ChEIs for the AD Continuum: Redefining Treatment Criteria

Although cholinesterase inhibitors (ChEIs), specifically donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), are considered first-line treatment for Alzheimer disease (AD), they are not FDA-approved for use in late-stage disease. Indeed, treatment guidelines recommend their discontinuation once patients progress to "severe disease." Stage classifications of AD may be arbitrary, however, and perhaps more relevant to regulatory bodies than to clinicians. As studies emerge suggesting that ChEIs may be of value across the continuum of AD, the treatment paradigm is being reexamined.

"The original approval of [ChEIs] for the management of mild and moderate AD was controversial, largely because of the difficulty in assessing outcomes in AD. Consequently, the FDA limited indication to patients with mild or moderate AD. All subsequent [ChEIs] have followed the same general rule; hence the limiting of their use to mild and moderate AD," said David Geldmacher, MD, associate professor of neurology and director of the Memory Disorders Program at the University of Virginia in Charlottesville. "Alzheimer disease is a continuum. It probably begins biologically before the first symptom emerges. There is no pathophysiologic line that distinguishes moderate from severe disease."

One of the difficulties reflected by the FDA approval process is measuring the effectiveness of the medication in a person whose dementia is advanced to the point where he or she can no longer comprehend the testing instrument. "That is an instrument failure, not a drug failure. Sometimes those two things are confused," Geldmacher said.

GAUGING ChEI VALUE IN ADVANCED AD

Although more sensitive tests may be needed, cognitive batteries used to determine treatment effectiveness may not be germane in guiding patient management. "In the end-and this is my personal opinion-cognitive tests don't matter," Geldmacher said. "They matter to regulators because regulators and insurance companies have to decide whether it's worthwhile to approve a medication. To patients and families and to physicians who care for those patients, what's really important is functional response. That is, when the patient takes the medicine, is he able to perform functionally for a longer time than if he didn't take it?"

For example, if a patient with AD is reaching a point where functional response can no longer be measured, it might be the time for the physician to advise the family to discontinue medication because the meaningfulness of stimulating cognition has ebbed. "If the patient can no longer tell that his spouse of 50 years is his spouse and not the nursing aid, I'm not providing them with a meaningful benefit," Geldmacher said. "However if when I stop the medicine the patient who had been ambulatory and continent becomes nonambulatory and incontinent, I'm likely to restart the medicine," he added.

"I'm always willing to pull the plug on the medication if the goals are not being met," Geldmacher said. "Whenever I do that, I also want to make sure that new adverse behaviors are not emerging as a result of my treatment change," he explained.

Therefore, it is imperative that treatment goals be individualized and formulated early on to suit the patient's circumstance as well as that of the family or other caregivers. By not identifying treatment goals in this way, physicians may instead end up abandoning the patient to preexisting and perhaps arbitrary care guidelines. "This is particularly problematic in long-term-care settings where it's often not a neurologist who's guiding the care the anymore, but rather a generalist or internist nursing home physician," Geldmacher said.

REDEFINING "SUCCESSFUL TREATMENT"

Given the current parameters within which "successful treatment" of AD is defined, greater awareness among clinicians is needed about the value of ChEIs. "any physicians say that [ChEIs] don't improve memory, so they stop treatment. However, if we look at the data and the theoretical basis for how the agents work and what's happening to the brain, true improvement from baseline is not very likely," Geldmacher said. Instead, stabilization of the disease course or reduction of progression is the more likely outcome. "We do this all the time with [other diseases]. When we use statins, for example, we measure lowered cholesterol, but our desired outcome is delay in stroke or heart attack," Geldmacher said.

If the goal of treatment with ChEIs were improved memory, most patients would fail; however, if the goal of therapy were disease stabilization or maintenance of function and cognition at current levels, the majority of patients would pass that hurdle for at least 6 months, Geldmacher explained.

Theoretically, a time comes in the course of AD when not enough acetylcholine may be left for cholinesterase inhibition to have a meaningful impact. Geldmacher explained that if at symptomatic onset of AD the amount of acetylcholine in the brain is 90% of baseline, ChEIs can increase the acetylcholine level by 10%. "With the use of the [ChEI], the amount of acetylcholine in the brain would return to 99% of the original amount. In more advanced disease, levels might be down to 10% of original. Increasing that by 10% might not be clinically detectable."

Still, recent research suggests that ChEIs do indeed have value in advanced disease. A recent study reported at the annual meeting of the American Academy of Neurology (AAN) last April in San Diego and published in The Lancet¹ showed that donepezil preserved function and improved cognition in patients with severe AD.

The team, led by Bengt Winblad, MD, PhD, a professor in the Department of Clinical Neuroscience and Family Medicine and director of the Alzheimer Center at the Karolinska University Hospital in Huddinge, Sweden, compared donepezil with placebo in 248 patients with advanced disease. The dosage was 5 mg/d for 30 days, which was increased to 10 mg/d for the remainder of the 6-month study. One hundred twenty-eight patients received the study drug and 120 age-matched controls received placebo. Patient status was measured at baseline and at months 3 and 6 using the Severe Impairment Battery (SIB) and the modified Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) inventory.

Whereas patients receiving donepezil showed a mean improvement on the SIB of 3.4, patients receiving placebo showed a mean decline of 2.2. Furthermore, the decline at 6 months in ADCS-ADL inventory scores among patients in the active-treatment group was half of that seen in the placebo-treated group (21.4 vs 23.0).

Winblad and colleagues concluded that donepezil is effective even when initiated in patients with severe Alzheimer disease. Winblad noted, in speaking with Applied Neurology during last spring's AAN meeting, that more aggressive use of ChEIs in persons with AD-indeed, use even in persons with advanced disease-had the potential to alleviate the economic burden that AD care imposes on the health care system precisely because disease progression is delayed. He also noted that ChEIs are relatively inexpensive therapeutic agents.

The study by Winblad's Karolinska team confirmed findings reported in 2003 by Howard Feldman, professor and head of the Division of Neurology, and colleagues at the University of British Columbia in Vancouver.² This multinational, randomized, double-blind, placebo-controlled trial was similar to that of the Karolinska Institute. It included 290 patients with moderate to severe AD who were randomly assigned to receive either donepezil 5 mg/d for 4 weeks (increased to 10 mg/d thereafter if deemed appropriate by the treating clinician) or placebo.

Declines in activities of daily living scores were much slower for patients receiving active therapy than for those receiving placebo. The drug was equally effective in patients with moderate and severe disease. Furthermore, the impact of the disease on caregivers in terms of stress and time spent assisting the patient was less severe for those persons caring for patients who were receiving the study drug.

CURRENT DATA ON ChEIs

A recent Cochrane database systemic review by Jacqueline Birks,³ a medical statistician and coordinating editor of the Cochrane Dementia and Cognitive Improvement Group, Division of Geratology, Department of Clinical Medicine at Oxford University, showed that donepezil, rivastigmine and galantamine are equally effective in mild to moderate disease for outcomes of cognitive function and activities of daily living. The review included 13 studies with a total of 7298 participants in North America, Australia, and Europe. The data showed greater tolerability for donepezil than for rivastigmine and galantamine. In commenting on her study, Birks said that there is nothing to suggest that the effects are lesser for patients with severe dementia, although she conceded that there is currently little evidence for the use of these drugs in anything other than mild to moderate disease.

Data from another study coauthored by Birks⁴ that evaluated the effectiveness of donepezil based on 23 clinical trials (N = 5272) showed that the drug was associated with improvements in global clinical state. Compared with placebo, the odds ratio at 24 weeks in favor of 5 mg of donepezil was 2.81 (P lesser than or equal to .0001), and 2.38 (P < .00001) for 10 mg. The study authors also suggested that donezepil use was economical. They noted that in the 2 studies that evaluated health resource use and associated cost, no significant differences were found between donepezil and placebo.

Finally, findings from another recently published study⁵ suggest that ChEIs might help patients with mild to moderate dementia retain new information. The team, from the Roskamp Institute Memory Clinic in Tampa, Florida, compared 14 persons with mild AD who had been taking ChEIs with 14 controls and found that those patients taking ChEIs were better able to retain new information. Patients were tested using the Consortium to Establish a Registry for Alzheimer's Disease battery word-list test. Differences in scores related to learning and delay-free recall were not statistically significant between patient groups, but patients receiving ChEIs made significantly less errors on recognition testing than did controls.

REFERENCES

1. Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet. 2006;367:1057-1065.

2. Feldman H, Gauthier S, Hecker J, et al. Efficacy of donepezil on maintenance of activities of daily living in patients with moderate to severe Alzheimer's disease and the effect on caregiver burden. J Am Geriatr Soc. 2003;51:737-744.

3. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006;(1):CD005593.

4. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2006;(1):CD001190.

5. Crowell TA, Paramadevan J, Abdullah L, Mullan M. Beneficial effect of cholinesterase inhibitor medications on recognition memory performance in mild to moderate Alzheimer's disease: preliminary findings. J Geriatr Psychiatry Neurol. 2006;19:13-15.

CLAIRE SOWERBUTT is a freelance medical news writer in Vancouver, British Columbia.