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With Comments by Jerry Cott, PhD
Source: van Dongen MC, et al. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: New results of a randomized clinical trial. J Am Ger Soc 2000;48:1183-1194.
Design: A 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial.
Subjects: Two hundred fourteen older persons with dementia (either Alz-
heimer’s or vascular dementia; mild-to-moderate degree) or age-associated memory impairment. Participants were recruited from 39 homes for the elderly in the southern part of The Netherlands. Patients randomized to the study included 63 patients with dementia and 151 patients without dementia.
Treatment/Dose/Duration: EGb 761 (either 240 mg/d or 160 mg/d) or placebo for 24 weeks. After 12 weeks of treatment, those initially randomized to ginkgo were re-randomized to ginkgo or placebo. Those initially randomized to placebo continued on placebo for another 12 weeks.
Outcome Measures: Neuropsychological testing (trail-making speed, digit memory span, and verbal learning,) clinical assessment (presence and severity of geriatric symptoms), depressive mood, self-perceived health and memory status, and behavioral assessment (self-reported level of instrumental daily life activities). Outcomes were assessed after 12 and 24 weeks.
Results: An intention-to-treat analysis showed no effect on any of the outcome measures for those assigned to ginkgo (n = 79) compared with placebo (n = 44) for the 24-week period. At the 12-week assessment, the combined high- and low-dose ginkgo groups (n = 166) performed slightly better with regard to self-reported activities of daily life but slightly worse with regard to self-perceived health status compared with the placebo group (n = 48). No subgroup was found to benefit from ginkgo. Ginkgo was not associated with any serious adverse events.
Funding: Dr. Willmar Schwabe Arzneimittel GmbH, Karlsruhe, Germany (the makers of EGb761).
Comments: These results are in contrast to those of previous ginkgo trials. Most of the previously reported trials found positive effects for ginkgo compared with placebo. Most studies of ginkgo have used EGb761, an extract standardized to 6% terpene lactones (ginkgolides and bilobalide) and 24% flavonol glycosides. The largest trial to date, a randomized, double-blind, placebo-controlled trial of 309 patients with Alzheimer’s or multi-infarct dementia, found that patients who received EGb 761 (120 mg/d) scored higher on the Alzheimer’s Disease Assessment Scale-Cognition subscale (ADAS-Cog).1 After one year of treatment, 29% of patients receiving ginkgo showed at least a four-point improvement on the test compared with 14% of those receiving placebo. Although improvement was not apparent in the Clinician’s Global Impression of Change, beneficial treatment effects were apparent to caregivers as measured by the Geriatric Evaluation by Relative’s Rating Instrument.
A recent meta-analysis by Oken identified more than 50 published articles on the use of ginkgo for dementia; however, only four studies, with a total of 424 patients, met all inclusion criteria.2 Overall, there was a significant effect (P < 0.0001) that translated into a 3% difference in the ADAS-Cog. The authors concluded that there is a small but significant effect of three to six months of treatment with 120-240 mg ginkgo on objective measures of cognition in Alzheimer’s disease.
It should be noted that the effect size of ginkgo in these trials is equivalent to marketed cognitive enhancers.3
Why are the results of the van Dongen study so different from previous trials? Earlier trials were limited largely to patients with dementia; it is possible that the treatment does not work as well or as quickly for age-associated memory impairment. The largest previous trial lasted a year (however, other trials have shown a benefit at three or six months). It also is possible that ginkgo is more effective at preventing deterioration than in improving memory
This study attempted to answer too many questions at the same time, including the effects of both dose and duration. While these are important, relevant questions, this trial was too limited in number of subjects and too brief in duration to bear so heavy a burden of questions; the second randomization added unnecessary complexity and further reduced the number of subjects in each cell. It is unclear whether any cognitive enhancer could have been shown effective under these conditions. Al-
though the authors expressed surprise at the lack of effect, they offered no compelling explanation for why their results differed from others. Future trials should be larger, of longer duration, and include a positive comparison drug whenever possible.
1. Le Bars PL, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA 1997;278:1327-1332.
2. Oken BS, et al. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998;55:1409-1415.
3. Wettstein A. Cholinesterase inhibitors and ginkgo extracts—are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months’ duration. Phytomedicine 2000;6:393-401.