It is only in the past decade that pharmacologic

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1 IS THERE TREATMENT FOR ALZHEIMER S DISEASE? Gary M. Levin, PharmD, BCPP, FCCP * ABSTRACT There are now 5 approved drugs for the primary symptoms of Alzheimer s disease (AD), 4 of which inhibit acetylcholinesterase and 1 that acts as a noncompetitive antagonist to the N-methyl- D-aspartate (NMDA) glutamate receptor. The acetylcholinesterase inhibitors are approved for use in mild to moderate AD, whereas the drug that acts as a noncompetitive antagonist to the NMDA glutamate receptor is approved for moderate to severe AD. Therefore, patients have different treatments available for different stages of the disease. These medications have demonstrated efficacy in delaying cognitive decline in numerous randomized, controlled trials. Recent studies are focusing on longer-term follow-up (1 year and beyond), in addition to more clinically relevant outcomes, such as measures of function and nursing home placement. The AD drugs also appear to offer benefit with these outcomes. In addition, treatments such as vitamins E and C, nonsteroidal anti-inflammatory drugs, and statins (cholesterollowering drugs) show some promise in preventing or delaying AD progression, although more data are needed. This article reviews the pivotal clinical studies of each drug, the more recent studies of other outcomes, and the therapies currently undergoing investigation. The guidelines from leading medical authorities are also briefly reviewed (ie, the American Academy of Neurology, the American Geriatrics Society, the *Professor and Chairman, Department of Pharmacy Practice, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, Florida. Address correspondence to: Gary M. Levin, PharmD, BCPP, FCCP, Professor and Chairman, Department of Pharmacy Practice, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL glevin@nsu.nova.edu. American Psychiatric Association, and the American Association of Family Physicians). Although some may argue that the measured effect of these drugs is minimal, in reality any preservation of function and delay of nursing home placement has important and permanent consequences for the patient and caregiver, and all parties should be aware of the expected outcomes with these medications. (Adv Stud Pharm. 25;2(5):16-174) It is only in the past decade that pharmacologic treatments for the primary symptoms of Alzheimer s disease (AD), namely memory loss and cognitive impairment, have become available. Four of 5 approved therapies (tacrine, donepezil, rivastigmine, and galantamine) act by inhibiting the enzyme acetylcholinesterase, which is responsible for breaking down acetylcholine postsynaptically. Inhibition of this enzyme thus keeps acetylcholine in the synapse longer. It should be noted that tacrine and rivastigmine also inhibit the enzyme butyrylcholinesterase, which also breaks down acetylcholine, primarily in cholinergic neurons that project to the frontal cortex. 1-3 Cholinergic neuron loss is the primary type of neurodegeneration in AD. The fifth drug, memantine, acts as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, curtailing the low-level but steady NMDA receptor activation that is thought to occur in AD and contribute to excitotoxicity. 4,5 Several other treatments that address not only the symptoms but also the pathophysiologic processes in AD are also under investigation. CHOLINESTERASE INHIBITORS Although there are 4 approved cholinesterase 16 Vol. 2, No. 5 October 25

2 inhibitors, only 3 are used in the United States. Tacrine is still available but rarely prescribed because of the potential hepatotoxicity associated with its use; it also has a complicated titration schedule. Tacrine should probably never be recommended as first-line therapy for AD. Although it is still on the market, there is no practical use for tacrine, but pharmacists may still encounter prescriptions for tacrine. In all of the clinical studies to evaluate the efficacy and safety of cholinesterase inhibitors for US Food and Drug Administration (FDA) approval, patients were assessed by 2 measures of cognition the cognition subscale of the Alzheimer s disease assessment scale (ADAScog) and an overall clinical effect through the Clinician s Interview-Based Impression of Change plus (CIBIC+). The CIBIC+ also requires caregiver information. DONEPEZIL Donepezil was the first clinically successful drug for the symptoms of mild to moderate AD. Its efficacy was established in 2 randomized, double-blind, placebo-controlled studies, which are summarized in Table 1. 6,7 Donepezil has also been evaluated in longerterm studies. Rogers et al evaluated the long-term efficacy of donepezil in a 24-week (4.9 years), open-label continuation of a 14-week double-blind, placebo-controlled study (n = 133). 6 The results showed evidence of clinical benefit (ie, maintenance of baseline scores for ADAS-cog and a subset of the Dementia Rating Scale [CDR]) during the first 6 to 9 months of open-label treatment, with cognitive decline gradually deteriorating after that. The treatment group was compared to historical controls and the results showed that the rate of cognitive decline throughout the study was slower for those receiving donepezil than what was estimated if the patients had not been treated (Figure 1). Although the study has important limitations (suboptimal dosing of 3 mg at study start, comparison to historical controls), this is one of the longest follow-up studies of a treatment for AD and the data suggest important benefits with donepezil use. 8 The potential benefits of donepezil may differ between patients with mild, moderate, or severe AD. Donepezil was compared to placebo in patients with early stage (mild) AD in a 24-week study. 9 The results showed clinical improvement with donepezil use, based on ADAS-cog (Figure 2) and Mini-Mental State Examination (MMSE) scores (Figure 3). The placebo group showed virtually no signs of cognitive decline as measured by MMSE during the 24-week study period. However, as measured by ADAS-cog, patients receiving placebo showed cognitive decline during the study. This difference in treatment response may be unique to early stage (mild) AD compared to more advanced stages. 9 At the other end of the severity spectrum, Feldman et al have evaluated the efficacy of donepezil in patients with moderate to severe AD (MMSE scores of 5 17). 1 (As a reminder, the MMSE is not a diagnostic tool, but rather is used to assess cognitive function. Generally speaking, typical MMSE scores in a patient without pathology should range from 26 3, whereas scores in the mid to low 2s indicate a possible affective disorder or mild dementia.) Although the ADAS-cog was not used in these studies, the results showed significant improvement in CIBIC+ (the primary outcome; Figure 4) and the MMSE (Figure 5) scores at all time points during the 24-week study, in addition to all other secondary measures. 1 Recent studies are measuring clinically relevant outcomes, such as functional decline (ie, ability to perform activities of daily living [ADLs] or instrumental ADLs [IADLs]), nursing home placement, and effect on caregiver burden. ADLs focus on basic functioning, such as toileting, feeding, dressing, bathing, walking, and grooming. IADLs are more complex activities, which most adults of normal mental capacity can perform, such as operating household appliances, paying bills and managing money, shopping, preparing meals, and participation in hobbies. The effect of medications on ADLs is important for several reasons. ADLs instill and maintain a sense of independence, which is critical for patients and caregivers quality of life. In AD, ADLs once lost never return, and loss of basic ADLs is a significant predictor of institutionalization. Therefore, preservation of ADLs is a critical outcome with permanent ramifications. 11 Mohs et al conducted a 1-year preservation of function study of patients with moderate AD taking donepezil or placebo. 12 A clinically evident decline in function was defined as any of the following: decline in ability to perform 1 or more basic ADLs that were present at baseline, decline in ability to perform 2% or more of IADLs that were present at baseline, or increase in CDR score of 1 point or more. The ADLs and IADLs evaluated in this study are listed in Table 2. Donepezil extended the time to clinically evident functional decline by 5 months versus placebo. The probability of no clinically evident functional loss at 48 weeks was Advanced Studies in Pharmacy 161

3 Table 1. Summary of the Studies for FDA Approval of the Currently Available Drugs for AD Length, Subjects, Author wks n Treatment Impact Comments Donepezil Rogers et al 6 3* 473 Rogers et al Rivastigmine Corey-Bloom et al 2 Rosler et al Anand et al Galantamine Tariot et al Raskind et al Wilcock et al Rockwood et al Memantine Reisberg et al Tariot et al mg and 1 mg donepezil, placebo 5 mg and 1 mg donepezil, placebo 1 4 mg and 6 12 mg rivastigmine, placebo 1 4 mg and 6 12 mg rivastigmine, placebo 3, 6, and 9 mg rivastigmine, placebo 8, 16, and 24 mg galantamine, placebo 24 and 32 mg galantamine, placebo 24 mg and 32 mg galantamine, placebo 24 mg or 32 mg galantamine, placebo 2 mg memantine, placebo 2 mg memantine, placebo Significant improvements in cognitive measures for both doses versus placebo; no significant differences in treatment effect between the 2 doses Significant improvements in cognitive measures for both doses versus placebo; no significant differences in treatment effect between the 2 doses Significant cognitive improvement with both doses; significant improvement in global measures and measures of ADLs only with higher dose Significant improvement only for higher dose; no difference between lower dose and placebo Significant improvement over placebo with 6 and 9 mg only for cognition measures; no significant difference among groups for global measure, but trend toward superiority Significant improvement over placebo for 16- and 24-mg doses; improvement over baseline for all doses throughout study (except for 8 mg at 21 weeks) In cognitive scores, improvement from baseline in both doses; worsening from baseline with placebo In cognitive scores, improvement from baseline in both doses; worsening from baseline with placebo In cognitive scores, improvement from baseline in both doses; worsening from baseline with placebo Slower decline from baseline than placebo group Slower decline from baseline than placebo group in AD Cooperative Study ADL inventory; improvement from baseline in Severe Impairment Battery with memantine; decline from placebo *24 weeks of treatment, followed by 6 weeks washout. 12 weeks of treatment, followed by 3 weeks washout. AD = Alzheimer s disease; ADL = activity of daily living; FDA = US Food and Drug Administration. After the 6-week washout period at study end, cognition scores of the 2 donepezil groups were indistinguishable from the patients receiving placebo, suggesting that the effects of donepezil abate after 6 weeks but the disease process appears to be unchanged; patients had a wide range of responses to donepezil After the 3-week washout period at study end, cognition scores decreased but were still higher than for patients receiving placebo; patients had a wide range of responses to donepezil Patients had a wide range of responses to rivastigmine Patients had a wide range of responses to rivastigmine Patients age, gender, or race did not predict clinical outcome Patients had a wide range of responses to galantamine During a 26-week extension, only the 24- mg dose group maintained higher cognitive scores than the other groups; at 52 weeks, the final cognitive score for the 24- mg group was back to baseline; the other subjects worsened to below baseline Patients had a wide range of responses to galantamine Patients had a wide range of responses to galantamine Study participants had moderate to severe AD Study participants were also on stable doses of donepezil 162 Vol. 2, No. 5 October 25

4 Figure 1. Mean Change from Baseline in ADAScog Scores Over 254 Cumulative Weeks of Study with Donepezil Figure 2. Mean Change from Baseline in ADAScog Score for Patients with Early Stage AD Taking Donepezil or Placebo for 24 Weeks Mean change from baseline ADAS-cog score (±SE) Donepezil-treated group 95% confidence interval Historical control Cumulative weeks of donepezil treatment Change from baseline on ADAS-cog scores End Point (LOCF) Donepezil Group Sample Size Placebo Group Sample Size Donepezil Group Placebo Group Improvement Baseline Decline Week Patients Evaluated Week Patients Evaluated Patients were initially dosed with 3 mg/day donepezil, which could be increased up to 1 mg/day. ADAS-cog = Alzheimer s disease assessment scale-cognitive. Reprinted with permission from Rogers et al. Eur Neuropsychopharmacol. 2;1: Patients had early-stage (or mild) AD. Patients received placebo (n = 57) or 5 mg donepezil (n = 96) with forced titration to 1 mg after the first 6 weeks. AD = Alzheimer s disease; ADAS-cog = Alzheimer s disease assessment scale-cognitive; LOCF = last observation carried forward. Reprinted with permission from Seltzer et al. Arch Neurol. 24: 61: % for the donepezil group versus 35% for the placebo group a 31% reduction in the risk of functional decline. The authors make an important conclusion in their study: the scores of ADL measures for patients on donepezil tended to stabilize over time, rather than to improve over baseline, suggesting that clinicians should aim for stability rather than actual improvement in ADLs. 12 This is a critical message for patients and their caregivers. More recently, Feldman et al evaluated the effect of donepezil on measures of ADLs and caregiver burden (stress and time required to assist the patient with ADLs). 13 In 29 patients with moderate to severe AD, those treated with donepezil (for 24 weeks) showed significantly slower decline in measures of ADLs and IADLs compared to placebo-treated patients. Importantly, significant differences between the 2 groups in favor of donepezil were also observed in the components required for completing each ADL (initiation, planning and organization, and effective performance). Caregivers reported spending a mean of 52.4 fewer minutes/day on ADLs and 17.2 fewer minutes/day on IADLs with donepeziltreated patients. Components of the caregiver stress scale Figure 3. Mean Change from Baseline in MMSE Score for Patients with Early Stage AD Taking Donepezil or Placebo for 24 Weeks Change From Baseline on MMSE Scores End Point (LOCF) Donepezil Group Sample Size Placebo Group Sample Size Donepezil Group Placebo Group Improvement Baseline Decline Patients had early stage (or mild) AD. Patients received placebo (n = 57) or 5 mg donepezil (n = 96) with forced titration to 1 mg after the first 6 weeks. AD = Alzheimer s disease; LOCF = last observation carried forward; MMSE = Mini-Mental State Examination. Reprinted with permission from Seltzer et al. Arch Neurol. 24: 61: Advanced Studies in Pharmacy 163

5 Figure 4. CIBIC+ Scores during 24 Weeks of Treatment with Donepezil in Patients with Moderate to Severe AD P =.8.1 <.1 P <.1 improvement P =.4 P < No change Donepezil decline 4.6 Placebo Week 24 Study week LOCF Donepezil n = (14) Placebo n = (146) LS mean score ± SE The mean Clinician s Interview-Based Impression of Severity at baseline was 4.39 ±.7 and 4.4 ±.7 for the donepezil and placebo groups, respectively. AD = Alzheimer s disease; CIBIC+ = Clinician s Interview-Based Impression of Change plus; LOCF = last observation carried forward; LS = least squares. Reprinted with permission from Feldman et al. Neurology. 21;57: all favored donepezil except for management of distress, caregiving competence, and personal gain. It is unclear why these measures did not follow the trend. As with the previous study, the authors note the importance of focusing on stabilization of cognitive function: The placebo group declined more steeply in ADLs than had been previously reported in mild to moderate AD without encountering a floor effect [ie, where no further decline is measurable]. This underscores the significance of being able to stabilize and preserve function even at the moreadvanced disease stage. The differences in function between donepezil- and placebo-treated groups continued to increase throughout the study with the largest effects noted at the final study visit. 13 Nursing home placement is another important milestone in AD progression. The desire and decision to place a patient with AD in full-time nursing care varies with each patient s circumstances (eg, severity of disease, presence of neuropsychiatric symptoms) and caregiver s circumstances (eg, finances, caregiver ability, and guilt). Most families would probably prefer to keep the patient at home as long as possible, in part because some caregivers suffer from guilt at relinquishing their loved one s care to others. In other situations, some caregivers cannot afford to place the patient in a nursing home as early as they would like. For example, if the patient is a widow/er and the adult children live far away, earlier placement would be preferred because geographic constraints prohibit at-home care. Because, in part, of these sometimes conflicting variables, studies that focus on the effect of donepezil on nursing home placement have provided mixed results. A study of community-dwelling patients with AD previously enrolled in 1 of several clinical trials of donepezil (n = 671) followed these patients to determine the effect of donepezil on nursing home placement. 14 When donepezil was taken at an effective dose (ie, at least 5 mg/day with at least 8% compliance) for 9 to 12 months, conservative estimates for time gained before nursing home placement was 21.4 months for a firsttime dementia-related placement and 17.5 months for permanent placement. Even patients who did not receive the full 5-mg/day dose during the initial clinical trial, but Figure 5. MMSE Scores During 24 Weeks of Treatment with Donepezil in Patients with Moderate to Severe AD LS mean change from baseline ± SE 2.5 P <.4 P <.1 2. P = Donepezil -.5 Placebo Week 24 Study week LOCF Donepezil n = (131) Placebo n = (139) LS mean change from baseline ± SE smmse SIB 8 P <.1 6 P =.51 P <.9 P =.1 4 P =.78 P < Donepezil Placebo Study week Week 24 LOCF Donepezil n = (139) Placebo n = (145) improvement Baseline decline improvement Baseline decline AD = Alzheimer s disease; LOCF = last observation carried forward; LS = least squares; MMSE = Mini-Mental State Examination; SIB = severe impairment battery. Adapted with permission from Feldman et al. Neurology. 21;57: Vol. 2, No. 5 October 25

6 Table 2. Functions Measured in the AD Functional Assessment and Change Scale Basic ADL Toileting Feeding Dressing Personal hygiene and grooming Bathing Walking Instrumental ADL Use of telephone Household tasks Using household appliances Managing money Shopping Food preparation Ability to get around inside and outside the home Hobbies and leisure activities Handling personal mail Grasp of situations or explanations AD = Alzheimer s disease; ADL = activity of daily living. Adapted with permission from Mohs et al. Neurology. 21;57: ultimately received that dose (with at least 8% compliance) for at least 6 months, had delayed placement (first time and permanent). The authors note that, because this is an observational study, the results do not prove conclusively that taking effective doses of donepezil delayed nursing home placement, but the results do suggest that donepezil is a valid explanation for the delay and that doctors and caregivers need to be educated that, in the same way as the actual benefits of treating hypertension or hyperlipidemia are seen only after years of treatment, treatment of AD with donepezil needs to be maintained to see important long-term benefits. 14 However, results of a large UK study (AD2) comparing the effects of donepezil versus placebo in 486 community-dwelling patients with mild to moderate AD showed no significant benefit of donepezil with regard to institutionalization, progression of disability, behavioral and psychological symptoms, caregiver psychopathology, costs of care, unpaid caregiver time, adverse events, or deaths. 15 An important difference between this study population and that in other trials was that patients with comorbidities were included, such as those patients with cerebrovascular disease, which can cause dementia. Inclusion criteria were loosely defined in that the doctor had to be substantially uncertain that the individual would obtain a worthwhile clinical benefit from donepezil, taking into account the available evidence and clinical circumstances. 15 It is unclear how these results would apply to a US population. Criteria for AD treatment, nursing home placement, and costs are different for each country. Also, study recruitment fell far short of its target (n = 566 with a target of 3). Therefore, the study was underpowered for most of its primary outcomes, except for the cognition measures. 16 With an improved understanding of the pathophysiologic processes underlying AD, researchers are now focusing on changes in these processes as markers of AD drug efficacy. In several small studies in patients with mild to moderate AD, donepezil treatment has resulted in significantly smaller mean decreases in hippocampal atrophy (as measured by magnetic resonance imaging) compared to placebo, in addition to a mean 22% increase in acetylcholinesterase inhibition in the brain RIVASTIGMINE Rivastigmine has shown clinical efficacy in delaying cognitive decline in 3 randomized, placebo-controlled studies in the United States and internationally (Table 1) A 26-week open-label extension of the American study (flexible dose) showed that all patients taking rivastigmine benefited, as observed by the change in ADAS-cog score from baseline (Figure 6). 23 Similar Figure 6. Mean Change from Baseline in ADAS-cog Score with Rivastigmine Versus a Projected Placebo Group Mean change from baseline = SEM Rivastigmine 6 12 mg Placebo Rivastigmine 1 4 mg Proj. placebo All patients taking rivastigmine Study week All 3 treatment groups (rivastigmine at 2 doses and placebo) were compared to a projected placebo group (developed from a mathematical model). Cognitive benefit was greatest in the 6- to 12-mg/day rivastigmine group, but all of the patients who received rivastigmine (including those originally receiving placebo in the double-blind phase) showed slower decline in cognitive function. ADAS-cog = Alzheimer s disease assessment scale-cognitive. Reprinted with permission from Farlow et al. Eur Neurol. 2;44: Advanced Studies in Pharmacy 165

7 Table 3. ADAS-cog and MMSE Performance (Change from Baseline) Between 1 and 2 Years for Rivastigmine-Treated Patients 12-month Change 18-month Change 24-month Change Mean (95% CI) Mean (95% CI) Mean (95% CI) ADAS-cog 2.8 ( ) 6.2 ( ) 8.6 ( ) MMSE -1.3 (-1.5 to -1.1) -2.9 (-3.19 to -2.68) -4.3 (-4.61 to -3.99) Patients (n = 21) had participated in two 26-week randomized, placebo-controlled studies of rivastigmine, then continued on for 2 years of open-label treatment. This table provides data from the open-label phase of the study. ADAS-cog = Alzheimer s disease assessment scale-cognitive; CI = confidence interval; MMSE = Mini-Mental State Examination. Adapted with permission from Grossberg et al. Am J Geriatr Psychiatry. 24;12: results were also seen in a subgroup analysis of the moderately severe patients in this study. 24 Some of the study patients were followed for 2 years. As shown in Table 3, the benefits of rivastigmine treatment on MMSE and ADAS-cog scores continued through 24 months. 25 Patients with more severe AD also appear to benefit from rivastigmine. A small study of 48 patients with moderately severe AD (MMSE of 14) showed that higher doses of rivastigmine (mean dose 1.7 ± 1.6 mg/day at 12 months) resulted in significant benefit in all outcome measures ADAS-cog, MMSE, and CIBIC+, in addition to several other outcome measures. 26 Two studies have analyzed the effect of rivastigmine based on disease severity, but from a different approach. Farlow et al, in another 26-week open-label extension of the original 26-week double-blind placebocontrolled study, considered the rate of AD progression (slowly progressive vs rapidly progressive) as a factor that may determine the response to rivastigmine. 27 Patients who had received placebo in the original double-blind study were classified into either of these 2 groups, and they were then treated with rivastigmine (2 12 mg/day) for 26 weeks. Significant differences were seen in the response to rivastigmine between these 2 patient groups. Patients who had progressed rapidly during the doubleblind phase obtained greater benefit from rivastigmine treatment, based on ADAS-cog scores (Figure 7), than did patients with a more slowly progressive disease course. 27 A retrospective analysis of the 3 randomized, doubleblind, placebo-controlled studies showed that rivastigmine had beneficial effect on ADLs, and that the type of ADL impairment differs across the stages of AD. Table 4 lists the ADLs in which there was a significant change from baseline based on the 3 levels of severity. 28 Other long-term studies have evaluated the effect of rivastigmine in patients with cerebrovascular disease (CVD) and in patients with mild AD or mild cognitive impairment (MCI). A 2-year study (an extension of one of the original studies) evaluated the effect of rivastigmine in patients with and without hypertension. 29 Vascular dementia is thought to co-occur in most patients with AD (patients with hypertension are more likely to have vascular dementia). The results of this study show that the hypertensive subgroup who received placebo during the original study (but received rivastigmine during the open-label extension and thus are termed late starters ) declined significantly faster than those who had been receiving rivastigmine all along. They were never able to catch up to the early starters, as shown in Figure Nonhypertensive patients showed a smaller difference in benefit between early starters and late starters, with the early starters able to catch up to the late starters by study end. 29 In a 12- month study of patients with mild AD (n = 11) or MCI (n = 22), cognitive function was slightly improved or maintained in the patients with mild AD and unchanged Figure 7.Treatment Response to Rivastigmine Based on Rate of Disease Progression Rapidly Progressive Patients Change from week 26 ADAS-cog score Baseline Placebo Rivastigmine Treatment, wk * Slowly Progressive Patients * Improvement * Decline The benefits peaked at week 38, but the difference between the 2 groups remained throughout the 52-week study. ADAS-cog = Alzheimer s disease assessment scale-cognitive. Reprinted with permission from Farlow et al. Arch Neurol. 21;58: Vol. 2, No. 5 October 25

8 or slightly worsened in the patients with MCI (both groups receiving rivastigmine); cognitive function was markedly worsened in untreated patients with AD. 3 There was also a significant correlation between dose of rivastigmine and degree of plasma acetylcholinesterase inhibition (mean inhibition: 34.7% with higher doses; -4% with lower doses). 3 GALANTAMINE The efficacy of galantamine was demonstrated in 4 randomized, double-blind, placebo-controlled studies (Table 1) 2 in the United States and 2 international studies Subsequently, 3 studies have evaluated the long-term safety and efficacy of galantamine in patients with AD in extensions of the initial clinical Table 4. ADLs Affected Based on Degree of AD Severity with Rivastigmine or Placebo Treatment GDS 3 GDS = 4 GDS 5 PDS Item Mean change Improvement, % Mean change Improvement, % Mean change Improvement, % Cannot handle money -.1 vs -4.1* 49 vs 33* Cannot tell time.5 vs vs 4 Dials telephone numbers 2.1 vs vs 44 Increased time doing hobbies/pursuits 2.4 vs vs 43 Takes normal precautions 1. vs vs 4 Unable to drive alone 1.3 vs vs 42 Has a clear concept of time.1 vs vs 4 Discusses politics -.1 vs vs 38 Dresses properly -.5 vs vs vs vs 32 Drives car safely -1.9 vs vs 33 Forgets things.9 vs -3.3* 52 vs 32* -1.5 vs -5.3* 4 vs 28* Rearranges objects.7 vs vs vs -5.8* 45 vs 3* Stops participation in family finances -1.4 vs vs 32 Cannot use telephone -3.1 vs -7.6* 42 vs 3* Confusion in different settings -2.3 vs -6.5* 42 vs 28* Good eating manners -2.5 vs -6.7* 42 vs 28* Makes mistakes doing hobbies/pursuits -1.1 vs -6.8* 44 vs 27* Does hobbies/pursuits Stops household chores Walks/travels alone Tells time Uses tools properly Cannot discuss family finances Walks safely Cannot accurately care for finances Stops social attendance Drives own car Works at his/her job Meaningfully discusses TV, movies, and similar events with spouse, family, or caregiver This table shows the ADLs as listed in the PDS. The PDS items with data were significantly changed from baseline during the study in the observed cases dataset. AD severity was measured by the GDS and divided into 3 groups. As the GDS score increases, the severity of AD increases. *Indicates P <.5 for rivastigmine versus placebo in the intent-to-treat dataset. AD = Alzheimer s disease; ADL = activity of daily living; GDS = Global Deterioration Scale; PDS = Progressive Deterioration Scale. Reprinted with permission from Potkin et al. Prog Neuropsychopharmacol Biol Psychiatry. 22;26: Advanced Studies in Pharmacy 167

9 Figure 8. Effects of Rivastigmine on PDS Scores in Hypertensive and Nonhypertensive Patients Over 2 Years a) Hypertensive subgroup P = Week Riv n: Pla n: Early starters of rivastigmine treatment b) Nonhypertensive subgroup Late starters of rivastigmine treatment Week Riv n: Pla n: Change from baseline, PDS Change from baseline, PDS AD severity was based on scores from the PDS. AD = Alzheimer s disease; PDS = Progressive Deterioration Scale; Pla = placebo; Riv = rivastigmine. Reprinted with permission from Erkinjuntti et al. Int J Clin Pract. 23;57: trials. A 12-month extension of the original 5-month double-blind study revealed sustained cognitive benefits in persons who had taken galantamine during the entire study duration (Figure 9), maintaining cognition at or above baseline levels for at least 12 months and benefit up to 18.5 months. 35 Two other long-term studies, which were 36-month open-label extensions of the original double-blind studies, showed a roughly 5% slower cognitive decline in patients treated continuously with galantamine compared to predicted rates of decline in a clinically similar historical control sample of patients with AD. 36,37 In a 24-month openlabel extension of a 12-month double-blind study in patients with AD and CVD or vascular disease, galantamine treatment for the entire 36 months resulted in significantly lower cognitive decline compared to those patients who had originally received placebo. Baseline levels were maintained for approximately 12 months in patients with AD and CVD. 38 Galantamine has also recently been evaluated regarding its effect on nursing home placement and ADLs. A secondary analysis of the original 5-month study showed that galantamine treatment resulted in little or no decline from baseline in ADL measures compared to significant decline in the placebo group. ADL stabilization was seen throughout the range of AD severity, but the greatest differences were observed in those patients with severe disease. 32,39 Galantamine treatment resulted in maintenance or improvement in ADL and IADL measures, with significant improvement over placebo in 3 of 6 basic ADLs (toileting, bathing, and grooming) and 6 of 17 IADLs (conversation, managing personal belongings, current events, writing, hobbies, and operating household appliances). 39 The effect of galantamine on caregiver time is also impressive. Pooled data from 2 randomized, double-blind, placebo-controlled 6-month studies show that caregivers reported spending a mean of 32 fewer minutes per day (approximately 3.5 hours per week) with the galantamine-treated patients than with placebo-treated patients. In the subgroup of patients with moderate AD, the benefits were Figure 9. Mean Change in ADAS-cog Score from Baseline in a 12-Month Extension of a 5-Week Trial of Galantamine Versus Placebo* Mean change in ADAS-cog/11 from baseline Placebo Galantamine 16 mg/day Galantamine 24 mg/day 6-week washout Placebo washout Galantamine 24 mg/day Time, mo Patients received 16 or 24 mg/day galantamine or placebo during the 5- week phase. After a 6-week washout period, all of the patients then received 24 mg/day galantamine for an additional 12 months. *Reduced scores indicate improvement. ADAS-cog = Alzheimer s disease assessment scale-cognitive. Reprinted with permission from Lyketsos et al. Am J Geriatr Psychiatry. 24;12: Vol. 2, No. 5 October 25

10 even greater mean daily time savings of 53 minutes (>6 hours per week). Similarly, galantamine-treated patients could spend 27 more minutes per day unsupervised and, in the moderate AD group, the benefit was extended to 68 more minutes of unsupervised time per day. 4 Galantamine has an oral solution available. HEAD-TO-HEAD COMPARISONS Direct comparisons of cholinesterase inhibitors are rare in the published literature. Wilcock et al performed a long-term comparison of galantamine (24 mg/day) to donepezil (1 mg/day) at multiple centers in the United Kingdom in a rater-blinded, randomized study of 182 patients. 41 Measures of ADLs and neuropsychiatric symptoms did not differ significantly between the 2 treatment groups at study end (52 weeks). However, cognition measures showed a greater benefit with galantamine treatment. MMSE scores did not change appreciably from baseline in the galantamine group, but decreased significantly (indicating worsening of disease) in the donepezil group at 52 weeks. Although it favored galantamine, the betweengroup difference in MMSE score was not significant. However, in a subgroup of patients, the increased benefit with galantamine on ADAS-cog was significant compared to donepezil. 41 CHOLINESTERASE INHIBITORS AND ANTICHOLINERGIC DRUGS Anticholinergic drugs are part of many therapeutic drug classes and are commonly prescribed. They are notorious for undesirable cognitive effects, to which patients with AD are especially sensitive. Their concurrent use is likely to negate any of the cognitive benefit with cholinesterase inhibition. Carnahan et al reported on the concurrent use of anticholinergic drugs and cholinesterase inhibitors in a cross-sectional study of Iowa Medicaid beneficiaries aged 5 years and older. 42 A surprising 35.4% of these patients received concurrent anticholinergic agents and cholinesterase inhibitors. Roughly 33% of patients received an anticholinergic agent within 9 days (before or after) of starting the cholinesterase inhibitor. 42 Pharmacists should monitor their patients drug profiles when a cholinesterase inhibitor is prescribed to avoid this unfortunate situation, which incurs notable costs to the patient and the healthcare industry. NMDA ANTAGONISTS Memantine is the only NMDA antagonist approved for the treatment of AD. Its efficacy was demonstrated in 2 randomized, double-blind, placebo-controlled studies in the United States (Table 1). 43,44 Memantine has been studied and approved for use in patients with moderate to severe AD, as opposed to the cholinesterase inhibitors, which are approved for use in mild to moderate AD. In addition to these studies, memantine was compared to placebo in patients already receiving stable doses of donepezil. When memantine was coadministered with this cholinesterase inhibitor, there was an added benefit with regard to measures of cognition, ADLs, global outcome, and behavior. For example, using the CIBIC+, 55% of the memantine group improved or were unchanged compared to 45% of the placebo group. 44 An oral solution of memantine was recently approved by the FDA, which offers an alternative that may make administration easier for patients who have trouble swallowing tablets or prefer taking medication in liquid form. VITAMINS E AND C Vitamin E is a lipophilic vitamin found in all cell membranes; one of its primary roles is maintenance of cell membrane structure. Vitamin E also acts as an antioxidant by neutralizing the effects of oxygen free radicals (for a review, please see Dr Jackson-Siegal s article in Part 1 of this series). This important function is thought to play a role in preventing or treating the ravages of AD by addressing the oxidative stress hypothesis (ie, that β amyloid induces lipid peroxidation and creates reactive oxygen and nitrogen species). These species carry an unpaired electron, thus they are unstable; they look to bond with other molecules. Vitamin E is able to donate a hydrogen atom, thus stabilizing the reactive species. Vitamin C may be involved in recycling the vitamin E from its oxidized form for further use and is also a known antioxidant. 45 The recommended daily allowance of vitamin E is 22 IU for adults, which can typically be obtained through the diet. 45 As recently reviewed, the few studies evaluating vitamin E and/or C for prevention of AD (through diet or nutritional supplements) do not provide any clear direction. Some studies show a benefit with 1 or both vitamins, whereas other studies show no effect. 45,46 Variations in study design and source of the vitamins (diet, daily supplement, and multivita- Advanced Studies in Pharmacy 169

11 min) also make overall interpretation difficult. 45,46 Similarly, studies of vitamins E and C as treatments for AD have been mixed. 45,46 As one set of authors concludes, So, the answer to the question, Is tocopherol [vitamin E] worth prescribing to prevent Alzheimer s disease?, remains a resounding Maybe! 45 In a recent meta-analysis, Miller et al showed that high-dose vitamin E supplements may increase allcause mortality and should be avoided. 47 Nonetheless, as outlined later in this article, leading medical organizations endorse consideration of vitamin E for treatment of AD at a recommended dose of 2 IU, except in patients with vitamin K deficiency (in whom this large dose may exacerbate coagulation defects). Petersen et al, in a double-blind study, compared the effects of 2 IU vitamin E, 1 mg donepezil, or placebo in patients with MCI over 3 years. 48 There was no significant difference in the rate of progression to AD among the 3 groups, although donepezil showed some benefit during the first 12 months and in apolipoprotein E- 4 allele carriers. 48 ANTI-INFLAMMATORY AGENTS The inflammation hypothesis for AD maintains that β-amyloid deposits, neurofibrillary tangles, and damaged neurons may stimulate inflammation as a natural response to cell damage. However, these inflammatory processes may ultimately do more harm than good. Over the past 5 to 1 years, several studies have reported benefits with use of nonsteroidal antiinflammatory drugs (NSAIDs) with regard to lowering the risk of developing AD. A 23 meta-analysis of the existing literature (using 9 studies) showed that the pooled relative risk of AD among users of NSAIDs was.72 (95% confidence interval [CI],.56.94). 49 Among short-term users (ie, <1 month), the risk was.95 (95% CI, ), decreasing to.83 (95% CI,.65 1.) among intermediate users (<24 months) and further still to.27 (95% CI,.13.58) among long-term users (mostly >24 months). In studies of aspirin as the only NSAID, the pooled relative risk of AD was.87 (95% CI,.7 1.7). In all of the studies, users were older than 55 years of age. Thus, the benefits with NSAIDs may increase with longer use. 46 A more recent meta-analysis of 11 studies of exposure to nonaspirin NSAIDs showed that the combined risk for development of AD was.51 (95% CI,.4.66) with NSAID exposure. 5 Among the prospective studies, for lifetime exposure, the risk was.74 (95% CI,.62.89); for use of at least 2 years, the risk was.42 (95% CI,.26.66). 49 Therefore, NSAID use does appear to have a preventive benefit, but the appropriate timing of exposure remains to be studied. Placebo-controlled studies of prednisone (2 mg/day for 1 month, followed by 1 mg/day for 1 year) and a comparison of rofecoxib (a cyclooxygenase-2 inhibitor) and naproxen (an NSAID) showed no benefit on cognition measures in patients with AD. 51,52 Some clinicians think that the risk of side effects, such as adverse cardiac events or gastrointestinal bleeding and stomach ulcers, from using NSAIDs in the elderly outweighs any possible benefits, if any. STATINS In recent years, cholesterol has been implicated in the pathogenesis of AD, based on several findings. In the human body, cholesterol is synthesized only in the liver and brain through a complicated enzymatic pathway. One of these enzymes (HMG-CoA [3-hydroxy- 3-methylglutaryl coenzyme A] reductase) is inhibited by statins, which are drugs used to treat dyslipidemia. In the brain, cholesterol is synthesized primarily in astrocytes and is transported elsewhere through apolipoproteins, including apolipoprotein E (a specific allele of the gene that codes for this protein is a risk factor for AD). As reviewed by Wolozin, mutations in some of the genes involved in cholesterol catabolism and transport may be risk factors for AD, and some of the proteins that they encode have been shown to reduce β-amyloid production. 53 However, serum cholesterol levels do not appear to correlate with risk of AD, and statin levels do not affect production of β amyloid in humans, although they do have an effect in vitro and in mice. 53 Population-based studies suggest that statins reduce the risk of AD progression, although not AD development Analysis of various AD populations indicates that statin use reduces the risk of AD progression by up to 7%. 53,54 Therefore, it is thought that statins offer a neuroprotective or anti-inflammatory effect, rather than inhibiting accumulation of β-amyloid plaques. 53 There have been few clinical studies of statins for AD. A double-blind, placebo-controlled pilot study compared the effect of 8 mg/day atorvastatin versus placebo in patients with mild to moderate AD. After 1 year of statin exposure, the ADAS-cog and CIBIC+ 17 Vol. 2, No. 5 October 25

12 scores indicated benefit compared to placebo, but just barely avoided statistical significance (P =.55 and P =.7, respectively). 57 Because it was a pilot study, the final participant numbers at 12 months were low (n = 46). 57 Another study of simvastatin 2 mg/day for 6 months evaluated cerebrospinal fluid levels of various AD-related proteins (eg, tau, phosphorylated tau, β amyloid, and other proteins) and found significant reductions in some of them, and slight improvement based on ADAS-cog score (P <.5). 58 However, in a randomized double-blind study by Muldoon et al, comprising 38 hypercholesterolemic adults between 35 and 7 years of age, participants showed minor decrements in cognitive functioning with statins. 59 The participants received daily treatment with placebo, 1 mg of simvastatin, or 4 mg of simvastatin for 6 months. A neuropsychological test battery was administered to assess cognitive functioning at baseline and at the end of the treatment. Decremental effects of simvastatin treatment on cognitive functioning were found on tests previously observed to be sensitive to statins (P =.8; CI,.7.29) and on tests not previously administered (P =.4; CI,.5.29) compared to placebo. 59 Clearly, more clinical data are required to determine whether statins may have a role in the treatment options for AD. THERAPEUTIC CHOICES The American Psychiatric Association published their guidelines on treatment of patients with demen- Table 5. The Currently Available Treatments for AD Symptoms A Summary* Drug AD Indication Dosing Common Adverse Events Possible Drug Interactions Donepezil Mild to 5 or 1 mg; treatment with a 1-mg moderate dose should not be considered until patients have been on a daily dose of 5 mg for 4 6 weeks to avoid adverse events Rivastigmine Mild to 3 6 mg twice daily; starting dose: moderate 1.5 mg twice daily; increase to 3 mg twice daily after 2 weeks; other dose increases should be separated by at least 2 weeks Galantamine Mild to 8 12 mg twice daily, preferably with Nausea and vomiting moderate morning and evening meals; 24 mg/d may provide additional benefit for some patients, but is associated with more adverse events; starting dose: 4 mg twice daily; increase to initial maintenance dose after at least 4 weeks Memantine Nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia Nausea, vomiting, loss of appetite, dyspepsia, asthenia, and weight loss Moderate to Target dose: 2 mg/day; starting dose: Confusion, dizziness, headache, and severe 5 mg/day; titration: increase in 5-mg increments to 1 mg/d (5 mg twice daily), 15 mg/d (5 and 1 mg as separate doses), 2 mg/d (1 mg twice daily); minimum recommended interval between dose increases is 1 week; can be taken with or without food constipation Metabolized by CYP2D6 and CYP3A4 and undergoes glucuronidation No drug interactions with drugs metabolized by the following enzymes are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19 CYP2D6 and CYP3A4 are the major enzymes involved in galantamine metabolism; galantamine levels increase when coadministered with ketoconazole, paroxetine, erythromycin, and cimetidine; galantamine clearance decreased by coadministration of amitriptyline, fluoxetine, fluvoxamine, and quinidine; does not inhibit CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6, or CYP2E1 No induction of CYP1A2, CYP2C9, or CYP2E1; minimal inhibition of CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4; no pharmacokinetic interactions with drugs metabolized by these enzymes are expected *Tacrine continues to remain on the market, but it is rarely used because of its potential hepatotoxicity and other adverse events. Based on clinical studies. AD = Alzheimer s disease. Data from Donepezil US prescribing information 65 ; Galantamine US prescribing information 66 ; Memantine US prescribing information 67 ; Rivastigmine US prescribing information. 68 Advanced Studies in Pharmacy 171

13 tia in The guidelines were updated in 24 to incorporate the significant developments since the original publication. 61 The American Academy of Neurology s guidelines, published in 21, have been endorsed by the American Geriatrics Society. 62,63 Guidelines for family physicians have also been published. 64 All of these professional organizations recommend the use of acetylcholinesterase inhibitors for treatment of mild to moderate AD, noting comparable efficacy among the 3 drugs and the importance of clearly conveying expected outcomes to patients and family members/caregivers. Table 5 summarizes the dosing schedule, common adverse events, and common drug interactions of the 4 FDA-approved drugs for AD (excluding tacrine) All 3 guidelines recommend vitamin E or support consideration of its use to slow or delay disease progression (updated guidelines may change vitamin E recommendations), but they cite insufficient evidence to support the use of anti-inflammatory medications in patients with AD. However, it is worth noting that these guidelines were established before the publication of many of the NSAID studies. 6,62,63 Similarly, statins and memantine are not mentioned in any of the current guidelines. CONCLUSIONS Although some clinicians may argue that the measured effect of cholinesterase inhibitors or memantine is minimal, in reality any preservation of function and delay of nursing home placement has important and permanent consequences for the patient and caregiver. Physicians may also now be prescribing other treatments such as statins, vitamins E (updated guidelines may change vitamin E recommendations) and/or C, or NSAIDs to help delay AD progression, as new clinical data emerge. The pharmacist needs to be aware of the following: the expected outcomes with these drugs and their impact on the patient and caregiver, the importance of reiterating these expectations to the patient and caregiver, the common concurrent prescribing of cholinesterase inhibitors with anticholinergic drugs in older adults, the use of newer agents as possible preventive treatments for AD, and any updates in recommended treatment strategies from the leading medical organizations. REFERENCES 1. Lane RM, Potkin SG, Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol. 25;5: Giacobini E, Spiegel R, Enz A, et al. 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Am J Psychiatry. 25;162: Bohnen NI, Kaufer DI, Hendrickson R, et al. Degree of inhibition or cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer s disease. 172 Vol. 2, No. 5 October 25