Cholinesterase Debate

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Cholinesterase Debate
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Question

• Why is British Columbia special

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British Columbia is Special Because.

• Only province with no pharmacare coverage
• Two tier medicine exists
• We have politicians who are able to deflect
  responsibility and not be held accountable

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Alois Alzheimer 100 years
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Neurofibrillary Tangles
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Efficacy-Cognitive Improvement
benefit
no benefit
Lanctot et al, CMAJ, 2003
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Efficacy Clinical Global Impression
benefit
no benefit
9 6, 12 of patients show significant benefit
over placebo
Lanctot et al, CMAJ, 2003
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Number Needed to Treat for Benefit

• Numbers needed to treat to benefit were
• 7 (CI95 6, 9) for stabilization or better
• 12 (CI95 9, 16) for minimal improvement or
  better
• 42 (CI95 26, 114) for marked improvement

Numbers needed to treat for clinically
significant benefit are low. Homogeneous-all 3
ChEIs are similar
Lanctot et al, CMAJ, 2003
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Tolerability
Caveat Galantamine above recommended doses,
heterogeneity
8 5,11
7 3,10
8 5,12
Lanctot et al, CMAJ, 2003
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1-year Preservation of Function Study with
Donepezil

• Design
• 1-year, randomized, placebo-controlled,
  double-blind
• Subjects
• 431 patients with mild-to-moderate AD
• Aged 49-94, mean MMSE 17.1
• Primary Outcome
• Time to clinically evident functional decline,
  defined by
• Decline in ? 1 basic ADL present at baseline
• Decline of ? 20 of the instrumental ADL present
  at baseline
• Increase ? 1 point from baseline in global CDR
  score (Clinical Dementia Rating scale)

Mohs et al. Neurology. 2001
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Time to Clinically Evident Functional Decline
Kaplan-Meier survival estimates The probability
of survival (maintaining functional ability) at
48 weeks was 51 for donepezil 35 for placebo
Survival curve comparison p0.002 (log-rank
test) p0.005 (Wilcoxon test)
As judged by investigator, ITT population
Mohs et al. Neurology. 2001
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Rivastigmine-Placebo Group Does Not Catch Up To
Treated Group
612 mg/day rivastigmine
14 mg/day rivastigmine
Placebo
Proj. placebo
2 0 2 4 6 8
ADAS-Cog mean change from baseline
All patients restarted on rivastigmine
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0 10 20 30 40
50
Study week
B352 patients in Study B353 (OC) at week 52
plt0.05 vs projected placebo
Messina et al., 2000
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H
Time 0 18 months 36 months
Courtesy C Jack, Mayo Clinic, Rochester
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Donepezil-treated Patients Had Significantly Less
Reduction From Baseline in Hippocampal Volume
Hippocampal volume (mm3)
P0.036
P0.122
P0.018
Krishnan KRR, et al. Am J Psychiatry.
2003112003-2011
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AD2000 longer term study in mod-severeAD of
donepezil

• Two year, double blind, RCT in AD on
  donepezil versus placebo in a family practice
  setting in the UK
• Findings donepezil produced small improvements
  in cognition and activities of daily living in
  patients with moderate AD.
• However this was interpreted to be not
  clinically significant as no delay in NHP, loss
  of milestones, or reduction in caregiver costs
  was found
• ISSUES a) not clear if groups were matched
• b) large dropout ( 40 1-yr 77 2-year, 96
  3-year)
• c) 51 of total sample--CVD

(Lancet, 2004)
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Cholinesterase Inhibitors selectively benefit
multiple cognitive domains (1-Year)
Dementia Rating Scale

• Treated patients showed less decline on
• overall cognition
• naming
• visuospatial and visuoconstructive skills
• executive functions

plt0.0001 d 0.7
Behl et al 2006
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Multiple Cognitive Domains (2-Years)
Verbal Memory

• Treated patients showed less decline on
• overall cognition
• memory
• naming
• executive functions

p0.007 d1 0.8 d2 0.4
Behl et al 2006
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Function (1- 2-Years)
Basic ADL
Instrumental ADL
plt0.0001 d10.4 d2 0.7
p0.006 d0.60
Behl et al 2006
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Cholinesterase Inhibitors Patients and
Families Point of View

• Questionnaire posted to UK Alzheimers Society
  and memory clinics
• Asked whether, taking everything into
  consideration, they felt that the drug treatment
  they received had worked and to give 5 ways it
  had helped
• 2295 respondents with treatment exposure
• 68 stated that the drug treatment had worked
• Examples of benefits
• Increased awareness and activity
• Improved conversation
• Better quality of life
• Increased confidence
• Taking more interest in things
• Results similar to Australian survey indicating
  70 felt drugs had worked

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Translating Study Results to Real Patients

• More than 150 scales have been developed to
  measure possible changes
• Comparing statistical significance to clinical
  relevance
• Important to have realistic expectation Assess
  regularly Consider functional
  status Consider co-morbid illness

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What I tell Patients

• Not memory pills repetitive questions continue
• Behavior and function pills
• Stability (no decline) positive result
• Rule of thirds
• Not disease modifying agents honeymoon of 2 to 3
  years
• Document target symptom for monitoring

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This Patient and Others

• After 12 to 16 weeks improvement
• 69 yr old women traveling in Europe
• 82 yr old man with Lewy body dementia and
  hallucinations
• 86 year retired judge after 5 years of treatment

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10 Years Later- Where are we?

• More than 80 studies show improvement compared to
  placebo
• Benefits seen in first 2 years with waning after
  this
• Some Dementias eg. LBD show dramatic improvement
• Degree of improvement and clinical relevance of
  improvement best judged by patient , family and
  attending physician
• Side effects relatively mild