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Optimizing Outcomes in Patients with Alzheimer's Disease and ...


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Optimizing Outcomes in Patients with Alzheimer's Disease and ...

  1. 1. Clinical Update: FullClinical Update: Full Spectrum Treatment ofSpectrum Treatment of Alzheimer’s DiseaseAlzheimer’s Disease
  2. 2. Alzheimer’s DiseaseAlzheimer’s Disease Economic ConsequencesEconomic Consequences ► Third most expensive disease in the U.S.Third most expensive disease in the U.S. ► Costs overCosts over $100 billion$100 billion//yearyear ► FurtherFurther $$3333 billionbillion inin lost productivitylost productivity and other employer costsand other employer costs ► 3/4 of patients admitted to residential care3/4 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
  3. 3. Growth of the ProblemGrowth of the Problem Alzheimer’s Prevalence in 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 Percentage 2000 2010 2020 2030 2040 2050 4.0 5.8 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
  4. 4. Suggested DiagnosticSuggested Diagnostic Workup for DementiaWorkup for Dementia ► Diagnostic interview: Both the patient and a reliableDiagnostic 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 evaluationBrief quantified cognitive function evaluation (MMSE)(MMSE) ► Laboratory evaluation and imaging: CBC, chemistries, liverLaboratory evaluation and imaging: CBC, chemistries, liver function, thyroid, vitamin Bfunction, thyroid, vitamin B12;12; CT head scan or non contrastCT head scan or non contrast MRIMRI ► Neuropsychologic testing or functional scan (PET) ifNeuropsychologic testing or functional scan (PET) if diagnosis is uncleardiagnosis is unclear Alva, Clin Geriatr Med 19 (2003)763-776
  5. 5. The Stages of Alzheimer’s DiseaseThe Stages of Alzheimer’s Disease Mild Moderate Severe Memory Loss Language Problems Mood and Personality Changes Diminished Judgment Behavioral, Personality Changes Unable to Learn or Recall New Information Long-Term Memory Affected Wandering, Agitation, Aggression, Confusion Require Assistance with ADLs Unstable Gait Incontinence Motor Disturbances Bedridden Dysphagia Mute Poor/No ADLs Vacant LTC Placement Common Stage Symptoms ADL = activities of daily livingADL = activities of daily living LTC = long-term careLTC = long-term care
  6. 6. AP = amyloid plaques; NFT = neurofibrillary tangles Courtesy of George T. Grossberg M.D.; St. Louis University Neuropathological ChangesNeuropathological Changes Characteristic of ADCharacteristic of AD Normal AP AD NFT
  7. 7. ADAS-CogMean ChangefromBaseline Decline in ADAS-Cog score based on the natural history of untreated patients with moderate AD* -6 0 6 12 18 0 6 12 14 26 38 50 62 74 85 98 Improvement Decline Model-Based Analysis: ADAS-Cog ScoreModel-Based Analysis: ADAS-Cog Score Mean Change from BaselineMean Change from Baseline N=133 Rogers and Friedhoff, 1998; *Stern et al, 1994
  8. 8. Cognitive Decline in AD CorrelatesCognitive Decline in AD Correlates with Rate of Cerebral Atrophywith Rate of Cerebral Atrophy y = 0.48x + 0.34 r = 0.8 Fall in MMSE Score LossofBrainVolume(%) Fox, DRG98 12 10 8 6 4 2 0 0 2 4 6 8 10 12 14 16 18
  9. 9. UCI Brain Imaging CenterUCI Brain Imaging Center Alzheimer’s Disease Normal Control Decreased Temporoparietal Occipital Lobe Cerebellum 0.00 19.36 Frontal Lobe mg/100g/min
  10. 10. 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
  11. 11. Treatment Consideration:Treatment Consideration: When to Begin?When to Begin? ► Current guidelines (AAN) recommend that allCurrent 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 patientsWell established rationale for ChEI treatment in patients diagnosed with mild or moderate ADdiagnosed with mild or moderate AD Well established rationale for treating patients diagnosedWell 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 fromPatients 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.
  12. 12. Neurotransmitter Basis for CurrentNeurotransmitter Basis for Current Dementia Drug Treatment InterventionsDementia Drug Treatment Interventions ► Acetylcholine and glutamate are 2 neurotransmitterAcetylcholine and glutamate are 2 neurotransmitter systems known to be important in learning andsystems 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 orincrease available acetylcholine to improve or maintain cognitive functionmaintain cognitive function GlutamateGlutamate Excessive or erratic glutamate stimulation impairsExcessive or erratic glutamate stimulation impairs learning and can cause neuronal toxicitylearning and can cause neuronal toxicity Theory:Theory: normalize glutamatergic neurotransmission tonormalize glutamatergic neurotransmission to maintain or improve cognition and preventmaintain or improve cognition and prevent neurotoxicityneurotoxicity
  13. 13. 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 Postsynaptic Neuron AChE Acetyl CoA CholineACh Presynaptic Neuron Synaptic Cleft Cholinergic Receptors Acetate CholineCholine + + Astrocyte AChACh AChE BuChE BuChE ChA T Noncholinergic Action MR NR MR NR NR MR
  14. 14. Pharmacotherapy for Mild to ModeratePharmacotherapy for Mild to Moderate Alzheimer’s DiseaseAlzheimer’s Disease FDA Approved:FDA Approved: ► Cholinesterase inhibitors (ChEIs)Cholinesterase inhibitors (ChEIs) TacrineTacrine DonepezilDonepezil GalantamineGalantamine RivastigmineRivastigmine 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
  15. 15. Important Considerations inImportant Considerations in Alzheimer’s Disease Treatment*Alzheimer’s Disease Treatment* Galantamine Plasma protein binding Rivastigmine ≈ 40% Donepezil ≈≈96% 18% None Known† 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-drug interactions 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) Liver 50% Kidney 50% 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.
  16. 16. ChEI Monotherapy in MildChEI Monotherapy in Mild to Moderate AD: Efficacyto Moderate AD: Efficacy MeanChangeFromBaselineMeanChangeFromBaseline .2 .1 0 –.1 –.2 –.3 –.4 –.5 12 18 26 † * * * Week Placebo Rivastigmine 1- 4 mg Rivastigmine 6-12 mg Global: CIBIC-PlusGlobal: CIBIC-Plus22 RivastigmineRivastigmine ImprovementImprovementDeclineDecline Time (Months) –4 –2 0 –5 –3 –1 1 1 2 3 4 5 Galantamine 8 mg/day Galantamine 16 mg/day Galantamine 24 mg/day Placebo † † 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 Week 52362412 ‡ 0 LOCF ‡ * ‡ (LS)(LS)
  17. 17. ChEI Drug-Drug andChEI Drug-Drug and Drug-Disease InteractionsDrug-Disease Interactions ► PharmacodynamicPharmacodynamic Digoxin,Digoxin, ββ blockers —blockers — ChEIs may exert vagotonicChEIs may exert vagotonic effects on sinoatrial and atrioventricular nodeseffects on sinoatrial and atrioventricular nodes ChEIs may exaggerate succinylcholine-type muscleChEIs may exaggerate succinylcholine-type muscle relaxation during anesthesiarelaxation during anesthesia Concurrent anticholinergic or cholinergicConcurrent anticholinergic or cholinergic pharmacotherapypharmacotherapy ► PharmacokineticPharmacokinetic NoneNone —— rivastigminerivastigmine MinimalMinimal —— donepezildonepezil ModerateModerate —— galantamine + CYP450 inhibitors (2D6,galantamine + CYP450 inhibitors (2D6, 3A4)3A4) ► Renal impairmentRenal impairment Clearance of galantamine decreased in renalClearance of galantamine decreased in renal insufficiencyinsufficiency Source: Bentué-Ferrer D, et al. CNS Drugs. 2003;17:947-963.
  18. 18. Treatment Consideration: When toTreatment Consideration: When to Increase Dose or Switch Agents?Increase Dose or Switch Agents? ► Dose escalation may need to be slower thanDose escalation may need to be slower than suggested insuggested in Physicians’ Desk ReferencePhysicians’ Desk Reference ► Side effects to treatment are justifiableSide effects to treatment are justifiable reasons to switchreasons to switch ► Typically, switching ChEIs can be doneTypically, switching ChEIs can be done without washout period and with shorter titrationwithout washout period and with shorter titration periodsperiods ► Evidence shows that memantine, a non-Evidence shows that memantine, a non- cholinergic agent, is effective as monotherapycholinergic 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.
  19. 19. Treatment Consideration:Treatment Consideration: When to Stop?When to Stop? ► May not tolerate cholinergic side effectsMay not tolerate cholinergic side effects despite slow and careful escalationdespite slow and careful escalation ► When medication is prescribed, give itWhen medication is prescribed, give it time to work; gauge different domainstime to work; gauge different domains ► Establishing benefit in an individual patientEstablishing benefit in an individual patient may be influenced by their stagingmay be influenced by their staging ► Studies suggest that most subjects benefit andStudies suggest that most subjects benefit and that long-term treatment is usefulthat long-term treatment is useful ► May see some deterioration when medicationMay see some deterioration when medication is stoppedis stopped
  20. 20. 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 ofStatistically significant advantage of memantine over placebo at end point onmemantine 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 forNumerical advantage at end point for memantine (not statistically significant) overmemantine (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 therapy Numerical advantage at end point ofNumerical advantage at end point of memantine over placebo for cognitive,memantine over placebo for cognitive, functional, and global measures (notfunctional, 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.
  21. 21. DeclineDecline Memantine Monotherapy in Mild toMemantine 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. Cognition: ADAS-CogCognition: ADAS-Cog ImprovementImprovement LSMeanChangeFromBaseline(SE)LSMeanChangeFromBaseline(SE) *.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 MemantineMemantine PlaceboPlacebo 195195195195195195195195191191n = 195n = 195 198198198198198198197197195195n = 198n = 198 00 ImprovementImprovementDeclineDecline Treatment WeekTreatment Week MeanScore(SE)MeanScore(SE) 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 196196196196196196196196n = 194n = 194 197197197197197197197197n = 197n = 197 Intention-to-treat (ITT) population; last observation carried forward (LOCF); *P value for LS mean difference (memantine vs placebo)
  22. 22. Memantine/Rivastigmine CombinationMemantine/Rivastigmine Combination Therapy 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 controlledhistorically controlled PopulationPopulation ► 95 outpatients with mild to moderate AD95 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-weekMemantine 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 NumberofPatientsNumberofPatients →
  23. 23. Memantine Adverse EventsMemantine Adverse Events ► No clinically relevant differences betweenNo clinically relevant differences between memantine- and placebo-treated groups werememantine- 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/dMemantine 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 ofIs well tolerated and safe for the treatment of patients with ADpatients with AD
  24. 24. Memantine: Drug-Drug andMemantine: Drug-Drug and Drug-Disease InteractionsDrug-Disease Interactions ► PharmacokineticPharmacokinetic Clearance via filtrationClearance via filtration andand secretionsecretion——decreased renaldecreased renal clearance at alkaline urine pHclearance at alkaline urine pH Potential for decreased renal clearance drugsPotential 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 ChEIsNo 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 impairmentmemantine 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.
  25. 25. 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 occurMultiple 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)
  26. 26. Interventions for Dementia-RelatedInterventions for Dementia-Related Behavioral SymptomsBehavioral Symptoms NonpharmacologicNonpharmacologic ► Remove triggerRemove trigger ► Caregiver/familyCaregiver/family educationeducation ► Caregiver supportCaregiver support ► Increase staffing ratioIncrease staffing ratio ► Activity programsActivity programs ► Adult day careAdult day care PharmacologicPharmacologic ► AntidepressantsAntidepressants ► Mood stabilizersMood stabilizers ► Antipsychotics*Antipsychotics* ► CholinesteraseCholinesterase inhibitorsinhibitors ► NMDA-receptor antagonistNMDA-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)
  27. 27. 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 ChangeinNPIScoreMean (±SEM)fromBaseline Improvement Deterioration Baseline 1 2 3 4 5 -2 -1 0 1 2 3 4 5 Time (Weeks) * Placebo Galantamine 8 mg/day Galantamine 16 mg/day Galantamine 24 mg/day
  28. 28. Pharmacotherapy for ModeratePharmacotherapy for Moderate to Severe Alzheimer’s Diseaseto Severe Alzheimer’s Disease FDA Approved:FDA Approved: ►MemantineMemantine MonotherapyMonotherapy Combination TherapyCombination Therapy New Developments in Severe AD:New Developments in Severe AD: ►ChEIsChEIs MonotherapyMonotherapy Combination TherapyCombination Therapy
  29. 29. Increased Probability ofIncreased Probability of Institutionalization by Disease SeverityInstitutionalization by Disease Severity Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):351-360 Probabilityof Institutionalization 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
  30. 30. Effects of Donepezil on Behaviors inEffects of Donepezil on Behaviors in Nursing Home Patients at Week 24Nursing Home Patients at Week 24 ImprovementPlacebo (N=105) Donepezil (N=103) MeanChangefromBaseline NPI-NHIndividualItem ScoreatWeek24 Delusions Hallucinations Agitation/Aggression Depression/Dysphoria Anxiety Elation/Euphoria Apathy/IndifferenceDisinhibition Irritability/Lability AberrantMotorBehavior NighttimeBehavior Appetite/Eating * 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
  31. 31. * * * ** * * * 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 Behavior Apathy Depression Delusions Disinhibition Hallucinations Euphoria Nighttime Behavior Appetite MeanChangefromBaseline *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) Improvement 26-Week U.S. Nursing Home Study
  32. 32. Memantine/Donepezil Combination Therapy inMemantine/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 MeanChangeFrom BaselineinSIB Score ImprovementDecline P<.001 P<.001 P=.006 P<.001 P=.03 P=.06 198198 197197 190190 185185 181181 171171 198198 n =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 (5→10→15→20 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)
  33. 33. 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 ReceivingMemantine in Patients Receiving Ongoing Donepezil: BehaviorOngoing Donepezil: BehaviorDelusions DelusionsHallucinations Hallucinations Agitation/ Agitation/ Aggression Aggression Depression/ Depression/ Dysphoria Dysphoria Anxiety Anxiety Elation/Euphoria Elation/Euphoria Apathy/Indifference Apathy/IndifferenceDisinhibition DisinhibitionIrritability/Lability Irritability/Lability Aberrant Aberrant MotorBehavior MotorBehavior Nighttim e Behavior Nighttim e Behavior Appetite/ Appetite/ Eating Change Eating Change ImprovementImprovementDeclineDecline LSMeanChange(SE)LSMeanChange(SE) 1.01.0 0.80.8 0.60.6 0.40.4 0.20.2 00 -0.2-0.2 -0.4-0.4 ****** **** ** Memantine PlaceboNPI Single-Item DomainsNPI Single-Item Domains
  34. 34. Tolerability of Memantine/DonepezilTolerability 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*
  35. 35. Evaluating ResponseEvaluating Response ► Assess:Assess: At baselineAt baseline After reaching maximal tolerated doseAfter 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
  36. 36. SummarySummary ► AD is an expensive illness in human andAD is an expensive illness in human and economic terms for patients, their caregivers, andeconomic terms for patients, their caregivers, and society.society. ► Diagnosis is often not made, especially in earlyDiagnosis is often not made, especially in early and mild AD; clinical nihilism can interfere withand mild AD; clinical nihilism can interfere with initiating or sustaining treatment. The long terminitiating or sustaining treatment. The long term setting brings additional clinical challenges.setting brings additional clinical challenges. ► Cholinesterase inhibitors and NMDA receptorCholinesterase inhibitors and NMDA receptor antagonists attenuate symptomatic decline andantagonists attenuate symptomatic decline and may modify disease progression.may modify disease progression. ► Early treatment pays off; delaying treatment hasEarly treatment pays off; delaying treatment has long-term consequences.long-term consequences.
  37. 37. ► ChEls (mild to moderate AD) and memantineChEls (mild to moderate AD) and memantine (moderate to severe AD) monotherapies are(moderate to severe AD) monotherapies are associated with less decline (vs placebo) inassociated with less decline (vs placebo) in cognition and functioncognition and function ► Although not indicated, newer data support a roleAlthough 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 withIn moderate to severe AD, patients treated with combination therapy (ie, memantine + ChEIs)combination therapy (ie, memantine + ChEIs) exhibited improved cognitive outcomes andexhibited improved cognitive outcomes and delayed functional decline (vs patients treated withdelayed functional decline (vs patients treated with ChEI only)ChEI only) SummarySummary