Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Ginkgo biloba safely and modestly improved dementia

ACP J Club. 1998 May-June;128:70. doi:10.7326/ACPJC-1998-128-3-070


Source Citation

Le Bars PL, Katz MM, Berman N, et al., for the North American EGb Study Group. A placebo-controlled, double-blind, randomized trial of an extract of ginkgo biloba for dementia. JAMA. 1997 Oct 22/29;278:1327-32. [PubMed ID: 9343463]


Abstract

Objective

To determine the effectiveness and safety of the plant extract of ginkgo biloba, EGb 761 (EGb), in Alzheimer disease and multi-infarction dementia.

Design

Randomized, double-blind, placebo-controlled trial (RCT) with 52-week follow-up.

Setting

6 U.S. research centers.

Patients

327 patients were enrolled, and 309 (mean age 69 y, 54% women, 76% with Alzheimer disease) were included in the intention-to-treat (ITT) analysis. Inclusion criteria were ≥ 45 years of age, a diagnosis of uncomplicated dementia according to standard published disease criteria of Alzheimer disease or multi-infarction dementia, and a baseline Mini-Mental State Examination score of 9 to 26. Patients were excluded if they had other important medical conditions, another psychiatric disorder as a primary diagnosis, a brain mass, or intracranial hemorrhage.

Intervention

166 patients were allocated to EGb, 120 mg/d (24% ginkgo-flavoneglycosides and 6% terpenelactones), and 161 patients were allocated to placebo.

Main outcome measures

Changes in cognitive impairment were assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS) (an 11-item scale), daily living and social behavior were assessed by the Geriatric Evaluation by Relative's Rating Instrument (GERRI) (49 items each rated 1 to 5 by a caregiver), and general psychopathologic health was assessed by the Clinical Global Impression of Change (CGIC) (a 7-point scale based on clinician assessment of overall change from baseline).

Main results

ITT analysis was used. The group of patients who received placebo deteriorated more than the group who received EGb and had a mean ADAS score of 1.4 points (95% CI 0.0 to 2.7, P = 0.04) lower (i.e., worse) and a GERRI score of 0.14 points (CI 0.04 to 0.23, P = 0.004) worse. No difference was shown between the groups for CGIC scores. Similar results were seen in the subgroup of patients with Alzheimer disease (n = 236; of these, 120 received EGb and 116 received placebo). A clinically significant improvement of ≥ 4 points on the ADAS subscale was shown for 27% of patients who were treated with EGb compared with 14% of patients who were treated with placebo {P = 0.027}*. The groups did not differ for rate, incidence, or severity of adverse events.

Conclusion

Extract of ginkgo biloba was safe and modestly improved cognitive performance, daily living, and social behavior of patients with Alzheimer disease or multi-infarction dementia.

Source of funding: Dr. Willmar Schwabe Pharmaceuticals.

For article reprint: Dr. P.L. Le Bars, New York Institute for Medical Research, 150 White Plains Road, Tarrytown, NY 10591, USA. FAX 914-631-8816.

*P value calculated from data in article.


Commentary

The study by Le Bars and colleagues is the first published RCT in the United States of standardized EGb. This extract has been shown in European RCTs to modestly improve cognitive function in patients with dementia. Conceivable mechanisms of action of EGb in Alzheimer disease include reduction of free radicals and modulation of neurotransmitters, which could reduce the rate of cell death, enhance function of neurons, or produce an antidepressant effect.

Because many patients (77 treated, 95 controls) dropped out before 52 weeks, an ITT analysis was used. The most recent available outcome became the final outcome. This analysis likely biased results against a treatment effect, although an opposite bias cannot be ruled out. A positive treatment effect was found at 12, 26, 39, and 52 weeks of follow-up using the ITT analysis. The duration of effect is likely 26 weeks or longer, but an accurate estimate of duration is not possible from the data presented. Compared with controls, 13% more of those treated had a clinically meaningful improvement in the ADAS subscale (≥ 4 points), and 12% fewer had a decrease of equal magnitude. Results were similar for the GERRI score. Comparable ADAS results in an RCT that studied high-dose tacrine compared with placebo suggest that EGb may be as effictive as tactrine.

EGb seems to be safe and effective in modestly reducing the short-term rate of cognitive and functional decline in about 25% of patients with Alzheimer disease and multi-infarction dementia, but the overall effect on perceived quality of life for patients or caregivers was not measured. A 25% chance of a small increase in cognition and function of uncertain duration and uncertain effect on quality of life may make a trial of EGb worthwhile in some patients. EGb may be an effective alternative to tacrine and may have fewer side effects. Continuing EGb therapy only as long as cognitive function improves or remains stable based on a quantitative clinical cognitive examination may be a reasonable approach.

Roger Luckmann, MD, MPH
University of MassachusettsWorcester, Massachusetts, USA

Roger Luckmann, MD, MPH
University of Massachusetts
Worcester, Massachusetts, USA


Reference

1. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA. 1994;271:985-91. [PubMed ID: 8139083]