PL Detail-Document #280510

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PHARMACISTS LETTER / PRESCRIBERS LETTER
May 2012

Pharmacotherapy and Advancing Alzheimers Disease

Background
Pharmacotherapy options for Alzheimers
disease include the cholinesterase inhibitors
donepezil (e.g., Aricept), rivastigmine (Exelon),
and galantamine (Razadyne [U.S.], Reminyl
[Canada]), and the N-methyl-D-aspartic acid
(NMDA) receptor antagonist memantine
(Namenda [U.S.], Ebixa [Canada]). The
American College of Physicians and the American
Academy of Family Physicians have published
guidelines for pharmacologic treatment of
dementia based on two meta-analyses.1 They
conclude that there is not enough evidence to
recommend one agent over another based on
efficacy. Also, there is no way to determine if or
how a particular patient will respond to therapy.
If the chosen agent seems to benefit the patient,
what should be done when the patient ultimately
worsens? Should a different agent, combination
therapy, or higher dose be tried? Should
pharmacotherapy be continued at all? This article
reviews evidence to help guide these decisions.
Testing the Options: the DOMINO Study
Almost 300 noninstitutionalized patients with
moderate to severe Alzheimers disease (mini-
mental state exam score 5 to 13) who had been
taking donepezil for at least three months were
randomized to continue donepezil 10 mg daily,
discontinue donepezil, add memantine, or switch
to memantine. The patients were followed for a
year. Two hundred eighteen patients completed
the study, but one hundred fourteen patients had
less than 70% adherence (n=114). Intent-to-treat
analysis was used. The primary outcome
measures were the mini-mental state exam score
and the Bristol Activities of Daily Living Scale
(BADLS). Compared to patients who
discontinued donepezil, the mini-mental score of
patients who continued donepezil was 1.9 points
higher (95% CI 1.3 to 2.5, p<0.001), indicating
better cognitive function. They also had a 3-point
lower BADLS score on average (95% CI 1.8 to
Copyright 2012 by Therapeutic Research Center
P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
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4.3, p<0.001), indicating better function. Patients
with less severe disease benefited most from
donepezil. Patients who received memantine had
a mini-mental score that was 1.2 points higher on
average than patients who received placebo (95%
CI 0.6 to 1.8, p<0.001). BADLS score were 1.5
points lower on average (95% CI 0.3 to 2.8,
p=0.02). There was no benefit to adding
memantine to donepezil.2
The study authors considered a change of 1.4
points on the mini-mental score and a change of
three points on the BADLS score to be clinically
meaningful. However, others consider a 3-point
change in the mini-mental score to be the
minimum clinically meaningful change.1
More on Donepezil Plus Memantine
The DOMINO study may have been
underpowered to detect a benefit of combination
therapy over monotherapy. A previous larger
(n=404) study of memantine plus donepezil versus
donepezil alone in moderate to severe
Alzheimers disease (mini-mental state exam
score 5 to 14) showed a statistically significant
benefit of combination therapy in both cognitive
and functional performance.3 Primary efficacy
measures were the Severe Impairment Battery
(SIB), a 100-point measure of cognition, and the
ADCS-ADL19 (modified 19-item Alzheimers
Disease Cooperative Study-Activities of Living
Inventory), a measure of function. The intent-to-
treat method using the last observation carried
forward was used for missing data. The SIB
increased 0.9 points in the group using both
memantine plus donepezil, but decreased by 2.5
points in the donepezil-only group, a difference of
3.4 points (p<0.001).3 There is no accepted
clinically important change for the SIB.4
However, for comparison, in validity testing of
the SIB, the six-month rate of change was a
decrease of about three points in patients with
mini-mental scores of 5 to 15 who were not taking
dementia meds.5 The ADCS-ADL19 decreased by
More. . .

3.4 points in the placebo group and by 2 points in
the memantine group (p=0.03).3 This is a
relatively small change on a 0 to 54-point scale.
Differences in treatment groups occurred early
and were maintained through six months. No
additive effect on adverse events was noted with
combination therapy.
A subsequent study (n=433) included patients
with a mini-mental exam score of 10 to 22 (mild
to moderate disease) who had been taking a stable
dose of a cholinesterase inhibitor. Patients were
randomized to receive, in addition to their
cholinesterase inhibitor, memantine 20 mg once
daily or placebo. Primary outcome measures were
the ADAS-cog (Alzheimers Disease Assessment
Scale-cognitive subscale) and the Clinicians
Interview-Based Impression of Change Plus
Caregiver Input scale (CIBIC+), a measure of
global function. Three hundred eighty-five
patients completed the study, and 427 were
included in the intent-to-treat analysis. There was
no statistically significant difference between
memantine and placebo. Combination therapy
was not associated with an increased risk of
adverse effects.6
A recent systematic review that included these
two studies3,6 concluded that the addition of
memantine to an acetylcholinesterase inhibitor
provides no additional benefit on cognitive,
behavioral, functional, or global measures.7
Aricept 23 mg
In 2010, a new, higher dose of Aricept (23 mg)
was approved in the U.S. Donepezil 23 mg was
compared to donepezil 10 mg in over 1300
patients with probable Alzheimers disease with
moderate to severe impairment. Randomization
was stratified based on whether the patient was
taking memantine at baseline (about 36% of
patients). The study lasted 24 weeks. Primary
efficacy measures were the SIB and the CIBIC+.
By the end of the study, the CIBIC+ score was not
different between groups. The SIB score had
increased 2.6 in the high-dose group vs 0.4 in the
10 mg daily group, a difference of 2.2 points
(p<0.001).8
Almost 19% of patients in the Aricept 23 mg
group discontinued treatment due to side effects,
compared to about 8% of the patients in the
donepezil 10 mg daily group. The most common
adverse effects in the 23 mg daily and 10 mg daily
groups, respectively, were vomiting (9.2% vs
Copyright 2012 by Therapeutic Research Center
P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com
(PL Detail-Document #280510: Page 2 of 4)
2.5%), nausea (11.8% vs 3.4%), diarrhea (8.3% vs
5.3%), anorexia (5.3% vs 1.7%), dizziness (4.9%
vs 3.4%), and weight loss (4.7% vs 2.5%). The
adverse effects most commonly leading to
discontinuation were vomiting, nausea, diarrhea,
and dizziness.8
Commentary
Dementia medications provide only a modest
benefit, on average.1 Not all patients benefit. In
an analysis of cholinesterase inhibitor studies, the
NNT for minimal improvement on a global
assessment scale was 12.9 The number needed to
treat for clinical significance is likely higher, but
is unavailable because studies have not been
designed to assess clinically significant benefit.
The number needed to treat to cause an adverse
effect was also 12. The number needed to treat to
result in one patient withdrawing from the study
due to an adverse effect was 16.9
Any benefit from a dementia medication
should be seen within three to six months.1,10
Dementia medications do not slow the rate of
disease progression, and they have not been
proven to reduce the need for nursing home
placement.11
Continuing donepezil when a patient worsens
to moderate to severe disease maintains function
at a slightly higher level compared to stopping it
[Evidence level B; lower-quality randomized
controlled trial].2 Adding memantine is not likely
to benefit patients on a cholinesterase inhibitor
who have progressed to moderate to severe
disease.2,7
Caregivers should be warned that
discontinuation of pharmacotherapy may cause
cognitive and behavioral decline. The patient
should be monitored closely so that the
medication can be reinstituted quickly if
needed.12,13,18 Symptoms may not be fully
reversible if there is a delay in restarting
pharmacotherapy.18 For example, consider
reducing the donepezil dose from 10 mg to 5 mg
once daily for four weeks before stopping it.2
Aricept 23 mg very slightly improves
cognition compared to the 10 mg dose, but
doesnt improve overall function, a better measure
of what caregivers will notice.14 Also, it
significantly increases the risk of nausea and
vomiting.8
Cholinesterase inhibitors cause gastrointestinal
side effects including nausea, vomiting, diarrhea,
More. . .

and abdominal cramps. Donepezil seems to be
the best tolerated agent. Cholinesterase inhibitors
have also been associated with bradycardia and
syncope.11 Memantine is generally better
tolerated than the cholinesterase inhibitors, but is
not effective in mild to moderate disease.11 If
donepezil is intolerable, consider switching to
memantine in moderate to severe disease. It
doesnt work quite as well as staying on
donepezil, but it might be better than stopping
everything [Evidence level B; lower-quality
randomized controlled trial].2
As disease progresses, nonpharmacologic
interventions become more important.4 This
includes trying to identify and minimize causes of
problematic behaviors.15 Nonpharmacologic
interventions include maintaining a stable, low
stress environment, avoiding noise and glare,
providing security objects, and daytime activity to
improve nighttime sleep.15,16
Conclusion
Ultimately, caregivers and patients must
decide whether pharmacotherapy provides
meaningful improvement for Alzheimers
patients, and whether it is worth the side effects
and cost. Assess benefit based on caregivers
observations of the patients cognition, behavior,
and function, and possibly mini-mental state exam
score.17 Consider stopping dementia meds when a
patients impairment becomes severe (e.g., mini-
mental exam score of 10 or less). Such patients
are often incontinent, and unable to groom or
dress themselves or communicate effectively.
Even their distant memories may be gone.17
Admission to a nursing home or hospice care
might be a good time to consider whether
dementia medications should be continued.
Users of this PL Detail-Document are cautioned to use
their own professional judgment and consult any other
necessary or appropriate sources prior to making
clinical judgments based on the content of this
document. Our editors have researched the
information with input from experts, government
agencies, and national organizations. Information and
internet links in this article were current as of the date
of publication.
Copyright 2012 by Therapeutic Research Center
P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com
(PL Detail-Document #280510: Page 3 of 4)
Levels of Evidence
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF EVIDENCE
for the statements we publish.
Level Definition
A High-quality randomized controlled trial (RCT)
High-quality meta-analysis (quantitative
systematic review)
B Nonrandomized clinical trial
Nonquantitative systematic review
Lower quality RCT
Clinical cohort study
Case-control study
Historical control
Epidemiologic study
C Consensus
Expert opinion
D Anecdotal evidence
In vitro or animal study
Adapted from Siwek J, et al. How to write an evidence-based
clinical review article. Am Fam Physician 2002;65:251-8.
Project Leader in preparation of this PL Detail-
Document: Melanie Cupp, Pharm.D., BCPS
References
1. Qaseem A, Snow V, Cross JT Jr, et al. Current
pharmacologic treatment of dementia: a clinical
practice guideline from the American College of
Physicians and the American Academy of Family
Physicians. Ann Intern Med 2008;148:370-8.
2. Howard R, McShane R, Lindesay J, et al.
Donepezil and memantine for moderate-to-severe
Alzheimers disease. N Engl J Med 2012;366:893-
903.
3. Tariot PN, Farlow MR, Grossberg GT, et al.
Memantine treatment in patients with moderate to
severe Alzheimer disease already receiving
donepezil: randomized controlled trial. JAMA
2004;291:317-24.
4. Raina P, Santaguida P, Ismaila A, et al.
Effectiveness of cholinesterase inhibitors and
memantine for treating dementia: evidence review
for a clinical practice guideline. Ann Intern Med
2008;148:379-97.
5. Schmitt FA, Ashford W, Ernesto C, et al. The
severe impairment battery: concurrent validity and
the assessment of longitudinal change in
Alzheimers disease. Alzheimer Dis Assoc Disord
1997;Suppl 11:S51-6.
6. Porsteinsson AP, Grossberg GT, Mintzer J, et al.
Memantine treatment in patients with mild to
moderate Alzheimers disease already receiving a
cholinesterase inhibitor: a randomized, double-
blind, placebo-controlled trial. Curr Alzheimer Res
2008;5:83-9.
More. . .
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7. Peninsula Medical School. Universities of Exeter
and Plymouth. Peninsula Technology Assessment
Group (PenTAG). The effectiveness and cost-
effectiveness of donepezil, galantamine,
rivastigmine and memantine for the treatment of
Alzheimers disease (review of TA111): a Psychiatry 2003;18:282-4.
systematic review and economic model. June 18,
2010. http://www.nice.org.uk/nicemedia/live/122
48/49789/49789.pdf. (Accessed April 16, 2012).
8. Farlow MR, Salloway S, Tariot PN, et al.
Effectiveness and tolerability of high-dose (23
mg/d) versus standard-dose (10 mg/d) donepezil in
moderate to severe Alzheimers disease: a 24-
week, randomized, double-blind study. Clin Ther
2010;32:1234-51.
9. Lanctot KL, Herrmann N, Yau KK, et al. Efficacy
and safety of cholinesterase inhibitors in
Alzheimer's disease: a meta-analysis. CMAJ
2003;169:557-64.
10. AAGP position statement: principles of care for
patients with dementia resulting from Alzheimer
disease.
http://www.aagponline.org/index.php?src=news&su
bmenu=Tools_Resources&srctype=detail&category
=Position%20Statement&refno=35. (Accessed
April 13, 2012).
11. Herrmann N, Chau SA, Kircanshi I, Lanctot KL.
Current and emerging drug treatment options for
Alzheimers disease: a systematic review. Drugs
2011;71:2031-65.
12. Overshott R, Burns A. Treatment of dementia. J
Neurol Neurosurg Psychiatry 2005;76(Suppl 5):53-
9.
13. Singh S, Dudley C. Discontinuation syndrome
following donepezil cessation. Int J Geriatr
14. Schwartz LM, Woloshin S. How the FDA forgot the
evidence: the case of donepezil 23 mg. BMJ
2012;344:e1086. doi:10.1136/bmj.e1086.
15. American Psychiatric Association. Practice
guideline for the treatment of patients with
nd
Alzheimers disease and other dementias 2
edition. October 2007.
http://psychiatryonline.org/data/Books/prac/AlzPG1
01007.pdf. (Accessed April 4, 2012).
16. Alzheimers Association. Behavioral and
psychiatric symptoms of Alzheimers disease.
March 2008.
http://www.alz.org/national/documents/topicsheet_
behavepsych.pdf. (Accessed April 4, 2012).
17. American Geriatrics Society. A guide to dementia
diagnosis and treatment.
http://dementia.americangeriatrics.org/documents/
AGS_PC_Dementia_Sheet_2010v2.pdf.
(Accessed April 11, 2012).
18. Kwak YT, Han IW, Suk SH, Koo MS. Two cases of
discontinuation syndrome following cessation of
memantine. Geriatr Gerontol Int 2009;9:203-5.

Cite this document as follows: PL Detail-Document, Pharmacotherapy and Advancing Alzheimers Disease.
Pharmacists Letter/Prescribers Letter. May 2012.

Evidence and Recommendations You Can Trust

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