Cochrane for Clinicians

Putting Evidence into Practice

Cholinesterase Inhibitors for Alzheimer’s Disease



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Am Fam Physician. 2006 Sep 1;74(5):747-749.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/AB005593.html.

Clinical Scenario

A 72-year-old woman is brought into the office by her daughter, who complains that her mother has become increasingly forgetful over the past two years. On a Mini-Mental State Examination (MMSE) she scores 20 out of 30 points, and after an appropriate evaluation you diagnose Alzheimer’s disease. Her daughter asks if there are medicines that could help.

Clinical Question

Do cholinesterase inhibitors improve function in persons with mild, moderate, or severe dementia caused by Alzheimer’s disease, and is one cholinesterase inhibitor better tolerated or more effective than the others?

Evidence-Based Answer

Cholinesterase inhibitors produce a small benefit on several cognitive and noncognitive function scales. Although data for patients with severe dementia are sparse, there is no evidence to suggest a difference in effectiveness among patients with mild, moderate, or severe dementia. Compared with placebo, adverse reactions are significantly more common in treatment groups. Limited evidence suggests donepezil (Aricept) is better tolerated than rivastigmine (Exelon). There is no consistent evidence to suggest treatment reduces health care costs or prolongs time until institutionalization.1

Cochrane Abstract

Background. Since the introduction of the first cholinesterase inhibitor in 1997, most clinicians, and probably most patients, would consider the cholinergic drugs donepezil (Aricept), galantamine (Razadyne [previously Reminyl]), and rivastigmine (Exelon) to be first-line pharmacotherapy for mild to moderate Alzheimer’s disease.

The drugs have slightly different pharmacologic properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve would be to modify the manifestations of Alzheimer’s disease. Cochrane reviews of each cholinesterase inhibitor for Alzheimer’s disease have been completed.

Objectives. To assess the effects of donepezil, galantamine, and rivastigmine in patients with mild, moderate, or severe dementia caused by Alzheimer’s disease.

Search Strategy. The Cochrane Dementia and Cognitive Improvement Group’s Specialized Register was searched using the terms donepezil, E2020, Aricept, galanthamin*, galantamin*, reminyl, rivastigmine, Exelon, ENA 713, and ENA-713 on June 12, 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases.

Selection Criteria. All unconfounded, blinded, randomized trials in which treatment with a cholinesterase inhibitor at the usual recommended dose was compared with placebo or another cholinesterase inhibitor for patients with mild, moderate, or severe dementia caused by Alzheimer’s disease.

Data Collection and Analysis. Data were extracted by one reviewer and pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment, were estimated.

Primary Results. The results of 13 randomized, double-blind, placebo-controlled trials demonstrate that treatment for six months with donepezil, galantamine, or rivastigmine at the recommended dose for persons with mild, moderate, or severe dementia caused by Alzheimer’s disease produced improvements in cognitive function, on average −2.7 points (95% confidence interval,−3.0 to −2.3,P < .00001), in the midrange of the 70-point Alzheimer’s Disease Assessment Scale for Cognition (ADAS-Cog). Study clinicians rated global clinical state more positively in treated patients. Benefits of treatment also were seen on measures of activities of daily living and behavior. None of these treatment effects were large. The effects were similar for patients with severe dementia, although there is very little evidence, from only two trials. More patients leave cholinesterase inhibitor treatment groups (29 percent) on account of adverse events than leave the placebo groups (18 percent).

There is evidence of more adverse events in total in the patients treated with a cholinesterase inhibitor than with placebo. Although many types of adverse event were reported, nausea, vomiting, and diarrhea were significantly more frequent in the cholinesterase inhibitor groups than in the placebo groups.

There is no evidence of a difference between the effects of donepezil and those of rivastigmine on cognitive function, activities of daily living, or behavioral disturbance at two years. There were fewer reports of adverse events among patients taking donepezil than among those taking rivastigmine.

Reviewers’ Conclusions. The three cholinesterase inhibitors studied are effective for mild to moderate Alzheimer’s disease. Despite the slight variations in the mode of action of the three drugs, there is no evidence of any differences among them with respect to effectiveness. The evidence from one large trial shows fewer adverse effects associated with donepezil compared with rivastigmine.


These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).

Practice Pointers

Alzheimer’s disease affects 4.5 million persons in the United States, including one half of all nursing home residents.2 Family physicians sometimes can feel pressured by family members to attempt to slow the course of the disease.

This Cochrane review identified 13 randomized controlled trials of cholinesterase inhibitors.1 The average age of participants in each trial typically was between 72 and 75 years, and treatment durations were between six and 12 months. Multiple measures were used to assess cognition and well-being: the Alzheimer’s Disease Assessment Scale for Cognition (ADAS-Cog), the MMSE, the Severe Impairment Battery scale, global clinical state assessments, activities of daily living scales, and a behavioral disturbance scale. After six to 12 months, pooled data showed modest benefits favoring the treatment groups. The reviewers found a 2.7-point improvement on the 70-point ADAS-Cog and a 1.4-point improvement on the 30-point MMSE in patients receiving treatment compared with those receiving placebo. The U.S. Preventive Services Task Force equates a difference of two to three points on the ADAS-Cog after one year to a delay in disease progress of about two to seven months.3

Patients taking a cholinesterase inhibitor are more likely to discontinue treatment as a result of adverse reactions than are those taking placebo (29 versus 18 percent, respectively; number needed to harm = 9). Common reactions include nausea, vomiting, and diarrhea. In a study sponsored by the manufacturer of rivastigmine, rivastigmine was less well tolerated than donepezil.1

Although their benefit is modest, cholinesterase inhibitors remain first-line treatment for Alzheimer’s disease and should be titrated as tolerated to target dosage.4 Donepezil is started at a dosage of 5 mg daily and increased to 10 mg daily after one to four weeks. Galantamine (Razadyne [previously Reminyl]) is started at a dosage of 4 mg twice daily and gradually titrated to 12 mg twice daily with stepups at one- to four-week intervals. Rivastigmine is started at a dosage of 1.5 mg twice daily and titrated over one to three months to 6 mg twice daily. The costs of one month’s supply of the target dosages are $166, $175, and $188, respectively.5

When Alzheimer’s disease becomes moderate to severe, memantine (Namenda), anN-methyl-D-aspartate antagonist, sometimes is added to therapy. In limited studies of short duration (six to seven months), memantine was found to produce modest improvement in cognition, function, and behavior when used alone or in conjunction with donepezil.6 In these studies, patients taking memantine did not experience more adverse reactions than those taking placebo. Target dosing is 10 mg twice daily, and the cost is comparable to that of a cholinesterase inhibitor.5

Many patients with Alzheimer’s disease live with and are cared for by family members; therefore, family physicians can help by referring families to the Alzheimer’s Association Web site, http://www.alz.org.

The Author

NATHAN HITZEMAN, M.D., is a faculty physician at Sutter Health Family Medicine Residency Program in Sacramento, Calif., where he also completed his residency. He received his medical degree from the University of California at Los Angeles School of Medicine.

Address correspondence to Nathan Hitzeman, M.D., Sutter Health Family Medicine Residency Program, 1201 Alhambra Blvd., Suite #300, Sacramento, CA 95816 (e-mail: hitzemn@sutterhealth.org). Reprints are not available from the author.

REFERENCES

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

2. Herbert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the U.S. population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119–22.

3. U.S. Preventive Services Task Force. Screening for dementia: recommendations and rationale. Rockville, Md.: Agency for Healthcare Research and Quality, 2003. Accessed May 18, 2006, at: http://www.ahrq.gov/clinic/3rduspstf/dementia/dementrr.htm.

4. Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, et al. Practice parameter: management of dementia (an evidence-based review). Reportof the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56:1154–66.

5. Red Book Montvale, N.J.: Medical Economics Data, 2006.

6. Areosa SA, Sherriff F, McShane R. Memantine for dementia. Cochrane Database Syst Rev. 2005;(3):CD003154.

This Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Nathan Hitzeman, M.D., presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a full critique of the review.



Copyright © 2006 by the American Academy of Family Physicians.
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