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

998 views
826 views

Published on

0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
998
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
45
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide
  • <number>
    Am J Public Health. 1994 Aug;84(8):1261-4. The US economic and social costs of Alzheimer's disease revisited.Ernst RL, Hay JW.Department of Pharmaceutical Economics and Policy University of Southern California, Los Angeles 90033.OBJECTIVEs. An earlier paper estimated the per-case and national incidence costs of Alzheimer's disease for 1983. This paper updates the estimates of costs per case to 1991 and presents new national prevalence estimates of the economic and social costs of the disease. METHODS. All data for the cost estimates were taken from published sources or provided by other researchers. RESULTS. At midrange values of the estimated cost and epidemiological parameters, the discounted (at 4%) direct and total costs of Alzheimer's disease were $47,581 and $173,932 per case, respectively. The estimated 1991 national direct and total prevalence costs were $20.6 billion and $67.3 billion, respectively. Assuming conservatively that the prevalence of the disease remains constant, the estimated discounted present values of the direct and total costs of all current and future generations of Alzheimer's patients are $536 billion and $1.75 trillion, respectively. CONCLUSIONS. The $536 billion and $1.75 trillion figures are minimum estimates of the long-term dollar losses to the US economy in 1991 caused by Alzheimer's disease.PMID: 8059882 [PubMed - indexed for MEDLINE]
  • <number>
    Guttman R, Altman RD, Nielsen NH.Arch Fam Med. 1999 Jul-Aug;8(4):347-53.
      Alzheimer disease. Report of the Council on Scientific Affairs.Guttman R, Altman RD, Nielsen NH.Council on Scientific Affairs, American Medical Association, Chicago, Ill., USA.Alzheimer disease (AD) takes a heavy economic, social, physical, and psychological toll on patients, families, and society. Because of the increasing life expectancy in the United States, AD is expected to afflict approximately 14 million people within the next few decades. There is currently no cure, only interventions that can temporarily ameliorate the profound cognitive losses and behavioral manifestations of the disorder. Community services are fragmented and underutilized. Physicians, in their traditional role as gatekeepers, can encourage more families to use supportive services. This article reviews the guidelines on the diagnosis and treatment of AD of the Agency for Health Care Policy and Research, the American Academy of Neurology, the Veterans Health Administration, and the American Psychiatric Association. Although these guidelines contain valuable information, they do not adequately address the role of the family physician and the need for continuity of care. Recommendations regarding AD from the Council on Scientific Affairs, which were adopted as American Medical Association policy in December 1997, are included in this article.
  • This slide reviews the stages of Alzheimer’s disease. It may be easier to talk to families in terms of the kind of symptoms they will see, and those are listed in the boxes on the slide.
    In patients with mild disease, symptoms may be subtle, while in patients with moderate disease, symptoms are usually apparent. Patients with severe disease are typically incapacitated.
  • <number>
    Widespread, diffuse atrophy with resulting ventricular enlargement is seen in AD brains, especially in later stages of the disease.Neurofibrillary tangles and amyloid plaques are the most distinctive neuropathological features of AD. Amyloid plaques begin in a diffuse form and mature into a compact, fibrillar form surrounded by dystrophic neurites and glial cells. In the photomicrograph of the left, a large plaque with a light staining core and dense staining halo is visible centrally.The photomicrograph on the right shows neurofibrillary tangles that contain abnormal cytoskeletal elements and appear as dense staining ‘flames’ within the neurones.Acetylcholine (ACh), 5-HT, and noradrenaline (NA) levels are decreased following neuronal losses in nucleus basilis of Meynert (ACh), nuclei of Raphe (5-HT) and nucleus caeruleus (NA). Immunoreactivity to substance P is also reduced.
  • <number>
    These results are from a multicentre, non-randomised, open-label extension study in 133 patients with mild to moderate AD who had completed a previous 14-week double-blind, placebo-controlled trial of donepezil. Patients in the 14-week study received double-blind treatment for 12 weeks followed by a single-blind placebo washout period before entering the open-label extension.Patients in the open-label extension study initially received 3 mg/day of donepezil. Depending on clinical presentation, doses of donepezil were increased by 2 mg/day up to 7 mg/day in the first 12 weeks of treatment and by 3 mg/day thereafter to a maximum of 10 mg/day, or the dose could be decreased by 1 or 2 mg/day to a minimum dose of 3 mg/day.Treatment continued for 192 weeks followed by a 4-week placebo washout. Data in this slide are from an interim analysis undertaken 98 weeks after commencement of the initial double-blind study.The plotted data represent the change observed for the whole population regardless of the original treatment (donepezil or placebo). Demographics of the 133 patients enrolled included a mean age of 71 years; ADAS-Cog mean score at baseline, 27.4; and Clinical Dementia Rating–Sum of the Boxes (CDR-SB) mean score at baseline, 6.72.An improvement from baseline score was seen using the ADAS-Cog through week 38, which included the single-blind washout period. Beginning with week 38, however, performance declined relative to baseline. Note that this extension study was not placebo controlled. Instead, the results are compared with those of a longitudinal placebo-controlled study (Stern et al., 1994).
  • <number>
  • We’ve learned thus far that acetylcholine and glutamate are the two neurotransmitter systems known to be important in learning and memory, and we now have medications to intervene in the progression of AD. We know that cholinergic neurons are lost in AD and that anticholinergic agents impair cognition. So the theory was if they could find a way to increase acetylcholine (ACh), they could improve and maintain cognitive function, and in fact that is what the cholinesterase inhibitors appear to do.
    More recently we’ve started to learn about glutamate. Excessive or erratic glutamate stimulation also can impair learning and may even cause neuronal toxicity. So the theory was that if we could normalize glutamatergic neurotransmission, we could maintain or improve cognition, and it may possibly prevent some of the neurotoxicity or slow the actual disease process.
  • <number>
  • <number>
    Important considerations in Alzheimer’s disease treatment
    Because many elderly patients suffer from comorbid medical or psychological disorders, there are various important considerations when selecting an Alzheimer’s disease (AD) therapy.
    Due to rivastigmine’s low plasma protein binding and minimal metabolism by the cytochrome P450 isoenzyme system, there is a decreased risk for dangerous drug-drug interactions. In addition, rivastigmine can be used in AD patients with renal or hepatic impairments with no need for dose adjustments based on these disorders. Therefore, rivastigmine can be used in AD patients with comorbid conditions taking concomitant medications.1-4
    As you can see, unlike memantine, rivastigmine requires no dosage adjustment for renal or hepatic impairment.
    In controlled clinical trials, the most common adverse events were nausea, vomiting, anorexia, asthenia, and dyspepsia.
    References: 1. EXELON® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004. 2. Aricept® [package insert]. New York, NY: Pfizer Inc; 2003. 3. Reminyl® [package insert]. Titusville, NJ: Janssen Pharmaceutica Products, L.P.; 2003. 4. Namenda™ [package insert]. St Louis, Mo: Forest Laboratories, Inc; 2003.
  • Hepatic metabolism by CYP 2D6 and CYP 3A4
    May need to use lower daily doses if combined with paroxetine or ketoconazole
    Caution advised when co-administered with other 2D6 and 3A4 inhibitors
    Carbamazepine may decrease levels
    Decreased renal function (CrCl 10-70ml/min) – assess tolerability; daily dose generally should not exceed 16mg/day
    A) Effect of Other Drugs on Galantamine
    In vitro
    CYP3A4 and CYP2D6 are the major enzymes involved in the
    metabolism of galantamine. CYP3A4 mediates the formation of
    galantamine-N-oxide; CYP2D6 leads to the formation of O-desmethylgalantamine.
    Because galantamine is also glucuronidated and
    excreted unchanged, no single pathway appears predominant.
    In vivo
    Cimetidine and Ranitidine: Galantamine was administered as a
    single dose of 4 mg on day 2 of a 3-day treatment with either
    cimetidine (800 mg daily) or ranitidine (300 mg daily). Cimetidine
    increased the bioavailability of galantamine by approximately 16%.
    Ranitidine had no effect on the PK of galantamine.
    Ketoconazole: Ketoconazole, a strong inhibitor of CYP3A4 and an
    inhibitor of CYP2D6, at a dose of 200 mg BID for 4 days, increased
    the AUC of galantamine by 30%.
    Erythromycin: Erythromycin, a moderate inhibitor of CYP3A4, at a
    dose of 500 mg QID for 4 days, affected the AUC of galantamine
    minimally (10% increase).
    Paroxetine: Paroxetine, a strong inhibitor of CYP2D6, at 20 mg/day
    for 16 days, increased the oral bioavailability of galantamine by about 40%
    Renal Impairment: Following a single 8 mg dose of galantamine,
    AUC increased by 37% and 67% in moderate and severely renalimpaired
    patients compared to normal volunteers (see
  • <number>
  • Purpose:
    To illustrate graphically the results on the SIB
    Key Points:
    This figure depicts the mean change from baseline by visit and end point on the SIB (using OC and LOCF).
    There was a statistically significant difference in cognitive performance favoring memantine over placebo as measured by the SIB rating scale as early as week 8, and lasting for the duration of the study.
    Statistically significant differences between the groups from week 8 onward; P = .057 at week 4
    Memantine: end point +1.1, showing improvement above baseline. Placebo end point –2.3 (P<.001)
    Additional Information:
    The SIB is a 40-item scale that evaluates cognitive performance—attention, language, praxis, visuospatial ability, construction, memory, and social interaction—in moderate to severe AD. The test is scored from 0 (greatest impairment) to 100.
    SIB baseline scores were roughly 78 in both groups.
    ADCS reports that for untreated patients with AD whose scores were 5-9, average deterioration rate on the SIB was roughly 3.19 points per month; and for untreated patients with AD whose MMSE were 10-15, the rate of change was 2.08 points per month. The patients in this trial are not declining at that rate; remember the patients are stabilized on donepezil, so they are considered “treated” prior to entering the study.
    — A study of treating patients stabilized on donepezil is unprecedented. The fact that significant changes are even
    seen speaks to the sensitivity of the SIB in this patient population.
    Patients with SIB scores less than 63 are considered to be very severely impaired. This range typically corresponds with a MMSE of < 4.
  • Plasma protein binding for memantine is low (45%)
    Interactions with drugs that are highly bound to plasma proteins such as warfarin or digoxin are unlikely
    Memantine’s primary route of excretion is renal; patients with compromised renal function should be monitored closely
  • <number>
    In a US, 5-month multicentre, placebo-controlled, double-blind trial, following a ~4-week placebo run-in, 978 patients with mild to moderate AD were randomly assigned to placebo treatment or galantamine escalated to final maintenance doses of 8, 16 or 24 mg/day (Tariot et al., 2000). Patients included in the trial did not have a high level of behavioural disturbances at baseline (baseline NPI scores: placebo=11; 8 mg/day=12.9; 16 mg/day= 12.4; 24 mg/day=11.9).At 5 months, both 16 and 24 mg/day groups had significantly better NPI total scores than placebo (OC and ITT analyses; p<0.05). For these two treatment groups, the NPI total scores at 5 months were not significantly different from baseline, whereas the NPI total scores of patients receiving 8 mg/day galantamine or placebo declined significantly compared with baseline (p<0.05 both groups).
  • Purpose:
    To summarize cognitive outcomes in the Reisberg trial
    Key Points:
    Orientation to slide:
    —Points on the y-axis represent mean change in SIB score from baseline while points on the
    x-axis represent time.
    — As higher scores indicate better performance than placebo on cognitive tasks, positive mean
    changes above baseline indicate clinical improvement.
    There was a significant difference on the SIB outcome measure favoring memantine treatment at end point
    Over the 6-month period, memantine patients decreased by 3.9 points at end point, while placebo patients decreased by 9.8 points. Therefore, memantine patients had significantly less cognitive decline on the SIB total score compared with placebo.
    Additional Information:
    The SIB evaluates cognitive performance in moderate to severe AD. It includes a 40-item scale, which measures such skills as attention, language, praxis, visuospatial ability, construction, memory, and social interaction. The test is scored from 0 (greatest impairment) to 100.
    SIB baseline scores were 68.33 for placebo and 65.86 for memantine.
    ADCS reports that for patients with untreated AD whose MMSE scores are 5-9, the average deterioration rate on the SIB is roughly 3.19 points per month; and for patients with untreated AD whose MMSE are 10-15, the rate of change is 2.08 points per month. Over the 6-month period, this resulted in a 12- to 18-point drop.
  • 9. INCREASED PROBABILITY OF INSTITUTIONALIZATION BY DISEASE SEVERITY
    Hauber and colleagues1 used a hazard model to estimate direct cost savings attributable to delay in cognitive decline with rivastigmine treatment in the US.
    Disease progression was defined in terms of intervals in the MMSE scale. Clinical trial data2,3 were then used to determine the time at which a particular patient moved into a more severe stage of the disease.
    Direct and indirect costs (US $) of transition from one stage of AD to another based as a function of MMSE, using a formula established by Ernst and colleagues.4
    Probability of institutionalization at each MMSE score1 based on CERAD database5
    Cost savings due to rivastigmine = (incremental cost of transitioning from one disease severity to the next)  (additional days spent in the less severe stage)
    The probability of institutionalization increased with AD progression, suggesting that early intervention is the optimal management strategy with ultimate expectations for decreased overall costs.
    ---------------------------------------------------------------------------------
    Pharmacoeconomics. 2000 Apr;17(4):351-360Comment in:
    Pharmacoeconomics. 2000 Dec;18(6):609-12.Potential savings in the cost of caring for Alzheimer's disease. Treatment with rivastigmine.Hauber AB, Gnanasakthy A, Snyder EH, Bala MV, Richter A, Mauskopf JA.Research Triangle Institute, Research Triangle Park, North Carolina, USA.OBJECTIVE: To estimate savings in the cost of caring for patients with Alzheimer's disease (AD) during 6 months, 1 year and 2 years of treatment with rivastigmine. An intermediate objective was to estimate the relationship between disease progression and institutionalisation. DESIGN AND SETTING: We assessed the relationship between Mini-Mental State Examination (MMSE) score and institutionalisation using a piecewise Cox proportional hazard model. To estimate cost savings from treatments lasting 6 months, 1 year and 2 years, estimates of the probability of institutionalisation were integrated with data from two 6-month phase III clinical trials of rivastigmine and a hazard model of disease progression. MAIN OUTCOME MEASURES AND RESULTS: Our data suggest that savings in the overall cost of caring for patients with mild and moderate AD can be as high as $US4839 per patient after 2 years of treatment. Furthermore, the probability of institutionalisation increases steadily as MMSE score falls. Among our study individuals, age, race, level of education and marital status were significant predictors of institutionalisation, whereas gender had little effect. CONCLUSIONS: Using rivastigmine to treat AD results in a delay in disease progression for patients who begin treatment during the mild or moderate stages of the disease. By delaying the probability that a patient will be institutionalised, the cost of caring for AD patients can be significantly reduced.Publication Types: Review; Review, TutorialPMID: 10947490 [PubMed - indexed for MEDLINE]
    Clin Ther. 2000 Apr;22(4):439-451Savings in the cost of caring for patients with Alzheimer's disease in Canada: an analysis of treatment with rivastigmine.Hauber AB, Gnanasakthy A, Mauskopf JA.Research Triangle Institute, Center for Economics Research, Research Triangle Park, North Carolina 27709-2194, USA. Hauber@RTI.orgOBJECTIVE: To estimate per-patient potential cost savings using rivastigmine in the treatment of Alzheimer's disease (AD) in Canada. BACKGROUND: In recent years, new members of a class of pharmaceuticals known as cholinesterase inhibitors have been introduced for the treatment of patients with AD. Two recent studies conducted in the United Kingdom and the United States estimated potential cost savings from the new cholinesterase inhibitor rivastigmine. The present study combined the disease-progression model used in those 2 studies with Canadian costs to estimate per-patient potential savings resulting from the treatment of AD in Canada. METHODS: Efficacy data from 2 pivotal, phase III clinical trials of rivastigmine were used in a hazard model of disease progression to estimate long-term differences in cognitive functioning between patients receiving rivastigmine and patients receiving no treatment. We used the Mini-Mental State Examination (MMSE) score as our measure of disease progression. We also used Canadian costs of AD care, estimated as a function of MMSE score, to estimate cost savings experienced by treated patients compared with patients receiving no treatment. All costs and cost savings are presented in 1997 Canadian dollars. We used a societal perspective in this analysis. RESULTS: Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively. For patients with the mild stage of AD, estimated average daily cost savings (excluding the cost of rivastigmine) ranged from Can $0.45 per patient per day at 6 months to Can $6.44 per patient per day after 2 years of treatment. For all patients, these estimated average daily cost savings ranged from a low of Can $0.71 per patient per day after 6 months of treatment to a high of Can $4.93 per patient per day after 2 years. CONCLUSION: On average, treatment with rivastigmine yields savings in the direct cost of caring for AD patients that exceed the cost of the drug after 2 years of treatment.Publication Types: Clinical Trial; Clinical Trial, Phase IIIPMID: 10823365 [PubMed - indexed for MEDLINE]
  • <number>
             The Neuropsychiatric Inventory Nursing Home version (NPI-NH) is the same as the standard NPI, except that two additional symptom domains are included: night-time behaviour and appetite/eating changes.
             In this 24-week, placebo-controlled, US study, donepezil 10 mg/day failed to significantly improve behavioral symptoms in 208 nursing home patients with AD (Baseline NPI-NH score 21.0).
             As shown on the slide, improvement from baseline NPI-NH scores was greater in placebo-treated patients compared with patients treated with donepezil for total score (-4.9 vs -2.3 points) and for 10 of the 12 individual NPI-NH items.
             A secondary analysis revealed a statistically significant response in favor of donepezil for agitation/aggression.
     
    Reference
    Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind, placebo-
    controlled study of the efficacy and safety of donepezil in patients with
    Alzheimer's disease in the nursing home setting. J Am Geriatr Soc. 2001;49:1590-
    1599.
    ****************************************************************************************
    [ref 1]
    J Am Geriatr Soc 2001 Dec;49(12):1590-9
    A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting.Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, Whalen E.Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, New York 14620, USA.
  • <number>
    Similar study K Edwards poster AAGP: half the pts with sx at baseline had a 30% improvement in the NPI-NH ( Dose 1.5-6.0 bid of exelon)
    General improvement in behavioural sx as evidenced by 46% decrease in neuroleptic therapy
  • Purpose:
    To illustrate graphically the results on the SIB
    Key Points:
    This figure depicts the mean change from baseline by visit and end point on the SIB (using OC and LOCF).
    There was a statistically significant difference in cognitive performance favoring memantine over placebo as measured by the SIB rating scale as early as week 8, and lasting for the duration of the study.
    Statistically significant differences between the groups from week 8 onward; P = .057 at week 4
    Memantine: end point +1.1, showing improvement above baseline. Placebo end point –2.3 (P<.001)
    Additional Information:
    The SIB is a 40-item scale that evaluates cognitive performance—attention, language, praxis, visuospatial ability, construction, memory, and social interaction—in moderate to severe AD. The test is scored from 0 (greatest impairment) to 100.
    SIB baseline scores were roughly 78 in both groups.
    ADCS reports that for untreated patients with AD whose scores were 5-9, average deterioration rate on the SIB was roughly 3.19 points per month; and for untreated patients with AD whose MMSE were 10-15, the rate of change was 2.08 points per month. The patients in this trial are not declining at that rate; remember the patients are stabilized on donepezil, so they are considered “treated” prior to entering the study.
    — A study of treating patients stabilized on donepezil is unprecedented. The fact that significant changes are even
    seen speaks to the sensitivity of the SIB in this patient population.
    Patients with SIB scores less than 63 are considered to be very severely impaired. This range typically corresponds with a MMSE of < 4.
  • Purpose:
    To provide an overview of the effect of memantine on behavioral outcomes in moderate to severe AD, a study of which was presented as a poster at the American Association for Geriatric Psychiatry’s 17th Annual Meeting in Baltimore, Maryland from February 21-24, 2004, by J.L. Cummings, et al.
    Key Points:
    Of the 12 single-item, behavioral domains measured by the NPI, memantine treatment resulted in significant improvement in agitation/aggression, irritability/lability, and appetite/eating change compared to placebo (LOCF).
  • Purpose:
    To illustrate that memantine is safe and well-tolerated
    Key Points:
    This is a list of AEs frequently reported in  5% of either treatment group.
    As shown here, the memantine + donepezil treatment group has an adverse event profile similar to the placebo + donepezil treatment.
    Although confusion was reported in a great number of memantine-treated patients, it was rated as mild and transient and occurred at a median of 32 days and remitted within 2 weeks.
    In the placebo group, confusion was rated as severe and occurred at a median of 55 days and did not remit.
    Memantine + donepezil therapy also appears to reduce the incidence of agitation compared to rates of placebo + donepezil therapy, which suggests that memantine may be able to reduce agitation in AD patients.
    The gastrointestinal AEs (diarrhea, fecal incontinence) associated with donepezil were more commonly reported by patients taking placebo + donepezil compared with those taking memantine + donepezil, which may suggest that memantine improved these GI events in patients on a stable dose of donepezil.
  • <number>
    Effect may be seen in one or more domains
  • <number>
    Purpose:
    To provide overall conclusions on the findings of the 9605 trial.
    Key Points:
    As stated in slide.
  • 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

    ×