Word finding
0.02
Remembering instructions
0.008
Concentration
0.0005
N=28
*P=.004 vs baseline
Giladi, et al, 2003.
Effects of Rivastigmine Treatment on Clinical
Global Impression of Change from Baseline
Week 12
Week 26
Mean dose (mg/d)
7.3
7.5
Patient perspective
1.6*
1.5*
Caregiver perspective
1.7*
1.3*
Neurologist perspective
1.8*
1.7*
*P<.0001
CGIC=clinical global impression of change
CGIC Scale: 3=marked improvement, 2=moderate improvement, 1=mild improvement, 0=no change,
-1=mild worsening, -2=moderate worsening, -3=marked worsening; N=28
Giladi, et al, 2002.
Reasons to Consider Switching
ChE Inhibitors
 Switching should be considered when
there is
– A lack of initial response to treatment
– Loss of response during long-term treatment
 Switching should not be considered in
patients responding to current treatment
Emre, 2002.
Switching: Medical Rationale
 Therapeutic strategy performed routinely in
daily medical practice
 Employed across a spectrum of medical
conditions
–
–
–
–
Depression (SSRIs)
Migraine (triptans)
Microbial infection (antibiotics)
Heart failure (ACE inhibitors)
 Purpose of switching is to maximize the
benefits of treatment
100
20
16
12
9
8
8
4
0
Per
ADAScog
Per
ADCS/
ADL
Patients in Whom Switch
Was Beneficial (%)2
No. of Donepezil Nonresponders
Who Responded to Galantamine1
Changing from Donepezil
to Galantamine and Rivastigmine
80
60
40
20
0
Side Effects
Donepezil
Group (n=18)
Lack/Loss of
Efficacy Group
(N=22)
N=17; 12-month, open-label extension of a 6-week open-label trial; week 18 vs baseline; Rasmusen L,
et al. Clin Ther. 2001;23(suppl A):A25-A30; Bullock R, Connolly C. Int J Geriatr Psychiatry.
2002(March);17(3):288-289
Lack of Tolerability and Efficacy With Donepezil
Do Not Preclude Response to Rivastigmaine
Lack of efficacy of donepezil (n=304)
Unable to tolerate donepezil (n=78)
40
0
11.5
Discontinued
Rivastigmine
Due to AEs
Rivastigmine
Responders
Patients (%)
Patients (%)
54.5
60
20
74.4
80
80
60
40
20
0
15.4
Discontinued
Rivastigmine
Due to AEs
Rivastigmine
Responders
Auriacombe S, Pere JJ, Loria-Kanza Y, Vellas B. Curr Med Res Opin. 2002;18(3):129-138
Guidelines for Switching ChEIs
Donepezil or galantamine
to rivastigmine
Unsatisfactory
treatment on donepezil
Patient
experiencing lack
of response or
loss of efficacy
Safety or tolerability
problem
Washout for 7 days or
No washout period
until symptoms resolve
required
Initiate rivastigmine
therapy at
3 mg daily (1.5 mg
twice daily)
Minimum of 4 weeks
Monitor patient for efficacy, safety, and tolerability,
as with standard dosing guidelines
Escalate dose to 6 mg daily (3 mg twice daily) and
recheck in 4 weeks*
Donepezil or rivastigmine
to galantamine
Is the patient
stabilized on
current therapy (ie,
no tolerability
problems)?
NO
7-day washout is
recommended or
until symptoms
resolve
YES
No washout period required
Initiate galantamine therapy at
8 mg daily (4 mg twice daily)
4 weeks
Monitor patient for efficacy, safety, and
tolerability, as with standard dosing guidelines
Escalate dose to 16 mg daily (8 mg twice daily)
and recheck in 4 weeks
*Patients may derive clinical benefit from escalating the dose further to 9 mg daily
(4.5 mg twice daily), and 12 mg daily (6 mg twice daily), at intervals of no less than 4 weeks. Emre, 2002; Morris, 2002.
Medical Rationale for Switching
 Switching is a relatively new concept in AD
treatment
 Many physicians stop ChE inhibitor
treatment altogether if patient fails to show
response or loses response to current agent
 However, evidence suggests that switching
between ChE inhibitors represents a
valuable therapeutic option to maximize
treatment benefits over a longer period
Memantine in Moderate-to-Severe AD
 252 patients randomly assigned to placebo
or 20 mg of memantine for 28 weeks
 Memantine superior to placebo on
– CIBIC-plus
– ADCS-ADL severe
– Severe Impairment Battery (SIB)
 No AEs observed
 Memantine recently FDA approved for
moderate to severe AD
Reisberg B, Doody R, Stoffler A, et al. N Engl J Med. 2003(April 3);348(14):1333-1341
Summary
 AChE inhibitors and dual ChEIs are proven




effective in the treatment of the ABC of AD
Patients with severe AD maintain robust
behavioral responses to ChEI
Behavioral disturbances often result in patient
institutionalization
As AD progresses, the number and severity of
behavioral disturbances increases
ChE inhibitors can reduce the need for
concomitant antipsychotics, antidepressants and
anxiolytic medications
Summary
 AD associated with vascular risk factors, cerebral
vascular disease, and vascular angiopathy
 Cholinergic deficits in VAD, AD, and mixed
dementias
 There is increasing evidence of efficacy for ChEIs
in PDD, DLB, and VAD, which may result in an
extended role for these agents
 All ChEIs have differing modes of action and
pharmacokinetic profiles; therefore, switching can
be efficacious