the management of alzheimer’s disease and related dementias the role of cholinesterase inhibitors...
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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
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
Mild4 Moderate4 Severe4
Number of patients1 Diagnosed2 Treated with AChE inhibitor3
1Mattson Jack; 2MMI MDAD, 2001; 3On CHeI—midpoint of last year’s treatment by severity rates and rates reported in Reminyl uptake 2001; 4Decision Resources.
Nu
mb
er o
f P
atie
nts
Disease Stages
Potential to Increase Diagnosis and Treatment Across Disease Stages
Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):351-360
Pro
bab
ilit
y o
f In
stit
uti
on
aliz
atio
n
0.0
0.2
0.4
0.6
0.8
1.0
Mild(MMSE: 21–30)
Moderate(MMSE: 11–20)
Severe(MMSE: 0–10)
Severity of AD
0.017
0.345
0.867
Increased Probability of Institutionalization by Disease Severity
Inab
ility
to
hand
le m
oney
Inab
ility
to te
ll tim
e
Tim
e do
ing
hobb
ies
Dre
sses
pro
perly
Forg
etfu
lnes
sTi
me
rear
rang
ing
obje
cts
Con
duct
ing
fam
ilyfin
ance
s
Abi
lity
to u
se p
hone
Con
fusi
onEa
ting
man
ners
Mild AD(GDS 3)
Moderate AD(GDS 4)
Severe AD(GDS 5 or 6)
80
70
60
50
40
30
20
Adapted from Grossberg, 1999.
Mo
re i
mp
airm
ent
Mea
n P
DS
Sco
reEffects of Disease Severity on Impairment of ADL in Patients With AD
Improvement
Deterioration
Baseline 4 8 12 16 20
1
0
–1
–2
–3
–4
–5–6A
DC
S/A
DL
Sco
res
Mea
n(±
SE
M)
Ch
ang
e fr
om
Bas
elin
e
Time (Weeks)
AD Cooperative Study Activities of Daily Living Inventory; OC analysisTariot et al, 2000.
Placebo (n = 234)
Galantamine 8 mg/day (n=106)
Galantamine 16 mg/day (n=211)
Galantamine 24 mg/day (n=212)
Effects of Galantamine on ADL: ADCS/ADL Scores Mean Change from Baseline
*
Mohs et al, 2001; Feldman et al, 2001; Winblad et al, 2001.
*P<.05 vs placebo**P<.01 vs placeboOC analysis
0
10
20
30
Ch
ang
e fr
om
Bas
elin
e (%
)
Donepezil
Placebo
Clinicaldecline
Assessmentscale PDS ADFACS DAD
n=181 n =196n = 97 n=126n=95 n=121
MMSE=17.1
MMSE=19.35
MMSE=12.05
**
Effect of Donepezil on ADL at Endpoint: Change in Assessment Scale Score from Baseline
Corey-Bloom et al, 1998.
2
1
0
–1
–2
–3
–4
–5
–6
–7
Mea
n C
han
ge
fro
m B
asel
ine
0 12 18 26
Improvement
Decline
6–12 mg (n=231)
1–4 mg (n=233)
Placebo (n=235)
*
*P<.05 vs placebo; **P<.001 vs placebo
Weeks
**
Effects of Rivastigmine on ADL: Progressive Deterioration Scale (PDS)
Improvement in ADL: Rivastigmine Treatment vs Placebo (PDS)
Potkin et al, 2002.
ItemMild
(GDS ≤3)Moderate (GDS=4)
Severe(GDS ≥5)
Ability to handle money
Ability to tell time
Time spent on hobbies
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
Agitation
Diurnalrhythm
IrritabilityWandering
Aggression
HallucinationsMoodchange
Socially unacceptable behavior
DelusionsSexually inappropriate behavior
Accusatorybehavior
Suicidalideation
Paranoia
Depression
Months before/after Diagnosis
Anxiety
Socialwithdrawal
100
80
60
40
20
0–40 –30 –20 –10 0 10 20 30
Fre
qu
ency
(%
of
Pat
ien
ts)
Jost and Grossberg, 1996.
Peak Frequency of Behavioral Symptoms as AD Progresses
N=69; CDR=clinical dementia rating scale; most common psychotic symptoms: agitation, wandering, irritability, withdrawal, physical assaultFarber NB, et al. Arch Gen Psychiatry. 2000(Dec):57(12):1165-1173
Pat
ien
ts A
ffec
ted
(%
)
0
20
40
60
80
CDR 0.5 CDR 1 CDR 2 CDR 3
Psychotic Symptom Frequency Increases With Disease Severity
NPI=neuropsychiatric inventory; Tariot et al, 2000.N=978
Effect of Galantamine on Behavioral Symptoms: NPI Total Scores
–3
–2
–1
0
1
2
3
4
Mea
n (
± S
EM
) C
han
ge
in N
PI
Sco
re f
rom
Bas
elin
e
Baseline 1 2 3 4 5
Placebo
Galantamine 8 mg/d
Galantamine 16 mg/d
Galantamine 24 mg/d
Time (Months)
Improvement
Deterioration
–3
–2
–1
0
1
2
3
4Mea
n C
han
ge
fro
m B
asel
ine
NP
I-N
H In
div
idu
al It
em S
core
at
Wee
k 24
Delusions
Hallucinatio
ns
Agitatio
n/aggression
Depression/dysphoria
Anxiety
Elation/euphoria
Apathy/indiffe
rence
Disinhibition
Irrita
bility/la
bility
Aberrant m
otor behavior
Night-tim
e behavior
Appetite/eatin
g
Placebo (n = 105)
Donepezil (n = 103)Improvement
Baseline
Decline
ITT, LOCF analysisNPI-NH=neuropsychiatric inventory-nursing home version Tariot et al, 2001
Donepezil Behavioral Effects in Nursing Home Patients at Week 24: Mean Change from Baseline in NPI-NH Individual Items
******
**
*
Mea
n c
han
ge
fro
m b
asel
ine
-3
-2
-1
0
1
2
3
4
*P<.05 vs baseline; **P<.001 vs baseline; OC analysis
Imp
rove
me
nt
Ag
itat
ion
Irri
tab
ility
An
xiet
yA
ber
ran
t m
oto
rb
ehav
ior
Ap
ath
yD
epre
ssio
nD
elu
sio
ns
Dis
inh
ibit
ion
Hal
luci
nat
ion
sE
up
ho
ria
Nig
ht-
tim
eb
ehav
ior
Ap
pet
ite
Cummings et al, 2002.
N=99
Rivastigmine: Change on NPI-NH at Week 52 for Patients Who Had the Symptom at Baseline
–3
–2
–1
0
1
2
3
Mea
n C
han
ge
fro
m B
asel
ine
n=234 n=212n=103
n=103
n=98
Imp
rove
men
t
Pla
ceb
o
Gal
anta
min
e(2
4 m
g/d
ay
Pla
ceb
o
Do
nep
ezil
(10
mg
/d)
Op
en-l
abel
Riv
asti
gm
ine
(3–1
2 m
g/d
)
MMSE=17.7 MMSE=14.4 MMSE=11.8 MMSE=9.2 MMSE=10.8NPI-101 NPI-122 NPI-123 NPI-124 NPI-125
OC analysis ITT, LOCF analysis OC analysis OC analysis OC analysisOutpatients Nursing home Community/ Nursing home Nursing home
assisted living
Adapted from Tariot et al,1 2000; Tariot et al,2 2001; Feldman et al,3 2001; Cummings et al,4 2000; Bullock et al,5 2001.
Pla
ceb
o
Do
nep
ezil
(10
mg
/d)
n=125n=119
Baseline
n=113
Op
en-l
abel
Riv
asti
gm
ine
(3–1
2 m
g/d
)
NPI Improvement following AChE Inhibitors and Dual AChE and BuChE Inhibitors Treatment in Five Studies (Mean Change per Item after Approximately 6 Months)
IncreasedDose
TerminatedMedication
Antipsychotics (n=55)
Anxiolytics (n=33)
Antidepressants (n=57)
Reduced Dose
Nursing Home AD Patients at Week 26
Anand R, et al. Neurobiol Aging. 2000;21:5220
0
5
10
15
20
25
30
35
Effects of Rivastigmine on Psychotropic Medication Use
Pat
ien
ts T
akin
g P
sych
otr
op
ic D
rug
s D
uri
ng
Riv
asti
gm
ine
Tre
atm
ent
(%)
Rivastigmine and Donepezil Administration Increases Basal ACh Release in Aged Rats
Chronic (21 Days)
Ach
(fm
ol/
µL
)
18 hours after the last administration; N=4–8; *P<.005 vs controlsScali et al. J Neural Transm. 2002;109(7-8):1067-1080
Most Frequent Adverse Events with 1-Week Dose Titration of ChE Inhibitors
Physicians’ Desk Reference, 2003; Raskind MA, et al. Neurology. 2000(June 27);54(12):2261-2268
Donepezil Galantamine Rivastigmine
AdverseEvent (%)
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 Events with 1- vs 4-Week Titration of Galantamine
Physicians’ Desk Reference, 2003; Raskind MA, et al. Neurology. 2000(June 27);54(12):2261-2268
1-Week Titration (%) 4-Week Titration (%)
AdverseEvent (%)
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
Tolerability of Donepezil: Incidence of Common Adverse Events by Titration Rate
Physicians’ Desk Reference, 2003.
No Titration 1-wk Titration 6-wk Titration
AdverseEvent (%)
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
Slow (4 Weeks)-Dose Titration with Rivastigmine Provides Low Potential for AEs
Shua-Haim et al, 2001.
N=212
Adverse Event N %
Nausea/vomiting 8 3.8
Abdominal pain 1 0.5
Diarrhea 5 2.4
Agitation 7 3.3
Confusion 4 1.9
Hallucinations 1 0.5
Total 26 12.4
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
Erythrocyte:GlobularDimer G2
Muscle:AsymmetricA12
CNS: Brain
PNS: Skeletal muscleErythrocyte
Globular TetramerG4
GlobularMonomerG1
Darvesh S. et al. Nature Reviews. 2003: 4:131-138.
Molecular Forms of AChE
Cortex Hippocampus
Rivastigmine
Heptylphysostigmine
Human Brain AChE
7
6
5
4
3
2
1
0
Rat
io IC
G4/
G1 5
07
Inhibitory Influence of ChE Inhibitors on Molecular Forms
Human Control Cortex G1/G416.0
S11.4
S
G1G4
Ratio G4/G1: 2.1
Ch
E A
ctiv
ity
nm
ol
x m
in–
1 x
ml–
1 F
ract
ion
4.8S
75
50
25
0
Physostigmine
Donepezil
0 5 10 15 20 25 30 35
Enz et al, 1993.
Ratio G4/G1: 2.1
G1G4
16.0S 11.0S
4.8S
Fraction Nr.0 5 10 15 20 25 30 35
75
50
25
0
Human Alzheimer Cortex G1/G4 G1 preferring
G4 preferring
Enz, et al. Prog Brain Res. 1993;98:431-8.
Number of Fraction
0 10 20 300.00
0.50
1.00
0 10 20 300
25
50
0 10 20 300
25
50
0 10 20 300
25
500 10 20 30
0
25
50
Caudate nucleus
Normal Adult Brain AD
AC
hE
(µ
mo
l/M
in.
x m
L F
ract
ion
)
Frontal cortex
Nucleus basalis
G1G4G1G4
0 10 20 300.00
0.50
1.00
AChE Isoforms in Normal and AD Brains
ChE Inhibitors: Tolerability
**Clinical significance is unclear; CV=cardiovascular; EPS=extrapyramidal symptoms; +/- little or none; + mild; ++ moderateInglis, 2002.
Donepezil Rivastigmine Galantamine
Cholinergically mediatedacute AEs Yes Yes Yes
Drug–drug interactionsYes* None known Yes*
Chronic AEs Sleep disturbances ++ +/– +/–
CV problems + +/– +
EPS ++ +/– +/–
Behavioral disturbances + +/– +
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7Rivastigmine
Donepezil
*P<.05; **P<.01 vs rivastigmineRizzo et al, 2001.
Ad
vers
e E
ven
ts
per
100
,000
Pre
scri
pti
on
s
All Adverse Serious Adverse Major Reactions Reactions Reactions from Clinical Trials
*
**
Adverse Events per 100,000 Prescriptions for Rivastigmine and Donepezil
2C9/10/19
1A2
3A4
2D6
31%
54%
11% 4%
CYP450=cytochrome P450AAnzenbacher 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
Significance of Drug-Drug Interaction
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
ChE Inhibitors: Pharmacokinetic Characteristics
Physicians’ Desk Reference, 2002; Nordberg and Svensson, 1998; Polinsky, 1998; Inglis, 2002.
AChE InhibitorsDual AChE/
BuChE Inhibitor
Characteristic Donepezil Galantamine Rivastigmine
Plasma half-life (hour)Brain half-life
~7070
~66
~112
Eliminationpathway Liver
50% kidney50% liver Kidney
Metabolism by2D6/3A4 isoenzymes Yes Yes Minimal
Administer with food? No Yes Yes
Enhanced G1 inhibition No Unknown Yes
Anand, et al, 2000.
Last Prescribed Dose ofRivastigmine (mg/d)
Imp
rove
men
t
LimitsPredicted response
–2.0
–1.0
0.0
1.0
2.0
3.0
4.00 2 4 6 8 10 12
1.5
1.0
0.5
0.0
–0.5
–1.0
–1.5
Last Prescribed Dose (mg/day)
Mea
n c
han
ge
fro
mb
asel
ine
on
MM
SE
0 2 4 6 8 10 12
Predicted responseLimits
Imp
rove
men
t
Predicted responseLimits
2.01.00.0
–1.0–2.0–3.0–4.0–5.0–6.0–7.0–8.0
Last Prescribed Dose (mg/day)0 2 4 6 8 10 12
Imp
rove
men
t
Mea
n c
han
ge
fro
m
bas
elin
e o
n P
DS
Mea
n C
han
ge
fro
m
Bas
elin
e o
n A
DA
S-C
og
ADAS-Cog PDS
MMSE
Linear Dose Response of Rivastigmine in ADAS-Cog, PDS, and MMSE Mean Change from Baseline at Week 26
6–12 mg/d 1–4 mg/d Placebo
–3
–2
–1
0
1
2
3
4
5
AD
AS
-Co
g S
core
Mea
n C
han
ge
fro
m B
asel
ine MHIS = 0 MHIS >0
***
**
*
Improvement
Decline
OC analysis, week 26*P<.002 vs placebo; **P=.02 vs 6–12 mg/day (MHIS = 0); ***P<.001 vs placeboMHIS=modified Hachinski ischemic scaleAdapted from Kumar, et al, 2000.
(n = 287) (n = 244)
Effects of Rivastigmine on Cognition in Patients With AD (MHIS score = 0) and AD with Vascular Risk Factors (MHIS >0)
-7
-6
-5
-4
-3
-2
-1
0
OC analysis, week 26*P<.05 vs placebo; **P<.001 vs placebo Adapted from Kumar, et al, 2000.
Improvement
Decline
PD
S S
core
Mea
n
Ch
ang
e fr
om
Bas
elin
e
MHIS=0 MHIS >0(n=287) (n=244)
6–12 mg/d 1–4 mg/d Placebo
*
**
Effects of Rivastigmine on ADL in Patients with AD (MHIS score=0) and AD With Vascular Risk Factors (MHIS >0)
VAD=vascular dementia MID=multi-infarct dementia
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
Other=(AD + CVD DLB, FTD, unknown); CVD=cerebrovascular disease; DLB=Lewy bodydementiaFTD=frontotemporal dementiaLobo, et al, Neurology. 2000.
AD53.7%
VAD15.8%
Other 30.5%
Prevalence of Dementias:European Study of 2346 Cases
Vascular Risk Factors
Hyperlipidemia Hypertension Diabetes Obesity Smoking history Alcohol history
TIA FHx, Hx: Strokes,
cardiac/periph vas disease
Coagulopathy EKG abnormalities Atrial fib or
arrhythmias
Scheltens, 2001.
VAD: MRI Required for Clinical Diagnosis
*P<0.01Sakurada, et al, 1990.
00.20.40.60.8
11.21.41.61.8
Control AD AD/MID MID
Control AD AD/MID MID
** *
9 9 6 4n =
Hippocampal ChAT Activity
0
50
100
150
200
250
300
350
Control AD AD/MID MID
QNP (pmol/g protein)
*P<.05Sakurada, et al, 1990.
*
9 9 6 4n =
Hippocampal Muscarinic Receptors
*P<.05 vs placeboErkinjuntti, et al, 2002.
Placebo
Galantamine 24 mg/d
3
2
1
0
–1
–2
–3
–4
–5
AD
AS
-Co
g S
core
Mea
n C
han
ge
fro
m B
asel
ine
*
VAD AD + CVD(n=188) (n=239)
Improvement
Effects of Galantamine Treatment for 26 Weeks on Cognition in VAD and AD Patients With CVD
*P<.001 vs cardioaspirin and P<.05 vs baselineMoretti, et al, 2002.
Rivastigmine (3–6 mg/d)Cardioaspirin
-4.0
-3.0
-2.0
-1.0
0
1.0
Improvement
Decline0 1 3 8 12 16 22
Months
Ch
ang
e fr
om
Bas
elin
e in
N
PI
Sco
re a
t 22
Mo
nth
s *
Rivastigmine in Subcortical VAD: Efficacy up to 22 Months in an Open-label Study
*P<.001 improvement vs cardioaspirin and P<.01 vs baselineTPC=ten point clock drawingMoretti, et al, 2002.
Rivastigmine (3–6 mg/day)Cardioaspirin
4.0
3.0
2.0
1.0
0
-1.0
Improvement
Decline0 1 3 8 12 16 22
Months
Ch
ang
e fr
om
bas
elin
e in
T
PC
sco
re a
t 22
mo
nth
s
*
Rivastigmine in Subcortical VAD: Efficacy up to 22 Months
*P<.01 vs cardioaspirin and P<.05 vs baselineRSS=relative stress scaleMoretti, et al, 2002.
Rivastigmine (3–6 mg/day)Cardioaspirin
-10.0
-7.5
-5.0
-2.5
0
-2.5
Improvement
Decline0 1 3 8 12 16 22
Months
Ch
ang
e fr
om
bas
elin
e in
R
SS
sco
re a
t 22
mo
nth
s *
Rivastigmine in Subcortical VAD: Efficacy up to 22 Months
15
10
5
0
15
10
5
0
4
3
2
1
0
*Lewy body variant of ADPerry, et al, 1985, 1994.
NC AD DLB PD NC AD DLB PD NC AD DLB* PD
Normal controls (NC)
AD
DLB
Parkinson’s disease (PD)
Parietalcortex
Temporalcortex
Occipitalcortex
Decreased Cholinergic Activity Associated With Neuropathology of AD, DLB, and PD
Ch
AT
(n
mo
l/h/m
gP
)
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
Campbell, Stephens, Ballard, 2001.
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%)
Dementia With Lewy Bodies (cont’d)
DLB is underdiagnosed and may constitute 15% of all dementias
Supportive Features
Transient loss of consciousness 40%
Falls and syncope 50%
Systematized delusions 70%
Neuroleptic sensitivity 50%
Depression 50%
REM sleep behavior disorder 25%
*
**
*
*P<.05Ballard C, Walker M. Curr Psychiatry Rep. 1999(Oct);1(1):49-60
0
10
20
30
40
50
60
70
80 DLBAD
Visual
Hallu
cinat
ions
Auditory
Hallu
cinat
ions
Delusi
ons
Mis
iden
tific
atio
n
Depre
ssio
n
Per
cen
tag
e o
f P
atie
nts
Per
cen
tag
e o
f P
atie
nts
wit
h S
ymp
tom
sw
ith
Sym
pto
ms
Neuropsychiatric Symptoms in DLB vs AD
Ranked by Frequency of Occurrence (% of Patients)
McKeith IG, Ballard CG, Perry RH, et al. Neurology. 2000(March 14);54(5):1050-1058
Apathy/indifference 72.5 Appetite; eating disorder 34.2Anxiety 70.0 Elation/euphoria 18.3Depression/dysphoria 65.8 Disinhibition 16.7Delusions 58.3Agitation/aggression 55.0Irritability/lability 55.0Aberrant motor behavior 53.3
Symptoms in >50% of Patients (%) Symptoms in <50% of Patients (%)
Behavioral Symptoms at Baseline (NPI)
0
1
2 AD (n=12)
DLB (n=4)
Ave
rag
e B
EH
AV
E-A
D
Sco
re
Baseline 6 months Baseline 6 months
P=NS
P=NS
0
1
2
Incr
ease
in
M
MS
E S
core
AD DLB
3
4
5
P=NS
P=NS
NS=nonsignificantSamuel, et al, 2000.
Behavioral and Cognitive Responses to Donepezil in AD and DLB (Open-label, 5 mg/d for 6 Months)
*P<.01 vs placebo; **P<.001 vs placebo†Responder definition recommended by NPI author (J Cummings)Adapted from McKeith, et al, 2000.
Baseline
Imp
rove
men
t
NPI 10-Item Score
*
Mea
n C
han
ge
fro
m B
asel
ine
–8
–7
–6
–5
–4
–3
–2
–1
0
Rivastigmine
Placebo
12 20
Weeks Rivastigmine 3–12 mg/d (n=59)Placebo (n=61)
NPI 10-Item Score—Percentage of Patients Improving by 30% from Baseline†
* *70
60
50
40
30
20
10
0
Pat
ien
ts Im
pro
vin
g (
%)
Week 20
Effects of Rivastigmine on Behavioral Symptoms in DLB (Double Blind)
Perry, et al, 1985; Korczyn, 2001.
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
Baseline
Rivastigmine 3–12 mg/d
*P<.02; **P<.015; OC analysisReading PJ, Luce AK, McKeith IG. Mov Disord. 2001(Nov);16(6):1171-1174
8
6
4
2
0
NP
I H
allu
cin
atio
n a
nd
Sle
ep S
core
s
IncreasingSymptoms
*
N=12
N=12
**
8
6
4
2
0Hallucination Sleep
NPI Hallucination and Sleep Scores in PD Patients Receiving Rivastigmine
*
**
*P<.05; **P<.01 vs baseline; OC analysis; Reading PJ, Luce AK, McKeith IG. Mov Disord. 2001(Nov);16(6):1171-1174
0
5
10
15
20
25
30
35
MMSE UPDRS
10
15
20
25
30
35
Imp
rove
men
t
Imp
rove
men
t0
2
4
6
8
10
12
NPI Caregiver Distress
0
5Im
pro
vem
ent
Baseline
Rivastigmine 3–12 mg/d
Rivastigmine in PD: Cognition, Motor Function, and Caregiver Burden
Effects of Rivastigmine Treatment on ADAS-Cog and UPDRS Motor Scores in PDD
N=28*P=.004 vs baseline Giladi, et al, 2003.
Baseline Week 12 Week 26
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 P
Naming 0.05
Recognition 0.007
Word finding 0.02
Remembering instructions 0.008
Concentration 0.0005
Effects of Rivastigmine Treatment on Clinical Global Impression of Change from Baseline
*P<.0001CGIC=clinical global impression of changeCGIC Scale: 3=marked improvement, 2=moderate improvement, 1=mild improvement, 0=no change,-1=mild worsening, -2=moderate worsening, -3=marked worsening; N=28Giladi, et al, 2002.
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*
Emre, 2002.
Reasons to Consider Switching ChE Inhibitors
Switching should be considered whenthere 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
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
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
No
. of
Do
nep
ezil
No
nre
spo
nd
ers
Wh
o R
esp
on
ded
to
Gal
anta
min
e1
Per ADAS-
cog
Per ADCS/ADL
9 8
0
20
40
60
80
100
Side EffectsDonepezil
Group (n=18)
Lack/Loss of Efficacy Group
(N=22)
Pat
ien
ts in
Wh
om
Sw
itch
Was
Ben
efic
ial (
%)2
0
4
8
12
16
20
Changing from Donepezil to Galantamine and Rivastigmine
15.4
74.4
11.5
54.5
Rivastigmine Responders
Auriacombe S, Pere JJ, Loria-Kanza Y, Vellas B. Curr Med Res Opin. 2002;18(3):129-138
Discontinued Rivastigmine
Due to AEs
0
20
40
60
80
Pat
ien
ts (
%)
0
20
40
60
80
Pat
ien
ts (
%)
Lack of efficacy of donepezil (n=304)Unable to tolerate donepezil (n=78)
Rivastigmine Responders
Discontinued Rivastigmine
Due to AEs
Lack of Tolerability and Efficacy With Donepezil Do Not Preclude Response to Rivastigmaine
Emre, 2002; Morris, 2002.
*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.
No washout periodrequired
Washout for 7 days oruntil symptoms resolve
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*
Safety or tolerabilityproblem
Unsatisfactory treatment on donepezil
Patient experiencing lack
of response or loss of efficacy
Donepezil or galantamineto rivastigmine
Donepezil or rivastigmineto galantamine
NO
Is the patient stabilized on
current therapy (ie, no tolerability
problems)?
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
7-day washout is recommended or until symptoms
resolve
Guidelines for Switching ChEIs
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
Reisberg B, Doody R, Stoffler A, et al. N Engl J Med. 2003(April 3);348(14):1333-1341
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
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