Cochrane for Clinicians
Putting Evidence into Practice
Cholinesterase Inhibitors for Alzheimer's Disease
|
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 Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing 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 step-ups 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), an N-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.
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). Report of 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.
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.
The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.
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.
Cochrane Briefs
Antibiotics for Exacerbations of COPD
Clinical Question
Does routine use of antibiotics in patients with an exacerbation of chronic obstructive pulmonary disease (COPD) improve clinical outcomes?
Evidence-Based Answer
There is consistent evidence from a small number of studies that antibiotics significantly reduce mortality (number needed to treat [NNT] = 8) and treatment failure (NNT = 3) in more severely ill patients with COPD who are hospitalized because of an exacerbation. Two smaller studies found no benefit of antibiotics for patients with an exacerbation of COPD who were treated in the community setting.
Practice Pointers
Many acute exacerbations of COPD are caused by bacterial infection, but many are caused by viruses or are noninfectious. Although some studies have found the routine use of antibiotics beneficial in patients with COPD exacerbations, others have failed to find a benefit. Ram and colleagues identified 11 studies of patients with COPD who experienced an exacerbation and who were randomly assigned to receive an antibiotic or placebo. An exacerbation was defined as one or more of the following: increased sputum purulence or volume, increased shortness of breath, increased wheeze, chest tightness, or fluid retention. Only two of the studies included outpatients. Study quality was high.
Three studies involving a total of 298 hospital inpatients and using an objective definition of COPD found mortality rates of 3 percent in the antibiotic group and 15 percent in the placebo group (relative risk [RR] = 0.24; 95% confidence interval [CI], 0.1 to 0.57; NNT = 8). Results between studies were consistent and remained so when a fourth study conducted in an intensive care unit was added.
Another important outcome is treatment failure, generally defined as failure to improve, deterioration, or death during the study period. Six studies with a total of 705 patients reported this outcome, but there was significant variation (heterogeneity) between studies, with some showing improvement in patients taking antibiotics and others showing no benefit. After exploring the data for patterns, the authors found that antibiotics consistently reduced the likelihood of treatment failure in four studies with a total of 321 hospitalized patients (28 percent with treatment versus 58 percent with placebo [RR = 0.47; 95% CI, 0.36 to 0.62; NNT = 3]). However, the same was not true for the two outpatient studies with a total of 384 patients. In these studies, antibiotics did not reduce the likelihood of treatment failure (40 percent with antibiotics versus 35 percent with placebo [RR = 1.14; 95% CI, 0.88 to 1.48]). The antibiotics used in the studies were amoxicillin/clavulanate (Augmentin), trimethoprim/sulfamethoxazole (Bactrim, Septra), and amoxicillin.
The most widely used evidence-based guidelines recommend antibiotics for patients with COPD who have at least two of the following: increased dyspnea, increased sputum production, or increased sputum purulence.1,2
Source: Ram FS, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;(2):CD004403.
REFERENCES
1. Global Initiative for Chronic Obstructive Lung Disease (GOLD), World Health Organization (WHO), National Heart, Lung and Blood Institute (NHLBI). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, Md.: GOLD, WHO, NHLBI, 2005. Accessed May 22, 2006, at: http://www.guideline.gov/summary/summary.aspx?ss=14&doc_id=8128&string=.
2. Celli BR, MacNee W, for the ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper [Published correction appears in Eur Respir J 2006;27:242]. Eur Respir J 2004;23:932-46.
Antioxidants and Minerals for Age-Related Macular Degeneration
Clinical Question
Does supplementation with high doses of antioxidant vitamins and minerals slow the progression of age-related macular degeneration (ARMD)?
Evidence-Based Answer
Supplementation with a combination of vitamin C, vitamin E, beta-carotene, and zinc modestly reduces the progression of ARMD in patients with disease in one or both eyes. High-dose vitamin supplements should not be recommended for patients without ARMD because of the possible harmful effects of vitamin E and beta-carotene at high doses.
Practice Pointers
ARMD is the most common cause of blindness in industrialized countries, with up to one third of adults older than 75 years showing at least early signs of the disease. High doses of vitamin C, vitamin E, carotenoids, lutein, selenium, and zinc are increasingly being recommended to prevent or treat ARMD. However, some studies have shown that high doses of vitamin E and beta-carotene may increase all-cause mortality.1,2
Evans reviewed any randomized trial comparing antioxidant vitamins with placebo in patients with ARMD in one or both eyes. The primary outcome was visual acuity. Eight studies were included in the systematic review. Patients had a mean age of 70 years. Three of the trials studied zinc alone, two studied an antioxidant combination, one studied lutein, and one vitamin E. The vitamin E trial (Vitamin E, Cataract and Age-related maculopathy study [VECAT]) had 1,204 participants and followed patients for four years. The largest study (Age-Related Eye Disease Study [AREDS]), which compared zinc alone, an antioxidant combination, or both, with placebo, included 3,640 patients and lasted six years.3 The other six studies each had fewer than 200 patients and lasted for no more than two years; thus, most of the data come from the VECAT and AREDS trials.
The AREDS trial found that supplementation with vitamin C, vitamin E, zinc, and beta-carotene slows the progression of disease in patients with ARMD (relative risk = 0.68; 99% confidence interval, 0.49 to 0.93).3 The VECAT study included healthy older patients and found no visual benefit to supplementation with vitamin E (500 IU per day) after four years. Given the potential risks of vitamin E, it cannot be recommended to protect vision in patients without ARMD. The single study of lutein included 52 patients and found no effect on visual acuity.
Vitamin supplements for "eye health" are increasingly used by patients who may have a family history of ARMD but who do not have macular degeneration. It is important to warn patients about the potential harms of these supplements and the lack of known benefit.
Source: Evans JR. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev 2006;(2):CD000254.
REFERENCES
1. Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
2. Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK, et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 1995;62(6 suppl):1427S-30S.
3. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119:1417-36.
| Copyright © 2006 by the American
Academy of Family Physicians. |
