Review: Tacrine has some benefits and many adverse effects in Alzheimer disease
ACP J Club. 1998 Nov-Dec; 129:68. doi:10.7326/ACPJC-1998-129-3-068
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• Companion Abstract and Commentary: Donepezil was safe and effective in Alzheimer disease
Arrieta JL, Rodriguez Artalejo F. Methodology, results and quality of clinical trials of tacrine in the treatment of Alzheimer's disease: a systematic review of the literature. Age Ageing. 1998 Mar;27:161-79.
What are the methodologic characteristics, quality, and results of trials of tacrine in the treatment of patients who have Alzheimer disease?
Studies were identified by searching the Cochrane Library and MEDLINE (1980 to May 1997).
Studies were selected if they involved patients who were ≥ 40 years of age; had Alzheimer disease; and were allocated to tacrine or placebo, with or without lecithin.
2 reviewers independently rated the quality of study reports and extracted data on setting, design, treatment, selection criteria, withdrawals, adverse events, and outcomes (scores on cognitive, behavioral, clinical global impression, functional ability, and global mental deterioration scales). Disagreements were resolved by discussion.
21 randomized, double-blind, placebo-controlled trials and 22 trials that were open, not randomized, or both met the selection criteria. Results of the 8 parallel-group and 13 crossover randomized trials were not pooled because of the small number of trials and their heterogeneous methods. The mean quality score of study reports was 11 of 32 points (range 5 to 16 points). The 21 randomized trials involved 3555 patients (mean age 69 y). Follow-up ranged from 53% to 100%. Tacrine doses ranged from 25 to 200 mg/d, and mean duration of treatment was 9.3 weeks (range 3 to 36 wk). 1116 of 1149 patients (97%) who withdrew received tacrine. Adverse events, the main reason for withdrawal, included such cholinergic events as digestive symptoms or sweating and serum transaminase elevations > 3 times the upper limit of normal. 50% of patients who received tacrine had adverse events that required dose adjustment. Patients who received tacrine had significant improvements in cognitive outcomes(12 trials, n = 1906, range 13 to 663 patients), overall ratings (7 trials, n = 2233, range 17 to 663 patients),global clinical impression ratings(3 trials, n = 1285, range 154 to 663 patients), functional ability (2 trials, n = 215 and n = 53), and behavioral outcomes (1 trial, n = 663). The trial with the best methodologic score (16 points) showed that tacrine led to improvement in more patients than did placebo (23% vs 17%). No improvement occurred in any of the outcomes in 6 trials (n = 581, range 10 to 440 patients).
Data from 15 of 21 heterogeneous trials show that tacrine leads to a modest improvement for ≤ 8 months. In patients who have Alzheimer disease, tacrine has substantial adverse effects.
Source of funding: In part, Fondo de Investigación Sanitaria.
For correspondence: Dr. F. Rodriguez Artalejo, Departmento de Medicina Preventiva y Salud Pública, Universidad del País Vasco, Avenida de la Universidad 7, 01006 Vitoria-Gasteiz, Spain. FAX 34-45-130756.
In 1986, a lead article (1) in New England Journal of Medicine reported the results of a small crossover trial of oral tetrahydroaminoacridine (THA) in patients with Alzheimer disease aged 40 years and older. The accompanying editorial explained how the improvement seen in most patients validated the hypothesis that Alzheimer disease is characterized by a cholinergic deficit. The paper and editorial helped create a general expectation and, for the public, hope that cholinergic enhancement therapy with cholinesterase inhibitors would help reverse the cognitive and behavioral impairments of Alzheimer disease, just as levodopa had revolutionized treatment of another neurodegenerative disease, Parkinson disease. The 1986 trial provided what was probably the most optimistic setting in which to show the efficacy of THA (now called tacrine).
The systematic review by López Arrieta and Rodriguez Artalejo confirms what many clinicians have known for years. Only a few patients benefit from tacrine, and most cannot tolerate it. The need for frequent dosing is also a problem in patients with cognitive impairment. With the advent of alternative agents, tacrine is no longer actively marketed in the United States.
Donepezil, a second-generation cholinesterase inhibitor, has replaced tacrine. Donepezil will probably be joined soon by other agents. Indeed, 23 drugs for dementia (19 specifically for Alzheimer disease) are currently undergoing active development (2).
Rogers and colleagues provide a good assessment of the short-term efficacy and safety of donepezil. Of carefully selected patients, 10% to 20% will have gastrointestinal side effects, increased insomnia,and even agitation. The incidence of side effects will probably be greater in everyday practice, where patients are less carefully screened. The treatment effects are modest and not nearly as dramatic as the benefits of dopaminergic agents in Parkinson disease. The scales used in research to detect improvement are difficult to apply clinically. Only an occasional patient will experience a dramatic benefit. Donepezil does not alleviate behavioral disturbances and may exacerbate or unmask some symptoms (such as agitation).
In practice, for patients and families who are interested in treatment for cognitive deficits, I recommend starting with a careful assessment of function and selection of a few focused outcomes (including general well-being) that are important to the family and patient. Start with a low dose of donepezil, 5 mg/d, for 1 month to look for side effects and assess benefits in the preselected areas. If no side effects or improvement occurs, a dose of 10 mg/d can be tried. For patients who improve at either dose, it is worthwhile to continue the medication. For patients with substantial side effects or no improvement, treatment with the drug can be stopped because it does not apparently affect the long-term course of the disease. Long-term safety is unknown.
On the basis of current research, I urge clinicians to be cautious in describing the expected benefits of cholinergic treatments. The experience of Alzheimer disease can be devastating for some patients and families and may make them particularly vulnerable to unrealistic expectations, including the mistaken belief that a “magic bullet” exists for the disease.
Eric B. Larson, MD
University of Washington Medical CenterSeattle, Washington, USA
Eric B. Larson, MD
University of Washington Medical Center
Seattle, Washington, USA