Which cholinesterase inhibitor for early dementia?

In a multicenter, double-blind trial,¹⁷ patients with vascular dementia or AD with vascular risk factors received galantamine, up to 24 mg/d, or placebo for 6 months. Compared with controls, those taking galantamine showed improved cognition, behavior, and function. The drug overall was well tolerated, with nausea and vomiting the most common side effects.

Parkinson’s dementia. Emre et al¹⁸ evaluated rivastigmine’s efficacy and safety in patients whose mild-to-moderate dementia developed at least 2 years after a clinical diagnosis of Parkinson’s disease (PD). Patients were randomly assigned to placebo or rivastigmine, 3 to 12 mg/d, for 24 weeks, and 410 of 541 enrollees completed the study. Compared with placebo, rivastigmine was associated with statistically significant improvements in cognition and global measures in dementia associated with PD but also with higher rates of nausea, vomiting, and tremor. PD’s motor symptoms did not change significantly in either group.

Mixed dementia states. As mentioned, galantamine improved cognitive and noncognitive abilities in patients with vascular dementia or AD with vascular risk factors in a 6-month, double-blind trial.¹⁷ Patients who received galantamine or placebo could then continue open-label galantamine, 24 mg/d, for another 6 months. In patients treated the full 12 months, galantamine continued to improve or maintain:

• cognition, based on Alzheimer’s Disease Assessment Scale-cognitive subscale scores
  
• functional ability, measured by the 40-item Disability Assessment for Dementia
  
• behavior, measured by the Neuro-psychiatric Inventory.¹⁹
  

After 12 months, the rivastigmine-treated patients were less behaviorally impaired than the matched patients, and their caregivers reported reduced stress. Rivastigmine did not prevent cognitive deterioration, as assessed with the Mini-Mental State Examination (MMSE).

Mild cognitive impairment. Persons with MCI have objective psychometric evidence of memory loss compared with their peers, but they are not significantly impaired in activities of daily living or other cognitive functions (language, abstract thinking, or problem-solving).

At this time, we do not recommend using ChEIs to treat MCI. These agents have shown little benefit and potential risk in patients who do not meet diagnostic criteria for dementia:

• Salloway et al²¹ tested donepezil’s efficacy and safety in 270 patients with MCI in a 24-week, double-blind, placebo-controlled trial. Donepezil was started at 5 mg/d for 42 days, then escalated to 10 mg/d. Compared with placebo, donepezil showed no significant effects on recall, but some improvements were seen in attention and psychomotor speed.
  
• In two unpublished placebo-controlled trials, galantamine did not improve memory when given for 2 years to elderly patients with MCI. A precaution was added to the drug’s prescribing information because 13 of the 1,026 patients taking galantamine died, compared with 1 of 1,022 taking placebo. Vascular disease caused one-half of the galantamine group deaths. No evidence of increased mortality risk has been seen in studies of galantamine in patients with mild-to-moderate AD, for which it is indicated.
  

Getting The Greatest Response

To gauge response to ChEI therapy, family reports about the patient are helpful—such as that cognition has improved or cognitive decline has not progressed as rapidly as before. Assessment tools such as the MMSE can document improvement or stabilization.

We recommend trying an initial ChEI for at least 6 months to determine its efficacy. If your patient cannot tolerate one ChEI or fails to respond to initial treatment, two consensus panels^22,23 recommend that you consider changing ChEIs:

• If switching because of intolerable side effects, wait at least 2 to 3 days after stopping the first ChEI before starting another.
  
• If switching because of poor response, you can start a different ChEI immediately after the first one is stopped.
  

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