Clinical Update: Full Spectrum Treatment of Alzheimers Disease.
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Transcript of Clinical Update: Full Spectrum Treatment of Alzheimers Disease.
Clinical Update: Full Clinical Update: Full Spectrum Treatment of Spectrum Treatment of
Alzheimer’s DiseaseAlzheimer’s Disease
Alzheimer’s DiseaseAlzheimer’s DiseaseEconomic ConsequencesEconomic Consequences
► Third most expensive disease in the U.S.Third most expensive disease in the U.S.
► Costs over Costs over $100 billion$100 billion//yearyear
► Further Further $$3333 billion billion in in lost productivitylost productivity and other employer costsand other employer costs
► 3/4 of patients admitted to residential care 3/4 of patients admitted to residential care within 5 years of diagnosiswithin 5 years of diagnosis
Evans DA, Scherr PA, Smith LA, et al. Aging (Milano). 1990(Sept);2(3):298-302; Ernst RL, Hay JW. Am J Public Health. 1994(Aug);84(8):1261-1264; Alzheimer’s Association, 2002
Growth of the ProblemGrowth of the Problem
Alzheimer’s Prevalencein the U.S. by Age (1997)
Projected Dementia Patients in the U.S. (in Millions)
70
50
30
10
45 55 65 75 85 90
Pe
rce
nta
ge
2000 2010 2020 2030 20402050
4.05.8 6.8
8.7
11.8
14.3
Age (Years) Year
Guttman R, Altman RD, Nielsen NH. Arch Fam Med. 1999(July-Aug);8(4):347-353
0
Suggested Diagnostic Suggested Diagnostic Workup for DementiaWorkup for Dementia
► Diagnostic interview: Both the patient and a reliable Diagnostic interview: Both the patient and a reliable informantinformant
► Office-based clinical assessmentOffice-based clinical assessment Comprehensive physical examinationComprehensive physical examination Neurologic and mental status evaluationNeurologic and mental status evaluation Brief quantified cognitive function evaluation Brief quantified cognitive function evaluation
(MMSE)(MMSE)
► Laboratory evaluation and imaging: CBC, chemistries, liver Laboratory evaluation and imaging: CBC, chemistries, liver function, thyroid, vitamin Bfunction, thyroid, vitamin B12;12; CT head scan or non contrast CT head scan or non contrast MRIMRI
► Neuropsychologic testing or functional scan (PET) if Neuropsychologic testing or functional scan (PET) if diagnosis is uncleardiagnosis is unclear
Alva, Clin Geriatr Med 19 (2003)763-776
The Stages of Alzheimer’s DiseaseThe Stages of Alzheimer’s Disease
Mild Moderate Severe
Memory LossLanguage ProblemsMood and Personality ChangesDiminished Judgment
Behavioral, Personality ChangesUnable to Learn or Recall New InformationLong-Term Memory AffectedWandering, Agitation, Aggression, ConfusionRequire Assistance with ADLs
Unstable GaitIncontinenceMotor DisturbancesBedriddenDysphagiaMutePoor/No ADLsVacant
LTC Placement Common
Stage
Symptoms
ADL = activities of daily living ADL = activities of daily living LTC = long-term careLTC = long-term care
AP = amyloid plaques; NFT = neurofibrillary tangles
Courtesy of George T. Grossberg M.D.; St. Louis University
Neuropathological ChangesNeuropathological ChangesCharacteristic of ADCharacteristic of AD
Normal
AP
AD
NFT
AD
AS
-Co
g M
ean
C
ha
ng
e f
rom
Ba
sel
ine
Decline in ADAS-Cog scorebased on the natural history ofuntreated patients with moderate AD*
-6
0
6
12
180 6 12 14 26 38 50 62 74 85 98
Improvement
Decline
Model-Based Analysis: ADAS-Cog Score Model-Based Analysis: ADAS-Cog Score Mean Change from BaselineMean Change from Baseline
N=133
Rogers and Friedhoff, 1998; *Stern et al, 1994Rogers and Friedhoff, 1998; *Stern et al, 1994
Cognitive Decline in AD Correlates Cognitive Decline in AD Correlates with Rate of Cerebral Atrophywith Rate of Cerebral Atrophy
y = 0.48x + 0.34r = 0.8
Fall in MMSE Score
Lo
ss o
f B
rain
Vo
lum
e (
%)
Fox, DRG98
12
10
8
6
4
2
00 2 4 6 8 10 12 14 16 18
UCI Brain Imaging CenterUCI Brain Imaging Center
Alzheimer’s Disease Normal Control
DecreasedTemporoparietal
OccipitalLobe
Cerebellum 0.00 19.36
FrontalLobe
mg/100g/min
Management of the AD PatientManagement of the AD Patient
► Maintain quality of lifeMaintain quality of life
► Maximize functionMaximize function
► Stabilize cognitionStabilize cognition
► Treat mood and behavior problemsTreat mood and behavior problems
► Ease caregiver burdenEase caregiver burden
Source: Cefalu C, Grossberg GT. Diagnosis and Management of Dementia. American Family Physician Monograph, No. 2. Leawood, Kan: American Academy of Family Physicians; 2001.
Treatment GoalsTreatment Goals
Treatment Consideration:Treatment Consideration:When to Begin?When to Begin?
► Current guidelines (AAN) recommend that all Current guidelines (AAN) recommend that all patients with AD be treated at time of diagnosispatients with AD be treated at time of diagnosis
Well established rationale for ChEI treatment in patients Well established rationale for ChEI treatment in patients diagnosed with mild or moderate AD diagnosed with mild or moderate AD
Well established rationale for treating patients diagnosed Well established rationale for treating patients diagnosed with moderate to severe AD with memantinewith moderate to severe AD with memantine
Patients with severe AD have been shown to benefit from Patients with severe AD have been shown to benefit from treatmenttreatment1-31-3
► Establish realistic expectations of treatmentEstablish realistic expectations of treatment
Sources: 1. Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146. 2. Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. 3. Tariot P, et al. J Am Geriatr Soc. 2003;51(S4):S225-S226.
Neurotransmitter Basis for Current Neurotransmitter Basis for Current Dementia Drug Treatment InterventionsDementia Drug Treatment Interventions
► Acetylcholine and glutamate are 2 neurotransmitter Acetylcholine and glutamate are 2 neurotransmitter systems known to be important in learning and systems known to be important in learning and memorymemory
AcetylcholineAcetylcholine
Cholinergic neurons are lost in ADCholinergic neurons are lost in AD
Theory:Theory: increase available acetylcholine to improve or increase available acetylcholine to improve or maintain cognitive functionmaintain cognitive function
GlutamateGlutamate
Excessive or erratic glutamate stimulation impairs Excessive or erratic glutamate stimulation impairs learning and can cause neuronal toxicity learning and can cause neuronal toxicity
Theory:Theory: normalize glutamatergic neurotransmission to normalize glutamatergic neurotransmission to maintain or improve cognition and prevent maintain or improve cognition and prevent neurotoxicityneurotoxicity
ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor
Adapted from: Adem, 1992
Normal Cholinergic FunctionNormal Cholinergic Function
PostsynapticNeuron
AChE
AcetylCoA
CholineACh
Presynaptic Neuron
SynapticCleft
Cholinergic Receptors
Acetate
CholineCholine+
+
Astrocyte
AChACh
AChE
BuChE
BuChE
ChAT
Noncholinergic Action
MR NR MR NR
NR
MR
Pharmacotherapy for Mild to ModeratePharmacotherapy for Mild to ModerateAlzheimer’s DiseaseAlzheimer’s Disease
FDA Approved:FDA Approved:► Cholinesterase inhibitors (ChEIs)Cholinesterase inhibitors (ChEIs)
TacrineTacrine DonepezilDonepezil Galantamine Galantamine Rivastigmine Rivastigmine Monotherapy as standard treatmentMonotherapy as standard treatment
New Developments in Mild AD:New Developments in Mild AD:► NMDA-receptor antagonist (memantine)NMDA-receptor antagonist (memantine)
– MonotherapyMonotherapy Combination TherapyCombination Therapy
Important Considerations in Important Considerations in Alzheimer’s Disease Treatment*Alzheimer’s Disease Treatment*
Galantamine
Plasma protein binding
Rivastigmine
40%
Donepezil
96% 18%
NoneKnown†
No
ketoconazole, quinidine, and
other drugs metabolized by CYP2D6/3A4
None stated
amitriptyline, cimetidine, erythromycin, fluoxetine,
fluvoxamine, ketoconazole, paroxetine, quinidine, and other drugs
metabolized by CYP2D6/3A4
Yes
Listed drug-druginteractions
Dosage adjustment required for renal/hepatic impairment
Memantine
45%
carbonic anhydrase
inhibitors, sodium bicarbonate
Yes
Metabolism
Elimination pathway
Not Hepatic CYP450 CYP450 Partially Hepatic
Kidney(inactive
metabolite)
Liver50% Kidney50% Liver Kidney
*Data as listed in US prescribing information for rivastigmine, donepezil, galantamine, and memantine.†Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by CYP1A2, 2D6, 3A4/5, 2E1, 2C9, 2C8, or 2C19 are expected.
ChEI Monotherapy in MildChEI Monotherapy in Mildto Moderate AD: Efficacyto Moderate AD: Efficacy
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
.2
.1
0
–.1
–.2
–.3
–.4
–.512 18 26
†
**
*
Week
PlaceboRivastigmine 1- 4 mgRivastigmine 6-12 mg
Global: CIBIC-PlusGlobal: CIBIC-Plus22
RivastigmineRivastigmine
Imp
rov
em
en
tIm
pro
ve
me
nt
De
clin
eD
ec
line
Time (Months)
–4
–2
0
–5
–3
–1
1
1 2 3 4 5
Galantamine 8 mg/dayGalantamine 16 mg/dayGalantamine 24 mg/dayPlacebo
†
†
Function: ADCS-ADLFunction: ADCS-ADL33
GalantamineGalantamine
*P<.05; †P<.01; ‡P≤.001.CIBIC-Plus = Clinician's Interview-Based Impression of Change with caregiver input; ADCS-ADL = Alzheimer's Disease Cooperative Study – Activities of Daily Living inventory.
Sources: 1. Winblad B, et al. Neurology. 2001;57:489-495. (Data represent change in least squares [LS] mean) 2. Corey-Bloom J, et al. Int J Geriatr Psychopharmacol. 1998;1550:55-65 3. Tariot PN, et al. Neurology. 2000;54:2269-2276
Cognition: MMSECognition: MMSE11
DonepezilDonepezil
–2.5
–2.0
–1.5
–1.0
–0.5
0
0.5
1.0
Donepezil
Placebo
Week52362412
‡
0 LOCF
‡
*‡
(LS
)(L
S)
ChEI Drug-Drug and ChEI Drug-Drug and Drug-Disease Interactions Drug-Disease Interactions
► PharmacodynamicPharmacodynamic Digoxin, Digoxin, ββ blockers — blockers — ChEIs may exert vagotonic ChEIs may exert vagotonic
effects on sinoatrial and atrioventricular nodeseffects on sinoatrial and atrioventricular nodes ChEIs may exaggerate succinylcholine-type muscle ChEIs may exaggerate succinylcholine-type muscle
relaxation during anesthesiarelaxation during anesthesia Concurrent anticholinergic or cholinergic Concurrent anticholinergic or cholinergic
pharmacotherapypharmacotherapy
► PharmacokineticPharmacokinetic None None — — rivastigminerivastigmine Minimal Minimal — — donepezildonepezil Moderate Moderate — — galantamine + CYP450 inhibitors (2D6, galantamine + CYP450 inhibitors (2D6,
3A4)3A4)
► Renal impairmentRenal impairment Clearance of galantamine decreased in renal Clearance of galantamine decreased in renal
insufficiencyinsufficiency
Source: Bentué-Ferrer D, et al. CNS Drugs. 2003;17:947-963.
Treatment Consideration: When to Treatment Consideration: When to Increase Dose or Switch Agents?Increase Dose or Switch Agents?
► Dose escalation may need to be slower than Dose escalation may need to be slower than suggested in suggested in Physicians’ Desk ReferencePhysicians’ Desk Reference
► Side effects to treatment are justifiableSide effects to treatment are justifiablereasons to switchreasons to switch
► Typically, switching ChEIs can be doneTypically, switching ChEIs can be donewithout washout period and with shorter titration without washout period and with shorter titration periodsperiods
► Evidence shows that memantine, a non-Evidence shows that memantine, a non-cholinergic agent, is effective as monotherapy cholinergic agent, is effective as monotherapy and in combination therapy with a ChEIand in combination therapy with a ChEI1,21,2
Sources: 1. Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. 2. Tariot P, et al. JAMA. 2004;291:317-324.
Treatment Consideration: Treatment Consideration: When to Stop?When to Stop?
► May not tolerate cholinergic side effects May not tolerate cholinergic side effects despite slow and careful escalationdespite slow and careful escalation
► When medication is prescribed, give it When medication is prescribed, give it time to work; gauge different domainstime to work; gauge different domains
► Establishing benefit in an individual patient Establishing benefit in an individual patient may be influenced by their stagingmay be influenced by their staging
► Studies suggest that most subjects benefit and Studies suggest that most subjects benefit and that long-term treatment is usefulthat long-term treatment is useful
► May see some deterioration when medication May see some deterioration when medication is stopped is stopped
MemantineMemantine in Mild to Moderate AD: in Mild to Moderate AD: Clinical TrialsClinical Trials
Monotherapy Trials:Monotherapy Trials:
US 24-week trialUS 24-week trial Statistically significant advantage of Statistically significant advantage of
memantine over placebo at end point on memantine over placebo at end point on cognitive and global measurescognitive and global measures
European 24-week trialEuropean 24-week trial Numerical advantage at end point for Numerical advantage at end point for
memantine (not statistically significant) over memantine (not statistically significant) over placebo for cognitive and global measuresplacebo for cognitive and global measures
Combination Therapy TrialsCombination Therapy Trials: :
US 24-week trial of patients on stable ChEI therapyUS 24-week trial of patients on stable ChEI therapyNumerical advantage at end point of Numerical advantage at end point of
memantine over placebo for cognitive, memantine over placebo for cognitive, functional, and global measures (not functional, and global measures (not statistically significant)statistically significant)
Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; September 4-7, 2004; Paris, France. September 4-7, 2004; Paris, France.
Declin
eD
ecline
Memantine Monotherapy in Mild to Memantine Monotherapy in Mild to Moderate AD: US 24-Week Trial ResultsModerate AD: US 24-Week Trial Results
Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; September 4-7, 2004; Paris, France. September 4-7, 2004; Paris, France.
Cognition: ADAS-CogCognition: ADAS-Cog
Imp
rovem
en
tIm
pro
veme
nt
LS
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
(S
E)
LS
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
(S
E)
*.003*.003 *.009*.009*.003*.003
*.002*.002
44 88 1212 1818 2424
-3-3
-2-2
-1-1
00
11
22
33
Treatment WeekTreatment Week
MemantineMemantinePlaceboPlacebo
195195 195195 195195 195195 191191n = 195n = 195198198 198198 198198 197197 195195n = 198n = 198
00
Imp
rovem
en
tIm
pro
veme
nt
Declin
eD
ecline
Treatment WeekTreatment Week
Me
an
Sc
ore
(S
E)
Me
an
Sc
ore
(S
E)
Global Change: Global Change: CIBIC-PlusCIBIC-Plus
44 88 1212 1818 2424
*.021*.021 *.024*.024*.015*.015
*.004*.004
3.53.5
44
4.54.5
55
MemantineMemantine
PlaceboPlacebo
196196 196196 196196 196196n = 194n = 194197197 197197 197197 197197n = 197n = 197
Intention-to-treat (ITT) population; last observation carried forward (LOCF); *P value for LS mean difference (memantine vs placebo)
Memantine/Rivastigmine CombinationMemantine/Rivastigmine CombinationTherapy in Mild to Moderate AD*Therapy in Mild to Moderate AD*
DesignDesign
► Multicenter (20), open-label, single-arm, Multicenter (20), open-label, single-arm,
historically controlled historically controlled
PopulationPopulation
► 95 outpatients with mild to moderate AD 95 outpatients with mild to moderate AD
(MMSE, 10-29) on stable rivastigmine (MMSE, 10-29) on stable rivastigmine
TreatmentTreatment
► Memantine 20 mg/d (10 mg bid) 4-week Memantine 20 mg/d (10 mg bid) 4-week
titrationtitration
(5 10 15 20 mg)(5 10 15 20 mg)
Duration:Duration: 12 weeks12 weeks
Assessments - Assessments - Primary: Primary: ADAS-CogADAS-Cog
*Memantine is not indicated for the treatment of mild AD. ADAS-Cog = Alzheimer’s Disease Assessment Scale–Cognitive Subscale.
Source: Riepe MW, et al. 17th U.S. Psychiatric and Mental Health Congress Research Abstract Presentation Book; Volume 1, #74, page 20; November 17-20, 2004; San Diego, Calif.
00
55
1010
1515
2020
2525
3030
-12-12 -8-8 -4-4 00 +4+4 +8+8
Change in ADAS-Cog Memory ScoreChange in ADAS-Cog Memory Score
Nu
mb
er o
f P
atie
nts
Nu
mb
er o
f P
atie
nts
Memantine Adverse EventsMemantine Adverse Events
► No clinically relevant differences between No clinically relevant differences between memantine- and placebo-treated groups were memantine- and placebo-treated groups were observed in: observed in:
Adverse event profileAdverse event profile Vital signs valuesVital signs values Laboratory parametersLaboratory parameters ECG valuesECG values
► Memantine at a dosage of 20 mg/d Memantine at a dosage of 20 mg/d Exhibits a safety profile similar to that of placeboExhibits a safety profile similar to that of placebo Is well tolerated and safe for the treatment of Is well tolerated and safe for the treatment of
patients with ADpatients with AD
Memantine: Drug-Drug and Memantine: Drug-Drug and Drug-Disease InteractionsDrug-Disease Interactions
► PharmacokineticPharmacokinetic Clearance via filtration Clearance via filtration andand secretion secretion——decreased renal decreased renal
clearance at alkaline urine pHclearance at alkaline urine pHPotential for decreased renal clearance drugs Potential for decreased renal clearance drugs
that undergo tubular secretion, eg, amantadine, that undergo tubular secretion, eg, amantadine, cimetidine, ranitidine, etc.cimetidine, ranitidine, etc.
Reduced bioavailability of hydrochlorothiazide (Reduced bioavailability of hydrochlorothiazide (↓↓20%) 20%)
► PharmacodynamicPharmacodynamic Avoid use with other NMDA antagonists: amantadine, Avoid use with other NMDA antagonists: amantadine,
ketamine, dextromethorphanketamine, dextromethorphan No interactions with ChEIs No interactions with ChEIs
► Renal ImpairmentRenal Impairment Consider decreased dose in moderate renal impairment; Consider decreased dose in moderate renal impairment;
memantine is not recommended in severe renal impairment memantine is not recommended in severe renal impairment
Sources: Guay D. The Consultant Pharmacist. 2003;18:625-634; Hartmann S, Mobius HJ. Int Clin Psychopharmacol. 2003;18:81-85; Namenda (memantine) package insert. Forest Laboratories, Inc.
Behavioral Symptoms in ADBehavioral Symptoms in AD
► CommonCommon
► Occur early in the diseaseOccur early in the disease
► May be part of the disease prodromeMay be part of the disease prodrome
► Symptoms emerge as disease progressesSymptoms emerge as disease progresses
► Once present, symptoms tend to persistOnce present, symptoms tend to persist
► Multiple types of symptoms that may occur Multiple types of symptoms that may occur simultaneously (eg, hallucinations, delusions, simultaneously (eg, hallucinations, delusions, depression, euphoria, agitation, aggression, depression, euphoria, agitation, aggression, abnormal vocalization, wandering, overactivity, abnormal vocalization, wandering, overactivity, sexual disinhibition, sleep disturbances,sexual disinhibition, sleep disturbances,and apathy)and apathy)
Interventions for Dementia-Related Interventions for Dementia-Related Behavioral SymptomsBehavioral Symptoms
NonpharmacologicNonpharmacologic
► Remove triggerRemove trigger
► Caregiver/familyCaregiver/familyeducationeducation
► Caregiver supportCaregiver support
► Increase staffing ratioIncrease staffing ratio
► Activity programsActivity programs
► Adult day careAdult day care
PharmacologicPharmacologic
► AntidepressantsAntidepressants
► Mood stabilizersMood stabilizers
► Antipsychotics*Antipsychotics*
► CholinesteraseCholinesteraseinhibitors inhibitors
► NMDA-receptor antagonist NMDA-receptor antagonist (memantine)(memantine)
*Public health advisory from FDA (April 2005): Clinical trials of antipsychotic drugs to treat behavioral disorders in elderly patients with dementia have shown a higher death rate compared to placebo. Specific causes of death were primarily due to heart-related events (eg, heart failure, sudden death) or infections (mostly pneumonia)
Effects of Galantamine on BehaviorsEffects of Galantamine on Behaviors
*p<0.05 vs. placebo; N=978
Tariot PN, Solomon PR, Morris JC, et al. Neurology. 2000(June 27); 54(12):2269-2276
Ch
an
ge
in N
PI S
core
Me
an (
± S
EM
) fr
om
Bas
elin
eImprovement
Deterioration
Baseline 1 2 3 4 5
-2
-1
0
1
2
3
4
5
Time (Weeks)
*
PlaceboGalantamine 8 mg/dayGalantamine 16 mg/dayGalantamine 24 mg/day
Pharmacotherapy for ModeratePharmacotherapy for Moderateto Severe Alzheimer’s Disease to Severe Alzheimer’s Disease
FDA Approved:FDA Approved:
► Memantine Memantine MonotherapyMonotherapy Combination TherapyCombination Therapy
New Developments in Severe AD:New Developments in Severe AD:
► ChEIsChEIs MonotherapyMonotherapy Combination TherapyCombination Therapy
Increased Probability of Increased Probability of Institutionalization by Disease SeverityInstitutionalization by Disease Severity
Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):351-360
Pro
bab
ility
of
Inst
itu
tio
na
liza
tio
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
Effects of Donepezil on Behaviors in Effects of Donepezil on Behaviors in Nursing Home Patients at Week 24Nursing Home Patients at Week 24
ImprovementPlacebo (N=105)
Donepezil (N=103)
Mea
n C
han
ge
fro
m B
asel
ine
NP
I-N
H I
nd
ivid
ual
Ite
m
Sco
re a
t W
eek
24
Del
usio
nsH
allu
cina
tions
Agi
tatio
n/A
ggre
ssio
n
Dep
ress
ion/
Dys
phor
iaA
nxie
tyE
latio
n/E
upho
ria
Apa
thy/
Indi
ffer
ence
Dis
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nIr
rita
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y/La
bilit
y
Abe
rran
t Mot
or B
ehav
ior
Nig
httim
e B
ehav
ior
App
etite
/Eat
ing
*
Baseline
Decline
-3
-2
-1
0
1
2
3
4
*p<0.05 vs. placebo, secondary analysis ITT, LOCF analysis
Tariot PN, Cummings JL, Katz IR, et al. J Am Geriatr Soc. 2001;49:1590-1599
* *
* *** *
*
Behavioral Improvement with Rivastigmine: Behavioral Improvement with Rivastigmine: NPI-Mean Change from BaselineNPI-Mean Change from Baseline
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0
Agitation
Irritability
Anxiety
Aberr. Motor B
ehavior
Apathy
Depression
Delusions
Disinhibition
Hallucinations
Euphoria
Nighttime Behavior
Appetite
Mea
n C
han
ge
fro
m B
asel
ine
*p<0.05 vs. baseline; **p<0.001 vs. baseline; Baseline MMSE = 9.2; OC analysis; N=98; Anand R, Kourmaras B, Hartman RD. Neurobiol Aging. 2000;21:S220; Cummings J. Presented at the American
Academy of Neurology. San Diego, Calif; April 26- May 6, 2000 (Poster presentation)
Imp
rovem
ent
26-Week U.S. Nursing Home Study
Memantine/Donepezil Combination Therapy in Memantine/Donepezil Combination Therapy in Moderate to Severe AD: EfficacyModerate to Severe AD: Efficacy
Source: Tariot P, et al. JAMA. 2004;291:317-324.
n =n =
Placebo + Donepezil
Memantine + Donepezil
Treatment Week
Me
an
Ch
an
ge
Fro
m
Ba
se
lin
e i
n S
IB
Sc
ore
Imp
rov
em
en
tD
ec
line
P<.001 P<.001
P=.006
P<.001
P=.03
P=.06
198198 197197 190190 185185 181181 171171 198198n =n = 197197 194194 180180 169169 164164 153153 196196
Design• US phase 3, multicenter
(37), randomized, double-blind, placebo-controlled study
Population• 404 outpatients with
moderate to severe AD on stable donepezil
• MMSE range, 5-14
Treatment• Memantine 20 mg/d
(10 mg bid) 4-week titration (5101520 mg)
Duration• 24 weeks
Cognition—SIBCognition—SIB
-4
-3
-2
-1
0
1
2
3
4
0 4 8 12 18 24 End Point(LOCF)
LOCF analysis; *P=.045; **P=.005; ***P=.001
Source: Cummings J, et al. Presented at: 56th Annual Meeting of the American Academy of Neurology; April 24–May 1, 2004; San Francisco, Calif.
Memantine in Patients Receiving Memantine in Patients Receiving Ongoing Donepezil: BehaviorOngoing Donepezil: Behavior
Del
usio
ns
Del
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nsH
allu
cina
tions
Hal
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gita
tion/
Agi
tatio
n/
Agg
ress
ion
Agg
ress
ion
Dep
ress
ion/
Dep
ress
ion/
Dys
phor
ia
Dys
phor
ia
Anx
iety
Anx
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Elat
ion/
Euph
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Elat
ion/
Euph
oria
Apa
thy/
Indi
ffere
nce
Apa
thy/
Indi
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nce
Dis
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n
Dis
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itabi
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1.01.0
0.80.8
0.60.6
0.40.4
0.20.2
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-0.2-0.2
-0.4-0.4 **********
**MemantinePlaceboNPI Single-Item DomainsNPI Single-Item Domains
Tolerability of Memantine/Donepezil Tolerability of Memantine/Donepezil Combination TherapyCombination Therapy
*Adverse events reported in 5% of either treatment group. Source: Tariot P, et al. JAMA. 2004;291:317-324.
Placebo + DonepezilPlacebo + Donepezil(n=201) n (%)(n=201) n (%)
17 (8.5)17 (8.5)
8 (4.0)8 (4.0)
14 (7.0)14 (7.0)
13 (6.5)13 (6.5)
4 (2.0)4 (2.0)
6 (3.0)6 (3.0)
16 (8.0)16 (8.0)
10 (5.0)10 (5.0)
10 (5.0)10 (5.0)
13 (6.5)13 (6.5)
5 (2.5)5 (2.5)
16 (8.0)16 (8.0)
24 (11.9)24 (11.9)
DiarrheaDiarrhea
Peripheral edemaPeripheral edema
FallFall
Influenza-like symptomsInfluenza-like symptoms
ConfusionConfusion
Urinary incontinenceUrinary incontinence
Accidental injuryAccidental injury
Fecal incontinenceFecal incontinence
Urinary tract infectionUrinary tract infection
Upper respiratory tract infectionUpper respiratory tract infection
HeadacheHeadache
DizzinessDizziness
Memantine + Memantine + DonepezilDonepezil
(n=202) n (%)(n=202) n (%)
9 (4.5)9 (4.5)
10 (5.0)10 (5.0)
15 (7.4)15 (7.4)
15 (7.4)15 (7.4)
16 (7.9)16 (7.9)
11 (5.4)11 (5.4)
10 (5.0)10 (5.0)
4 (2.0)4 (2.0)
12 (5.9)12 (5.9)
10 (5.0)10 (5.0)
13 (6.4)13 (6.4)
14 (6.9)14 (6.9)
19 (9.4)19 (9.4)AgitationAgitation
Adverse Event*Adverse Event*
Evaluating ResponseEvaluating Response► Assess:Assess:
At baselineAt baseline
After reaching maximal tolerated dose After reaching maximal tolerated dose
Every 6 – 12 monthsEvery 6 – 12 months
If change in statusIf change in status
► Family/Patient/Nursing interviewFamily/Patient/Nursing interview
► Documentation in medical recordDocumentation in medical record Cooperation in activities, tolerance of groupsCooperation in activities, tolerance of groups
ADL abilities & tolerance with assistanceADL abilities & tolerance with assistance
Eating, toileting, dressing, showering, etc. Eating, toileting, dressing, showering, etc.
Routine and psychotropic medication usageRoutine and psychotropic medication usage
SummarySummary
► AD is an expensive illness in human and AD is an expensive illness in human and economic terms for patients, their caregivers, and economic terms for patients, their caregivers, and society.society.
► Diagnosis is often not made, especially in earlyDiagnosis is often not made, especially in earlyand mild AD; clinical nihilism can interfere with and mild AD; clinical nihilism can interfere with initiating or sustaining treatment. The long term initiating or sustaining treatment. The long term setting brings additional clinical challenges.setting brings additional clinical challenges.
► Cholinesterase inhibitors and NMDA receptor Cholinesterase inhibitors and NMDA receptor antagonists attenuate symptomatic decline and antagonists attenuate symptomatic decline and may modify disease progression.may modify disease progression.
► Early treatment pays off; delaying treatment has Early treatment pays off; delaying treatment has long-term consequences.long-term consequences.
► ChEls (mild to moderate AD) and memantine ChEls (mild to moderate AD) and memantine (moderate to severe AD) monotherapies are (moderate to severe AD) monotherapies are associated with less decline (vs placebo) in associated with less decline (vs placebo) in cognition and functioncognition and function
► Although not indicated, newer data support a role Although not indicated, newer data support a role for memantine in mild AD and ChEIs in severe ADfor memantine in mild AD and ChEIs in severe AD
► In moderate to severe AD, patients treated with In moderate to severe AD, patients treated with combination therapy (ie, memantine + ChEIs) combination therapy (ie, memantine + ChEIs) exhibited improved cognitive outcomes and exhibited improved cognitive outcomes and delayed functional decline (vs patients treated with delayed functional decline (vs patients treated with ChEI only)ChEI only)
SummarySummary