Dementia: Update for the Practitioner

There is clear, strong, and repeated evidence that there is a rationale for the use of cholinesterase inhibitors in mild to moderate Alzheimer's disease patients, and they may also be useful in advanced Alzheimer's disease. There is also growing evidence for benefits in cognitive measures in nursing-home populations, but we know these effects are not huge and they will not reverse the disease.

There is clear evidence that higher doses are associated with better effects, and these are both larger and broader effects. For example, the higher approved doses of galantamine and with rivastigmine are shown to have benefits on measures of functional decline, improvements or stabilization of activities of daily living, and lower incidence of behavioral disturbances. It is important to recognize that there are guidelines for dose escalation for these agents, but slower escalation may have a benefit.

It is often worth trying a second agent if one does not work because there may be individual sensitivities, but it is very clear that there are some individuals who never tolerate the cholinergic side effects, no matter how slowly you titrate the dose. If you are looking at efficacy as an outcome for making a decision about stopping a drug, you need to recognize that the medication needs time to work, and that you may not see an improvement—you might simply be reducing decline. If the decision is made to discontinue a drug, often because of intolerance to the side effects, you may see some deterioration when the medication is stopped.

Cholinesterase inhibitors may have an effect in individuals outside the Alzheimer's disease population. A six-month double-blind placebo-controlled trial of galantamine in patients who had both vascular dementia and Alzheimer's disease showed an improvement in the overall population with a target dose of 24 milligrams. This study tells us that it may be important to pay attention to diagnostic specificity. Individuals who had Alzheimer's disease with evidence of cerebrovascular disease saw a clear significant effect, while the effect was smaller in individuals with pure vascular dementia. There was a borderline effect on the ADAS-cog and no effect on CIBIC.


Primary Efficacy Outcomes at Six Months in Diagnostic Subgroups

Assessment	Placebo	Galantamine	Treatment difference (95% CI)	p
ADAS-cog/11: mean(SE) change from baseline Alzheimer's disease with cerebrovascular disease (n=239) Vascular dementia (n=188)	1.8 (0.6)* -0.4 (0-78)	-1.0(0.46)† -2.4(0.59)†	-2.7 (-4.16 to -1.17) -1.9 (-3.88 to 0.08)	0.0005 0.06
CIBIC-plus: patients with improvement (number %) Alzheimer's disease with cerebrovascular disease (n=239) Vascular dementia (n=188)	16(19%) 16(23%)	49(32%) 37(31%)	" "	0.019 0.238
*p<0.05:†p<0.024 vs baseline. All statistics based on the intention-to-treat population.
Table 3: Primary efficacy outcomes at 6 months of follow-up in diagnostic subgroups

Results of a six-month double-blind placebo-controlled trial of Galantamine in patients with vascular dementia and Alzheimer's Disease. Courtesy of Dr. Mary Sano. Source of data: T. Erkinjuntti et al., "Efficacy of Galantamine in Probable Vascular Dementia and Alzheimer's Disease Combined with Cerebrovascular Disease: A Randomized Trial," The Lancet 359, no. 9314 (April 13, 2002): 1283–90.

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