Re: Systematic Review and Meta-analysis of Ginkgo in Dementia
Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr. 2010;10:14.DOI:10.1186/1471-2318-10-14.
Ginkgo (Ginkgo biloba)
extract EGb 761 is used to treat dementia and cognitive impairment. It is one
of the most well studied herbal extracts. Published results have been
inconsistent in regards to the efficacy of the extract. Analyses of studies
have revealed methodological limitations, small cohorts, and include various
dementia subtypes (e.g., vascular dementia, Alzheimer’s disease, mild cognitive
impairment). The authors point out that most studies subtype the participants,
whereas most dementia drugs, including EGb 761, are prescribed without a
comprehensive assessment of the patient's dementia subtype. Therefore, the
authors conducted a systematic review of the effects of ginkgo on various types
of dementia.
The
following databases were searched: MEDLINE (January 1, 1966 to August 2008),
EMBASE (January 1, 1980 to August 2008), PsycINFO (January 1, 1982 to August
2008), CINAHL (Cumulative Index to Nursing and Allied Health Literature), the Cochrane
Database of Systematic Reviews, and the Cochrane Controlled Trials Register (until
Issue 3, 2008). The following search terms were used: dementia, senile, Alzheimer,
cognition, memory, decline, impair, loss, diminish, ginkgo, bilobalide, Tebonin,
EGb 761, and LI1370. The manufacturer of EGb 761, Dr. Willmar Schwabe GmbH
& Co. KG, Karlsruhe, Germany, was queried for additional
information. Reference lists were hand searched. Study inclusion criteria included
controlled clinical trials, with or without randomization, and studies that
assessed people with a confirmed diagnosis of Alzheimer’s disease, vascular
dementia, or mixed dementia, according to internationally valid diagnostic
criteria. Standardized Ginkgo biloba extracts
needed to be used for at least 12 weeks, and there had to be ≥ 10 patients per
treatment group. Studies were excluded if they contained mostly patients with
non-vascular or non-Alzheimer’s dementia, such as Lewy-body dementia or
dementia due to Parkinson’s disease. The article had to be published in English,
German, French, Italian, or Spanish. The publication quality was assessed. When
possible, the data were pooled for a meta-analysis. To increase the power of
the meta-analysis, values of different outcome scales of the same domain were
pooled (i.e., data from 2 different measures of cognition were pooled).
Of 754
clinical publications located, only 17 publications, which reported on 9 studies,
met all of the inclusion criteria. All 9 studies were randomized, double-blind,
and had moderate to good methodological quality. Eight of the studies were
placebo-controlled, and 1 compared ginkgo with donepezil. All used EGb 761 (120
mg, 160 mg, or 240 mg per day). Two studies were performed in Germany, 2 in the USA,
2 in the Ukraine, 1 in Bulgaria, 1 in the Netherlands,
and 1 in Great Britain.
Together the studies included 2372 patients with mild to moderate Alzheimer’s
disease, vascular dementia, or mixed dementia.
Cognition
was evaluated in all 9 studies. The meta-analysis showed that EGb 761 was
statistically significantly superior to placebo in improving cognition for the
whole group of patients with dementia (i.e., no subgroup analysis of dementia
subtype) (P < 0.04). In a subgroup analysis of 6 studies that included
patients with Alzheimer’s disease, EGb 761 treatment was statistically superior
to placebo treatment in that population (P = 0.02).
Eight of
the 9 studies evaluated Activities of Daily Living (ADL). For the whole group
of patients, the difference in ADL between placebo and ginkgo treated patients
was not statistically significant. However, a subgroup analysis of patients
with Alzheimer’s disease (5 studies) showed that ginkgo treatment significantly
improved ADL compared with placebo treatment (P = 0.008).
Neuropsychiatric
symptoms were assessed in 7 studies. In some of these studies, only depressive
symptoms, which were hardly above the normal range, were monitored. The authors
note that based on the results of 2 studies which used the full Neuropsychiatric
Inventory, psychological or behavioral symptoms associated with dementia may
improve with ginkgo use (P < 0.05 versus placebo).
Quality of
life was assessed in 3 studies: 2 with no EGb 761-associated improvement, and 1
with a significant improvement with EGb 761. A subgroup analysis indicates that
a dose of 240 mg may be necessary for clinically relevant improvements in
quality of life. The authors conclude that additional quality of life data are
needed.
The
results of 9 studies indicate that EGb 761 was well tolerated. The number and
type of adverse events and study withdrawals were similar between EGb 761 and
placebo treated patients. However, randomized controlled trials do not evaluate
drug interactions and rare events, so these parameters could not be assessed.
Also, only 1 ginkgo product was used in all 9 studies, so other ginkgo products
could be associated with different adverse side effects. Mild gastrointestinal
symptoms, headache, dizziness, or allergic skin reactions have been reported
with EGb 761 use. Occasional reports of bleeding have been reported in patients
using ginkgo preparations. However, studies show that EGb 761 does not
influence blood clotting, bleeding times, or potentiate the effects of
anticoagulant or antiplatelet drugs.
The
results of this meta-analysis are consistent with the Cochrane analysis, which
indicates a small advantage of ginkgo compared with placebo at 12 and 24 weeks.
The difference between the 2 analyses are (1) the present meta-analysis only
included studies where patients had a validated dementia diagnosis; this was
not an inclusion criterion of the Cochrane analysis, (2) there was a higher
methodological quality of the studies included in the present meta-analysis,
(3) the present meta-analysis included 3 newly published studies, and (4) values
of different outcome scales of the same domain were pooled in the present
meta-analysis.
The
authors conclude that the duration of a study, the study setting, and
methodological design factors may strongly modify the study outcome. The
generalizability of the various studies, and of this meta-analysis, may be
limited. The studies excluded patients with severe somatic or psychiatric
comorbidities. Use of other medications was restricted. One study showing a
lack of ginkgo efficacy included only patients living in old people’s homes and
included mostly very old people. The meta-analysis only included 1 type of
ginkgo extract.
Overall,
the statistical effect size of EGb 761 treatment was moderate, but the clinical
relevance is generally difficult to determine. The clinical significance of
pharmaceuticals used to treat dementia is difficult to measure. Nonetheless, based
on the data and ginkgo usage patterns, the authors believe that ginkgo may be
beneficial for "a certain but unknown proportion of dementia patients."
The disparity in outcomes between studies is not fully explained by dementia
type or ginkgo dose. The authors "think that the hitherto gained results
justify both symptomatic treatment of dementia and further research."