Dementia treatment: vitamin E and ginkgo biloba. Does the evidence favor one over the other?
Barry SOken, neurologist, Oregon Health Sciences Universityoken@ohsu.edu
Submitted August 20, 2001
I am writing to express my concerns about the conclusions of the
recent article, "Practice parameter: Management of dementia (an evidence-
based review)" (1). This was a major undertaking for the American Academy
of Neurology because of the large number of clinical dementia research
articles cited. I agree with the parameter that the cholinesterase
inhibitors have more supporting data than any of the other interventions.
However, after the cholinesterase inhibitors, the data supporting
differentiation of some of the other interventions are less clear. This
becomes apparent when the evidence for the use of vitamin E was given
significantly greater credibility than the comparable, if not greater,
evidence supporting the use of ginkgo biloba extract (GBE).
I am concerned about the reviewers interpretation of the single
controlled trial of vitamin E in Alzheimer's disease (AD)(2). The
reviewers considered vitamin E a guideline but the study was much less
conclusive than the practice parameter suggests. The uncorrected, first-
pass data analysis revealed no effect of vitamin E significant at the p
<.05 level. After correction for a slight baseline difference among the
4 groups in MMSE (p value of 0.1), the selegeline, vitamin E and combined
groups had slightly better outcomes as defined by death, nursing home
placement, conversion to Clinical Dementia Rating (CDR) score of 3 or
decrease in activities of daily living.
The questions concerning the analysis have been raised already in the
New England Journal of Medicine (3) such as the lack of data about
correction for other potential baseline differences including those not
defined in advance by the authors. The trial also just studied patients
with moderately severe dementia (CDR 2) so there are no data regarding
vitamin E in the mild to moderate cases. Additionally, there were no
significant beneficial effects on cognitive measures in the study,
certainly raising the possibility that any poorly defined effect of
vitamin E on the outcome measure may have nothing specifically to do with
AD. While the combined outcome measure chosen by this trial has some
public health implications, it is markedly affected by types of behaviors
and clinical events other than severity of AD that contribute to nursing
home placement and death, e.g., aggressive behaviors, incontinence and
vascular disease. It could be argued that all these factors should have
been covariates in the analysis. Another formal independent assessment of
the vitamin E trial by the Cochrane Collaboration concluded that "there is
insufficient evidence of efficacy of vitamin E in the treatment of people
with Alzheimer's disease" (4).
The vitamin E trial did find a higher incidence of falls as adverse
events in the treated groups. The dose used in the study (2000 I.U.) is
above the tolerable upper intake levels recently suggested by the
Institute of Medicine of 1000 mg of natural vitamin E (about equivalent to
1100 I.U. of the racemic mixture used in the trial (5)). These suggestions
were probably not available until after the parameters were prepared and
also were unfortunately not based on any human data. However, it should be
noted that there is no human trial evidence to know what is the perfectly
safe maximal dose. This independent group also suggested that despite some
positive small intervention trials (at least small by epidemiologists'
standards), there were insufficient data to draw any conclusions about the
usefulness of vitamin E or C in neurodegenerative diseases.
Since vitamin E is relatively safe, this single inconclusive clinical
trial has resulted in myself and many other neurologists suggesting
vitamin E use to patients with AD. There has been much recent interest in
oxidative injury in AD and even some suggestion that this may be an
important precipitating factor. However, once the disease develops the
role of anti-oxidant therapy is clearly unproven. The preventative
situation may be similar to that in cardiovascular diseases where there is
an important role of diet and anti-oxidants, but clinical trials of
vitamin E once disease has developed have not been consistently
successful. The suggestion to use vitamin E in patients with AD may be
reasonable, but to consider it reflecting moderate clinical certainty (the
AAN definition of a Guideline) seems excessive. However, even given
possible publication length constraints, the omission of mention of any of
the problems with the single vitamin E study in the practice parameter
document is problematic.
In terms of the evidence on GBE, the review lacked completeness and
the practice guidelines understated the effect. There was an omission of
at least two reasonable papers published in the time frame that should
have been found with a full review of the literature (6, 7). There has
been a consistent effect of GBE on cognitive function in AD as evidenced
by a formal meta-analysis (8). It does not seem proper in an evidence-
based review to dismiss the formal meta-analysis (although I may have a
bias here since I was first author). If one chooses to ignore formal meta-
analyses or the specific meta-analysis, then at least all the relevant
cited articles in the meta-analysis should be included in an evidence-
based review. The two larger clinical GBE trials mentioned in the practice
parameters are listed with mixed dementia populations but both studies
clearly segregated the AD cases from vascular dementia cases. One trial
had a large 1-year dropout rate because of a poor design allowing subjects
to switch to active drug after 6 months, but the 6-month drop out rates
were reasonable and the 6-month data allowed for adequate evaluation of
the clinical response. Both of the larger trials had significant
beneficial effects on cognitive function. Although the data on outcomes
related to ADLs or global rating were not consistent, there have been some
effects in these measures in the trials. This does not seem that different
from the case with vitamin E where there was possible effects on gross
functional outcome but not an effect on cognition.
Since the practice guidelines review there has been an additional GBE
clinical trial that was negative (9). However, that study had some
significant design problems and was not focused on AD. Most of the
subjects in the study would probably fit closer into the diagnostic
category of Mild Cognitive Impairment.
In terms of safety, there have been no serious adverse events related
to GBE in the thousands of participants in various clinical trials (of
which several hundred have had dementia). The occasional case reports of
serious bleeding complications (8) are of unknown significance because of
the extremely large number of users of GBE in the US, possibly as high as
10% of healthy seniors (10). While there is a theoretical potential for an
anti-platelet effect due to GBE's terpenoid components that are platelet
activating factor antagonists, there have been no useful clinical data to
guide clinicians as to GBE's degree of safety. The data on GBE's degree of
safety is not dissimilar to that with 2000 I.U. of vitamin E.
I am concerned that there is no evidence to rank vitamin E above GBE
extract from a purely evidence-based approach. The bias against GBE is
highlighted by the failure to search adequately using the word "ginkgo"
and the omission of previously published meta-analyses and evidence-based
reviews in order to obtain all the articles. The authors of the published
practice parameters did not even pay sufficient attention to spell ginkgo
correctly, spelling it twice correctly ("ginkgo") and twice incorrectly
("gingko") including in their table 3. This bias against alternative
medicine such as botanicals can be found frequently throughout academic
medicine. A recently published study used academic reviewers as the
research subjects and sent two, almost identical, fabricated manuscripts
concerning a weight loss treatment out to 398 reviewers (11). In the two
manuscripts, the data were the same and there were similar justification
references for trying each treatment. The only difference was that one
article used an alternative therapy, homeopathic in this case (and I don't
wish to delve into the specific choice of alternative therapy chosen) and
one a conventional therapy. Not surprisingly there was a significant bias
against the alternative treatment despite the identical data. I think all
scientists should be aware of this bias, sometimes subtle and sometimes
not, against alternative therapies. While we often think we know what
therapies should work best, the goal of evidence-based medicine is to let
the quality trials lead us to recommendations without too many biases.
I think the Academy should ensure that the practice parameters based
on evidence-based reviews be of the highest standards. This includes
improving search strategies and also more clearly including discussions of
possible differences of opinion (12, 13). I do not think that a group of
experts in systematic reviews without any special expertise in AD (and the
biases that may accompany that AD expertise) would find the results of the
single vitamin E trial any more conclusive than the results from at least
four reasonable GBE trials. Thus, the practice parameters should reflect
GBE at least at the same level as vitamin E (Guideline or Practice Option)
if not higher. The AAN includes an associated disclaimer about the
practice parameters but hospital pharmacies and health maintenance
organizations may still use the published practice parameters for
decisions regarding treatment options and availability. Thus, there is an
onus on the AAN to ensure that the practice parameters meet the highest
quality possible.
1. Doody R, Stevens J, Beck C, Dubinsky R, Kaye J, Gwyther L, et al.
Practice parameter: Management of dementia (an evidence-based review).
Neurology 2001;56:1154-1166.
2. Sano M, Ernesto C, RG T, Klauber M, Schafer K, Grundman M, et al. A
controlled trial of selegiline, alpha-tocopherol, or both as treatment for
Alzheimer's disease. The Alzheimer's Disease Cooperative Study. New Eng J
of Med 1997;336(17):1216-1222.
3. Drachman D, Leber P. Treatment of Alzheimer's disease -- searching for
a breakthrough, settling for less. New England Journal of Medicine
1997;336:1245-1247.
4. Tabet N, Birks J, Evans J, Orrel M, Spector A. Vitamin E for
Alzheimer's disease. In: Cochrane Database of Systematic Reviews; 2000.
5. Food and Nutrition Board IoM. Dietary reference intakes for vitamin C,
vitamin E, selenium, and carotenoids. Washingotn, D.C.: National Academy
Press; 2000.
6. Hofferberth B. The efficacy of EGb 761 in patients with senile dementia
of the Alzheimer type; a double-blind placebo-controlled study on
different levels of investigation. Human Psychopharmacology 1994;9:215-
222.
7. Maurer K, Ihl R, Dierks T, Frolich L. Clinical efficacy of ginkgo
biloba special extract EGb 761 in dementia of the Alzheimer type. J.
psychiat. Res. 1997;31:645-655.
8. Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo Biloba on
cognitive function in Alzheimer's disease. Archives of Neurology
1998;55:1409-1415.
9. Dongen Mv, Rossum Ev, Kessels A, Sielhorst H, Knipschild P. The
efficacy of ginkgo for elderly people with dementia and age-associated
memory impairment: new results of a randomized clinical trial. Journal of
the American Geriatrics Society 2000;48:1183-1194.
10. Kishiyama S, Zajdel D, Syms M, Zitzelberger T, Guariglia R, Kaye J, et
al. Patterns of dietary supplement usage in healthy elder study
populations of rural and urban Oregon. Alternative Therapies in Health and
Medicine 2001;7:S18.
11. Resch K, Ernst E, Garrow J. A randomized controlled study of reviewer
bias against an unconventional therapy. Journal of the Royal Society of
Medicine 2000;93:164-167.
12. Mulrow C, Cook D. Systematic Reviews. Philadelphia: American College
of Physicians; 1998.
13. Collaboration C. The Reviewers Handbook. In. 4.1.2 ed: Cochrane
Collaboration; 2001.
I am writing to express my concerns about the conclusions of the recent article, "Practice parameter: Management of dementia (an evidence- based review)" (1). This was a major undertaking for the American Academy of Neurology because of the large number of clinical dementia research articles cited. I agree with the parameter that the cholinesterase inhibitors have more supporting data than any of the other interventions. However, after the cholinesterase inhibitors, the data supporting differentiation of some of the other interventions are less clear. This becomes apparent when the evidence for the use of vitamin E was given significantly greater credibility than the comparable, if not greater, evidence supporting the use of ginkgo biloba extract (GBE).
I am concerned about the reviewers interpretation of the single controlled trial of vitamin E in Alzheimer's disease (AD)(2). The reviewers considered vitamin E a guideline but the study was much less conclusive than the practice parameter suggests. The uncorrected, first- pass data analysis revealed no effect of vitamin E significant at the p <.05 level. After correction for a slight baseline difference among the 4 groups in MMSE (p value of 0.1), the selegeline, vitamin E and combined groups had slightly better outcomes as defined by death, nursing home placement, conversion to Clinical Dementia Rating (CDR) score of 3 or decrease in activities of daily living.
The questions concerning the analysis have been raised already in the New England Journal of Medicine (3) such as the lack of data about correction for other potential baseline differences including those not defined in advance by the authors. The trial also just studied patients with moderately severe dementia (CDR 2) so there are no data regarding vitamin E in the mild to moderate cases. Additionally, there were no significant beneficial effects on cognitive measures in the study, certainly raising the possibility that any poorly defined effect of vitamin E on the outcome measure may have nothing specifically to do with AD. While the combined outcome measure chosen by this trial has some public health implications, it is markedly affected by types of behaviors and clinical events other than severity of AD that contribute to nursing home placement and death, e.g., aggressive behaviors, incontinence and vascular disease. It could be argued that all these factors should have been covariates in the analysis. Another formal independent assessment of the vitamin E trial by the Cochrane Collaboration concluded that "there is insufficient evidence of efficacy of vitamin E in the treatment of people with Alzheimer's disease" (4).
The vitamin E trial did find a higher incidence of falls as adverse events in the treated groups. The dose used in the study (2000 I.U.) is above the tolerable upper intake levels recently suggested by the Institute of Medicine of 1000 mg of natural vitamin E (about equivalent to 1100 I.U. of the racemic mixture used in the trial (5)). These suggestions were probably not available until after the parameters were prepared and also were unfortunately not based on any human data. However, it should be noted that there is no human trial evidence to know what is the perfectly safe maximal dose. This independent group also suggested that despite some positive small intervention trials (at least small by epidemiologists' standards), there were insufficient data to draw any conclusions about the usefulness of vitamin E or C in neurodegenerative diseases.
Since vitamin E is relatively safe, this single inconclusive clinical trial has resulted in myself and many other neurologists suggesting vitamin E use to patients with AD. There has been much recent interest in oxidative injury in AD and even some suggestion that this may be an important precipitating factor. However, once the disease develops the role of anti-oxidant therapy is clearly unproven. The preventative situation may be similar to that in cardiovascular diseases where there is an important role of diet and anti-oxidants, but clinical trials of vitamin E once disease has developed have not been consistently successful. The suggestion to use vitamin E in patients with AD may be reasonable, but to consider it reflecting moderate clinical certainty (the AAN definition of a Guideline) seems excessive. However, even given possible publication length constraints, the omission of mention of any of the problems with the single vitamin E study in the practice parameter document is problematic.
In terms of the evidence on GBE, the review lacked completeness and the practice guidelines understated the effect. There was an omission of at least two reasonable papers published in the time frame that should have been found with a full review of the literature (6, 7). There has been a consistent effect of GBE on cognitive function in AD as evidenced by a formal meta-analysis (8). It does not seem proper in an evidence- based review to dismiss the formal meta-analysis (although I may have a bias here since I was first author). If one chooses to ignore formal meta- analyses or the specific meta-analysis, then at least all the relevant cited articles in the meta-analysis should be included in an evidence- based review. The two larger clinical GBE trials mentioned in the practice parameters are listed with mixed dementia populations but both studies clearly segregated the AD cases from vascular dementia cases. One trial had a large 1-year dropout rate because of a poor design allowing subjects to switch to active drug after 6 months, but the 6-month drop out rates were reasonable and the 6-month data allowed for adequate evaluation of the clinical response. Both of the larger trials had significant beneficial effects on cognitive function. Although the data on outcomes related to ADLs or global rating were not consistent, there have been some effects in these measures in the trials. This does not seem that different from the case with vitamin E where there was possible effects on gross functional outcome but not an effect on cognition.
Since the practice guidelines review there has been an additional GBE clinical trial that was negative (9). However, that study had some significant design problems and was not focused on AD. Most of the subjects in the study would probably fit closer into the diagnostic category of Mild Cognitive Impairment.
In terms of safety, there have been no serious adverse events related to GBE in the thousands of participants in various clinical trials (of which several hundred have had dementia). The occasional case reports of serious bleeding complications (8) are of unknown significance because of the extremely large number of users of GBE in the US, possibly as high as 10% of healthy seniors (10). While there is a theoretical potential for an anti-platelet effect due to GBE's terpenoid components that are platelet activating factor antagonists, there have been no useful clinical data to guide clinicians as to GBE's degree of safety. The data on GBE's degree of safety is not dissimilar to that with 2000 I.U. of vitamin E.
I am concerned that there is no evidence to rank vitamin E above GBE extract from a purely evidence-based approach. The bias against GBE is highlighted by the failure to search adequately using the word "ginkgo" and the omission of previously published meta-analyses and evidence-based reviews in order to obtain all the articles. The authors of the published practice parameters did not even pay sufficient attention to spell ginkgo correctly, spelling it twice correctly ("ginkgo") and twice incorrectly ("gingko") including in their table 3. This bias against alternative medicine such as botanicals can be found frequently throughout academic medicine. A recently published study used academic reviewers as the research subjects and sent two, almost identical, fabricated manuscripts concerning a weight loss treatment out to 398 reviewers (11). In the two manuscripts, the data were the same and there were similar justification references for trying each treatment. The only difference was that one article used an alternative therapy, homeopathic in this case (and I don't wish to delve into the specific choice of alternative therapy chosen) and one a conventional therapy. Not surprisingly there was a significant bias against the alternative treatment despite the identical data. I think all scientists should be aware of this bias, sometimes subtle and sometimes not, against alternative therapies. While we often think we know what therapies should work best, the goal of evidence-based medicine is to let the quality trials lead us to recommendations without too many biases.
I think the Academy should ensure that the practice parameters based on evidence-based reviews be of the highest standards. This includes improving search strategies and also more clearly including discussions of possible differences of opinion (12, 13). I do not think that a group of experts in systematic reviews without any special expertise in AD (and the biases that may accompany that AD expertise) would find the results of the single vitamin E trial any more conclusive than the results from at least four reasonable GBE trials. Thus, the practice parameters should reflect GBE at least at the same level as vitamin E (Guideline or Practice Option) if not higher. The AAN includes an associated disclaimer about the practice parameters but hospital pharmacies and health maintenance organizations may still use the published practice parameters for decisions regarding treatment options and availability. Thus, there is an onus on the AAN to ensure that the practice parameters meet the highest quality possible.
1. Doody R, Stevens J, Beck C, Dubinsky R, Kaye J, Gwyther L, et al. Practice parameter: Management of dementia (an evidence-based review). Neurology 2001;56:1154-1166. 2. Sano M, Ernesto C, RG T, Klauber M, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. New Eng J of Med 1997;336(17):1216-1222. 3. Drachman D, Leber P. Treatment of Alzheimer's disease -- searching for a breakthrough, settling for less. New England Journal of Medicine 1997;336:1245-1247. 4. Tabet N, Birks J, Evans J, Orrel M, Spector A. Vitamin E for Alzheimer's disease. In: Cochrane Database of Systematic Reviews; 2000. 5. Food and Nutrition Board IoM. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washingotn, D.C.: National Academy Press; 2000. 6. Hofferberth B. The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type; a double-blind placebo-controlled study on different levels of investigation. Human Psychopharmacology 1994;9:215- 222. 7. Maurer K, Ihl R, Dierks T, Frolich L. Clinical efficacy of ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type. J. psychiat. Res. 1997;31:645-655. 8. Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo Biloba on cognitive function in Alzheimer's disease. Archives of Neurology 1998;55:1409-1415. 9. Dongen Mv, Rossum Ev, Kessels A, Sielhorst H, Knipschild P. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. Journal of the American Geriatrics Society 2000;48:1183-1194. 10. Kishiyama S, Zajdel D, Syms M, Zitzelberger T, Guariglia R, Kaye J, et al. Patterns of dietary supplement usage in healthy elder study populations of rural and urban Oregon. Alternative Therapies in Health and Medicine 2001;7:S18. 11. Resch K, Ernst E, Garrow J. A randomized controlled study of reviewer bias against an unconventional therapy. Journal of the Royal Society of Medicine 2000;93:164-167. 12. Mulrow C, Cook D. Systematic Reviews. Philadelphia: American College of Physicians; 1998. 13. Collaboration C. The Reviewers Handbook. In. 4.1.2 ed: Cochrane Collaboration; 2001.