The first study reviewed published randomized trials of the 3 approved ChEIs and concluded that they were modestly and similarly effective for mild to moderate AD. The second study showed that treatment with donepezil and vitamin E appeared to slow rates of brain atrophy on magnetic resonance imaging (MRI) in patients with mild cognitive impairment (MCI) who were carriers of the e4 allele of the apolipoprotein E gene (APOE 4).

Both studies were presented at the 10th International Conference on Alzheimer's Disease and Related Disorders (ICAD 2006) held in Madrid, Spain.

"Despite the slight variations in the mode of action of the 3 cholinesterase inhibitors, there is no evidence of any differences between them with respect to efficacy," presenter Jacqueline Birks, MA, MSc, CStat, from the Cochrane Dementia and Cognitive Improvement Group, University of Oxford, England, told Medscape.

First-Line Therapies
"Since the introduction of the first ChEI as treatment for AD, many clinicians have used the approved cholinergic drugs ? donepezil, galantamine, and rivastigmine ? as first-line therapies for mild to moderate Alzheimer's," Ms. Birks said. "Yet, a debate on whether ChEIs are effective continues."

Tacrine was the first FDA-approved ChEI for Alzheimer's disease, but it is no longer recommended because of its complex titration schedule, risk of hepatic toxicity, and other adverse effects. In 2005, the National Institute for Clinical Excellence (NICE), the independent treatment advisory agency of the UK's government-funded National Health Service, reviewed its previous recommendation that the other 3 ChEIs be used for their approved indication in mild to moderate AD.

"The draft revision indicated that the ChEIs would no longer be recommended as they were not cost-effective," Ms. Birks said. "Due to widespread protests from the public and the medical profession, NICE is reconsidering and may recommend the ChEIs for moderate AD only."

To provide additional evidence regarding the efficacy and tolerability of donepezil, galantamine, and rivastigmine at the recommended optimal doses in mild to moderate AD, Ms. Birks conducted a systematic review of all blinded, randomized trials in which ChEI treatment for at least 5 months was compared with placebo or with another ChEI. Outcome measures included cognitive function, global function evaluated by a clinician, mood and behavior, activities of daily living, and adverse events.

In 10 trials enrolling a total of 7300 patients, treatment with donepezil, galantamine, or rivastigmine for periods of 6 months and 1 year produced improvements compared with placebo in cognitive function (average, -2.7 points [95% confidence interval [CI], ?3.0 to ?2.3] on the 70-point ADAS-Cog scale), activities of daily living, and behavior. Clinicians rated global clinical state more positively in ChEI-treated patients than in those who received placebo.

"There was plenty of evidence from 18 trials that the drugs are efficacious, cognitive function was improved, and the doctors assessed more patients as improved overall on the treatment than on the placebo, but the difference in numbers is not large," Ms. Birks said. "There was some evidence that patients were better at the activities of daily living on treatment, and that problems with difficult behavior improved. None of the treatment effects are large."

Study withdrawal for adverse events was higher with ChEIs (29%) than with placebo (18%).

"Patients suffered more adverse effects, such as nausea, vomiting, and diarrhea on the drugs, than on the placebo, but these side effects are not so bad that they outweigh the benefits," Ms. Birks said. "From the evidence provided by one trial there appear to be fewer adverse events associated with donepezil compared with rivastigmine."

One unblinded study compared donepezil with galantamine, and another compared donepezil with rivastigmine. There was no evidence of a treatment difference between donepezil and galantamine at 52 weeks, or between donepezil and rivastigmine at 2 years, for any efficacy measure. However, fewer patients suffered adverse events with donepezil than with rivastigmine. Evidence from 2 trials on the cost of health resource utilization showed no difference between donepezil and placebo. To date, there are no data on costs for galantamine or rivastigmine.

"The cholinesterase inhibitors donepezil, galantamine, and rivastigmine are efficacious for AD of mild to moderate severity, and they show similar treatment effects," Ms. Birks concluded. "There is some evidence that the results are similar for severe dementia. It would be inappropriate to base any decision regarding the availability of the ChEIs on their cost-effectiveness, for which there is no good evidence."

Strongest Evidence to Date
Earlier this month, the American Association for Geriatric Psychiatry (AAGP) developed a position paper to guide clinicians with evidence and expert opinion regarding the care of patients with AD with ChEIs and other medical and nonmedical therapies. The AAGP statement noted that the ChEIs are the class of drugs with the strongest evidence to date supporting their efficacy in treating the cognitive symptoms of mild to moderate AD. Although available direct comparison studies of ChEIs have shown some differences in tolerability and dropout rates, there are no consistent differences in efficacy, and there are no published long-term trials directly comparing all 3 ChEIs.

AAGP Task Force Chair Constantine Lyketsos, MD, MHS, who was not involved in the 2 studies presented at ICAD, reviewed these presentations for Medscape.

"ChEIs have an important role in the treatment of AD," said Dr. Lyketsos, who is a professor and chair of psychiatry at Johns Hopkins Bayview and School of Medicine in Baltimore, Maryland. "While their effects are small, as the AAGP guideline suggests, their availability and the pros and cons of their use should be discussed with every Alzheimer's patient and their proxy decision-makers as appropriate. They appear to have similar efficacy, although some carry more risk than others."

Donepezil to Prevent MCI?
The second study was an offshoot of the placebo-controlled vitamin E and donepezil study for the treatment of MCI, conducted at 69 centers with 769 participants. At 24 of these centers, 194 subjects underwent MRI, and 131 completed both a baseline and follow-up scan, either at the end of the study (36 months) or when they appeared clinically to convert from MCI to AD.

"We found a small but statistically significant reduction in the rate of brain shrinkage in patients with MCI who were treated with donepezil," presenter Clifford R. Jack Jr, MD, a professor of radiology at Mayo Clinic College of Medicine in Rochester, Minnesota, told Medscape. "This was seen only in those who carried the e4 allele of the apolipoprotein E gene, which is a risk factor for Alzheimer's disease. This is the first study to show that a treatment can reduce rates of brain shrinkage in MCI."

Rates of atrophy were greater in those who were diagnosed with AD during the course of the study. The rate of hippocampal shrinkage in donepezil-treated APOE 4 carriers was 4.5% per year compared with 6.14% per year in patients receiving placebo. Vitamin E did not significantly affect hippocampal atrophy in any patients.

Although donepezil is the only drug shown to affect the rate of hippocampal atrophy in APOE 4 carriers with MCI, the other 3 ChEIs have not been similarly tested for an effect on brain volume. Dr. Jack noted that donepezil had "a very small effect" on MRI findings. Rather than stopping the disease from progressing, it appeared to just slightly slow the rate. However, preventing conversion of MCI to AD is an important clinical goal.

In addition to small magnitude of the effect, other study limitations include small sample size, positive findings for only 1 of 4 MRI measures, and lack of generalizability beyond APOE 4 carriers.

"This study supports a previous study out of Duke utilizing magnetic resonance spectroscopy to suggest that donepezil may attenuate disease progression, but this has yet to be established clinically," Dr. Lyketsos said. "The AAGP position statement speaks for itself. In the future we may be using MRI to assess drug effects, but we are not there yet."

Ms. Birks and Dr. Jack report no relevant financial relationships. The donezepil-vitamin E trial was conducted under the auspices of the Alzheimer's Disease Cooperative Study and was funded by the National Institute of Aging (NIA), Pfizer, Eisai, and DSM Nutritional Products.

The MRI adjunct study was partially funded by the Institute for the Study of Aging. Dr. Lyksetos reports grant support from the National Institutes of Mental Health, NIA, Forest, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Eli Lilly & Company, Ortho-McNeil, Bristol-Myers Squibb, and Novartis. He is a consultant and advisor to AstraZeneca, GlaxoSmithKline, Eisai, Novartis, Forest, and Supernus, and he has received speaking honoraria from Pfizer, Eisai, Novartis, Forest, and GlaxoSmithKline.