Tools for Practice

#107 Cholinesterase inhibitors and treatment of Alzheimer’s dementia

What are the benefits and harms of cholinesterase inhibitors (ChEI) for Alzheimer’s dementia?

Evidence for ChEI in Alzheimer’s dementia is generally limited by small differences and high drop-out rates. Approximately one in ten patients show meaningful clinical improvement when treated for six months and ~1 in ten patients stop using the drug due to an adverse event. 

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Over 20 meta-analyses are published on ChEI (donepezil, galantaminerivastgimine) for Alzheimer’s dementia. 
  • Focus on Cochrane review1 of 13 trials (7,298 patients) and four other systematic reviews.2-5 Data shown when ≥2 studies provide values, generally for common doses and follow-up ≥6 months. 
    • ChEI vs. placebo statistically significant, but not clinically meaningful, mean change in cognition scores: 
      • ADAS-Cog (out of 70): overall -2.37,1 varying from -1.49 to  -3.91, depending on study.1-5 
      • MMSE (out of 30): overall 1.37, varying from -0.04 to 1.37, depending on study.1-3,5 
    • Number who had clinically meaningful improvement: 
      • ADAS-Cog >4: Number Needed to Treat (NNT) 6-18.3,4 
      • Global clinical improvement: NNT 6-17.1-4 
    • Harms: 
      • Drop-out due to adverse events: Number Needed to Harm (NNH) 10 overall.1 
      • Specific example with donepezil:2 anorexia (NNH 17), diarrhea (NNH 10), nausea (NNH 11), vomiting (NNH 13), weight loss (NNH 18), and insomnia (NNH 24). 
  • Potential biases: 
    • Trials: drop-out rates up to 35% and often more among ChEI,6 drop-outs analyzed like their cognition was stable,6,7 poor description of randomization.2,6 
    • Meta-analyses: using single reviewers1-3 or inclusion of biased studies. 
  • Dementia guidelines and reviews have ranged from supporting8,9 to not supporting10,11 their use. 
  • Three year non-profit community trial found no difference in institutionalization.12 Although anticipated to be a landmark study, there were multiple issues including <20% intended enrolment, >40% lost to follow-up in first year. 
  • Costs for three months13 are $495 donepezil, $130 galantamine, and $135 rivastigmine. 
  • The large number of meta-analyses likely speaks more about people’s willingness to accept the answer than the answer itself. 

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  • Candy Marcet MD PhD
  • G. Michael Allan MD CCFP

1. Birks J. Cochrane Database Syst Rev. 2006; (1):CD005593.

2. Birks J, Harvey RJ. Cochrane Database Syst Rev. 2006; (1):CD001190.

3. Birks J, Grimley Evans J, Iakovidou V, et al. Cochrane Database Syst Rev. 2009; (2):CD001191.

4. Loy C, Schneider L. Cochrane Database Syst Rev. 2006; (1):CD001747.

5. Raina P, Santaguida P, Ismaila A, et al. Ann Intern Med. 2008; 148(5):379-97.

6. Kaduszkiewicz H, Zimmerman T, Beck-Bornholdt HP, et al. BMJ. 2005; 331(7512):321-7.

7. Molnar FJ, Man-Son-Hing M, Hutton B, et al. Open Med. 2009; 3(2):e31-50.

8. National Institute of Health and Clinical Excellence (NICE 2006). NICE technology appraisal guidance 217. Available at: Last accessed January 7, 2013.

9. Gauthier S, Patterson C, Chertkow H, et al. Can Geriatr J. 2012; 15(4)120-6.

10. National Institute of Health and Clinical Excellence (NICE 2006). Appraisal consultation document: Alzheimer’s disease. Available at: Last accessed January 7, 2013.

11. Drugs for alzheimer’s disease. Therapeutics Initiative. Therapeutics Letter Issue 56 / Apr-Aug 2005. Available at: Last accessed January 7, 2013.

12. Courtney C, Farrell D, Gray R, et al. Lancet. 2004; 363(9427):2105-15.

13. Kolber MR, Lee J, Nickonchuk T. Price Comparison of Commonly Prescribed Pharmaceuticals in Alberta 2014. ACFP 2014. E-pub, 2014.

Authors do not have any conflicts of interest to declare.