Donepezil preserves cognition and global function in patients with severe Alzheimer disease
Black SE, Doody R, Li H, McRae T, Jambor KM, Xu Y, et al.;
Commented by , 15 Aug 2007
Aim of the study
To evaluate the efficacy and safety of donepezil for severe Alzheimer's disease (AD).
Method
Multinational, randomized, double-blind, placebo-controlled study comparing donepezil 5 then 10 mg in two doses versus placebo over 24 weeks in patients living in the community or assisted living with Mini Mental State Examination (MMSE) scores 1 to 12 and Functional Assessment Staging scores ≥ 6.
Primary endpoints were the Severe Impairment Battery (SIB) and the Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC+). Secondary outcomes included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ASL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), the Resource Utilization for Severe AD Patients (RUSP).
Efficacy analysis were performed using the intent-to-treat (ITT) population using last post-baseline observation carried forward (LOCF).
Results
343 patients were randomized to either donepezil or placebo; the mean MMSE at baseline was 7.5 and 7.4. 58.5% of patients allocated to donepezil and 61.2% of patients allocated to placebo had never been on a cholinesterase inhibitor (ChEI), memantine or propentofylline; a 3-month washout had been done for patients on these drugs.
The SIB scores were significantly better on donepezil at 2, 16, 24 weeks and endpoint (least square mean difference 5.32; p = 0.0001), giving a Cohen effect size of 0.4145; 63.3% of patients on donepezil had improvement or no change versus 39.4% on placebo.
CIBIC favored donepezil at endpoint (p = 0.0473) with 66.1% of donepezil patients and 51.9% of placebo patients rated as improved or no change. The MMSE at endpoint favored donepezil (p = 0.0267). Unfortunately there was no difference on ACDS-ADL-sev, NPI (trend for placebo-treated patients actually doing better than on donepezil), CBQ and RUSP.
Adverse events were consistent with the known cholinergic effects of donepezil, including diarrhea, nauseam, vomiting, anorexia; drop out rates were 33.5% on donepezil, 24% on placebo; 2 deaths on donepezil, 8 on placebo.
Professor Gauthier's comments
This study is important because it adds convincing evidence that donepezil can be beneficial for cognition and global functioning in patients with severe AD still living in the community.
This evidence is complementary to studies done in Canada/Australia/France with patients in moderate to severe stages of AD living in the community (ref. 1) and in Sweden with patients living in a nursing home setting (ref. 2).
The troubling finding is that except in the moderate to severe AD study, there is no demonstrable improvement of behavior using the NPI total score. Agitation may actually be higher in the current study on donepezil than on placebo, an observation often made by nurses in nursing home when cholinesterase inhibitors are used for the first time.
Further analysis of the NPI individual items may prove useful to better define the behavioral effects of donepezil (and by extension the class of ChEI) in severe AD.
These studies have been successful in convincing American and Canadian regulatory agencies to extend the label for use of donepezil in the severe stage of AD. It is now necessary to update the clinical use guidelines for this drug and agree on stopping rules when the severity of dementia makes the use of this drug no longer appropriate.
References
1. Feldman H, Gauthier S, Hecker J, Vellas B, Xu Y, Ieni JR, et al. Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial. International Journal of Geriatric Psychiatry 2005; 20(6); 559-569
2. Winblad B, Kilander L, Eriksson S, Minthon L, Båtsman S, Wetterholm AL, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006; 367 (9516); 1057-1065