As the U.S. population ages, dementia becomes a bigger public health concern because of associated problems (e.g., long disease duration, caregiver burden, cost of providing care) and an increasing prevalence, which is projected to rise to one in 45 Americans within the next 50 years. The most common types of dementia are Alzheimer's disease, vascular dementia, Lewy body dementia, and mixed dementia. Currently, there is no cure for dementia, but pharmacologic interventions can help to delay disease progression and ease symptoms. This guideline, which was created by the American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP), reviews the data on the effects of pharmacologic treatment of dementia for improving cognition, global function, behavior/mood, and quality of life (QOL)/activities of daily living (ADL).

Clinically Important Improvement vs. Statistical Significance

The AAFP and ACP evaluated statistically significant changes and clinically important improvements of various treatment options. Some of the studies in this guideline used a change of four or more points on the Alzheimer's Disease Assessment Scale for Cognition (ADAS-Cog) to define clinically important improvement; other studies used seven points or more. A change of three or more points on the Mini-Mental State Examination is considered to be a clinically important improvement. With the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) scale, any change is considered a clinically important improvement, but the results are also dependent on the physician's perceptions.

Cholinesterase Inhibitors

DONEPEZIL (ARICEPT)

Data were collected from a total of 21 studies (19 studies comparing donepezil with placebo, one with vitamin E, and one with galantamine [Razadyne]). These studies lasted less than one year. Adverse events were associated with a withdrawal rate of 0 to 57 percent in the treatment groups and 0 to 20 percent in the placebo groups. No statistically significant differences were noted in the number of serious adverse events in the treatment or placebo groups, with the exception of expected side effects from cholinesterase inhibitors (e.g., diarrhea, nausea, vomiting).

Overall, the average change in cognitive score among patients taking donepezil was statistically significant, but not clinically important. A subset of nine studies showed that, although a modestly higher proportion of patients had a clinically important change in cognitive score, usually statistical significance of the findings was not reported; therefore, there is insufficient evidence to determine whether a subgroup of patients taking donepezil had clinically important improvement in cognition. Many of the studies also found improvement on global assessments but, again, the clinical importance of these improvements was unclear. Some studies found improvement in ADL scores among patients with Alzheimer's disease and vascular dementia, with no serious adverse effects. Because of the short duration of the studies, long-term effects of donepezil are unknown.

GALANTAMINE

Data were collected from eight high-quality studies (seven studies comparing galantamine with placebo and one with donepezil). These studies lasted less than one year. Adverse events were associated with a withdrawal rate of 8 to 54 percent in the treatment groups and 4 to 17 percent in the placebo groups. Common adverse effects were gastrointestinal symptoms, eating disorders or weight loss, and dizziness.

Pooled evidence showed a statistically significant average improvement in cognition (as measured by the ADAS-Cog) in patients taking galantamine; however, this improvement was not clinically important. Interpretation of these data should be done cautiously because the improvement in cognition was not reported in all of the studies and because it was only a secondary outcome in the ones that did. Because of the short duration of the studies, long-term effects of galantamine are unknown.

RIVASTIGMINE (EXELON)

Data were collected from eight high-quality studies comparing rivastigmine with placebo. These studies lasted 14 to 26 weeks. Adverse effects were associated with a withdrawal rate of 12 to 29 percent in the treatment groups and 0 to 11 percent in the placebo groups. Adverse effects were similar to those of cholinesterase inhibitors (e.g., dizziness, nausea, vomiting, eating disorders or weight loss, headache).

Rivastigmine did not improve cognition as measured by the ADAS-Cog, but did show clinically important improvement as measured by global assessment with the CIBIC-Plus scale. Behavior, mood, and QOL/ADL did not improve significantly. Because of the short duration of the studies, long-term effects of rivastigmine are unknown.

TACRINE (COGNEX)

Data were collected from eight moderate-quality studies (six studies comparing tacrine with placebo, one with silymarin [the active ingredient of milk thistle], and one with idebenone [a synthetic variant of coenzyme Q10]). These studies lasted less than one year. Adverse effects were associated with a withdrawal rate of 0 to 55 percent in the treatment groups and 0 to 12 percent in the placebo groups. Adverse effects were serious and increased as dosages increased. Six of eight studies reported elevated ala-nine transaminase levels and other hepatic abnormalities. In addition to the serious liver abnormalities, nausea, vomiting, gastrointestinal problems, and dizziness were reported.

The data are insufficient to confirm a beneficial effect of tacrine on measures of cognition or behavior, although global assessment showed statistically significant improvement in two of three trials. Also, serious adverse effects were associated with tacrine use.

Neuropeptide-Modifying Agent

MEMANTINE (NAMENDA)

Data were collected from four high-quality studies comparing memantine with placebo. These studies lasted 24 to 48 weeks, with one study lasting only 12 weeks. Adverse effects were associated with a withdrawal rate of 9 to 12 percent in the treatment groups and 7 to 13 percent in the placebo groups. Adverse effects included nausea, dizziness, diarrhea, and agitation.

Treatment with memantine had statistically significant, but not clinically important, improvement in cognition scores for moderate to severe Alzheimer's disease and in level of severity for Alzheimer's disease and vascular dementia as measured by the ADAS-Cog. Estimates of global assessment with the CIBIC-Plus scale were statistically significant but of marginal clinical importance. Limited data show improvement in QOL/ADL, caregiver burden, and utilization of resources.

Summary

Many of these pharmacologic agents have demonstrated statistically significant, but not clinically important, improvements in scores on instruments used to measure dementia. However, most of the instruments are not routinely used in clinical practice and interpreting the clinical importance of improvements can be difficult. Data on improvements on global assessment were available for donepezil, galantamine, rivastigmine, and memantine, but the improvements were generally modest. The data were mixed regarding improvements in QOL/ADL. Data on tacrine showed that there were serious adverse effects related to its use; adverse effects from the other cholinesterase inhibitors were more tolerable. There are no convincing data that one agent is better than another for managing dementia. Most of the studies lasted less than one year; therefore, long-term effects of treatment are unknown.

Recommendations

• The decision to start a trial of therapy with cholinesterase inhibitors or memantine should be based on individual patient assessment (e.g., benefits, risks).

  If the patient has more advanced dementia, improving QOL should take precedence over stabilizing or slowing symptoms. All of the drug treatments were associated with adverse effects, and although the data show statistically significant improvements with some cholinesterase inhibitors and memantine, the improvements typically were not clinically important in cognition and were only modestly clinically important for global assessments. Currently, it is unclear how to predict which patients may have clinically important responses to treatment; therefore, these agents should not be prescribed to every patient with dementia. Data on optimal treatment duration and when to stop treatment are lacking. If slowing decline is no longer a goal of treatment, memantine or cholinesterase inhibitor use is no longer appropriate.

• Physicians should choose pharmacologic treatment based on tolerability, adverse effect profile, ease of use, and cost of medication. Data are insufficient to compare the effectiveness of different pharmacologic agents.

  The cholinesterase inhibitors mentioned above have been approved for treatment of mild to moderate dementia. Memantine has been approved for treatment of moderate to severe Alzheimer's disease and has shown mild benefits in patients with mild vascular dementia. Major contraindications of cholinesterase inhibitor and memantine use include uncontrolled asthma, angle-closure glaucoma, sick sinus syndrome, and left bundle branch block.

• Further research is needed to determine the clinical effectiveness of pharmacologic treatment of dementia.

  Research is also needed to determine the optimal therapy duration in patients who have stabilized or improved. A comparison of effectiveness of various agents, as well as an evaluation of effectivenss of combination therapy, would help physicians to determine the benefits of pharmacologic treatment of dementia.