Essay: Cholinesterase inhibitors improve cognitive function in Parkinson’s disease dementia

Cholinesterase inhibitors improve cognitive function in Parkinson’s disease dementia while increasing risk of adverse events
Clinical Bottom Line:  Cholinesterase inhibitors improve cognitive function decline in Parkinson’s Disease dementia (PDD) but increases adverse events, specifically parkinsonian symptoms and tremor.
Clinical Scenario: An elderly man has Parkinson’s disease with dementia.  He’s becoming increasingly forgetful and the patient and his family are hoping to find a safe drug that could help with his decline in cognitive function.
Search Process: PubMed was searched with the keywords “Parkinson’s Disease” and “cognitive function.”  Results were limited to meta-analysis, humans and English language.  There were four results, and one was a recent Cochrane review.
Chosen article: Rolinski M, Fox C, Maidment I, and McShane R. (2012) Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson’s disease dementia and cognitive impairment in Parkinson’s disease. Cochrane Database of Systematic Reviews, Issue 3. CD006504.  Chosen as the best available evidence because it is a Cochrane review.
Study Design and Validity: The study was a meta-analysis of 6 randomized, double-blind, placebo-controlled trials that were from both published and gray literature. Four of the trials were 18 weeks long and two were 10 weeks.  The total N=1236.
Strengths:  Two review authors independently selected trials from both published and gray literature using the Cochrane Handbook guidelines and excluded trials with significant bias.  The studies were required to be randomized, double-blind and placebo-controlled trials. There was heterogeneity in the trials considering the patient’s diagnosis (PDD, DLB, and cognitive impairment in Parkinson’s disease), but the analysis looked at the effects on the different diagnoses separately.
Weaknesses:  The authors may not have been blinded to the studies and it does not state that a consensus between the authors was needed.  The validity criteria were not stated, besides using the Cochrane database guidelines.  Though they searched gray literature, a funnel plot was not addressed.  Despite the significant finding in the improvements in cognitive function, the forest plot shows that one set of results lies not only outside the diamond, but on the opposite side of the line (favors control rather than experimental).  There was also heterogeneity in the type of cholinesterase inhibitor drug used, and the adverse reactions were significant in the studies using rivastigmine, but not donepezil.  The authors state that the randomization and blinding processes were not adequately described in some and all of the studies, respectively.  Additionally, they stated that the follow-up period for two of the studies was too short for significant disease progression. Lastly, the data from one trial, sponsored by Pfizer, has incomplete presentation of data, despite attempts to contact the authors.
The Evidence:
• Treatment with cholinesterase inhibitors in PDD, DLB and cognitive impairment with no dementia in PD compared to placebo benefits patients as the pooled estimated standardized mean difference = -.34, 95% CI = -.46 to -.23, p < .00001.
• The treatment group also experienced more adverse events than the placebo group (OR=1.64, 95% CI = 1.26-2.15, P = .004). ARR = .7-.79-= -.09.  NNH = 11.
Comments:
• The rate of severe adverse effects was equal in the placebo and treatment groups.
• The results are only significant for PDD (as the studies are dominantly PDD patients) and should not be generalized to DLB or cognitive impairment with no dementia in PD.
• Cholinesterase inhibitors were also shown to have positive effects on global assessment, behavioral disturbances and activities of daily living rating scales in patients with PDD.
• Despite the weaknesses of the study, it shows that cholinesterase inhibitors can have a slight positive effect on cognitive abilities, but the increased risk of adverse effects should be considered.