Valery L.

Feigin
Herbal Medicine in Stroke : Does It Have a Future?
ISSN: 1524-4628
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doi: 10.1161/STROKEAHA.107.487132
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Herbal Medicine in Stroke
Does It Have a Future?
Valery L. Feigin, MD, MSc, PhD, FAAN
See related article, pages 19731979.
T
he lack of effective and widely applicable pharmaco-
logical treatments for ischemic stroke patients may
explain a growing interest in traditional medicines, for
which extensive observational and anecdotal experience has
accumulated over the past thousand years. The World Health
Organization (WHO) defines traditional medicine as health
practices, approaches, knowledge and beliefs incorporating
plant, animal and mineral based medicines, spiritual thera-
pies, manual techniques and exercises, applied singularly or
in combination to treat, diagnose and prevent illnesses or
maintain well-being.
1
Unlike Western medicine, which fo-
cuses on disease, traditional medicine takes the approach that
the body provides external clues to an internal imbalance that
can be addressed by interventions such as herbs and acupunc-
ture (holistic treatment approach).
2
According to a 2003
WHO report,
1
traditional medicine is very popular in all
developing countries, and its use is rapidly increasing in
industrialized countries. For example, traditional herbal prep-
arations account for 30% to 50% of the total medicinal
consumption in China. In Europe, North America and other
industrialized regions, over 50% of the population have used
traditional medicine at least once. The global market for
herbal medicines currently stands at over US $60 billion
annually and is growing steadily.
1
In recent years, several reviews have been published on the
effect and potential benefits of traditional Eastern medicine in
stroke.
37
It has been suggested that some herbal medicines,
or their products, may improve microcirculation in the
brain,
4,8
protect against ischemic reperfusion injury,
8,9
pos-
sess neuroprotective properties
3,4
and inhibit apoptosis,
10
thus
justifying their use in ischemic stroke patients. However,
unlike industrially manufactured pharmacological drugs used
in Western medicine, the active (potent) components of
herbal medicines often have not been specified and measured
precisely, although there have been recent attempts to regu-
late dosages and use of these medicines by some govern-
ments. This inevitably leads to variations between formula-
tions and batches of the same herbal medicines and, as a
consequence, to difficulties in the evaluation and comparison
of the results of trials testing these medicines. The issue is
further complicated by the fact that most publications on the
efficacy of herbal medicines are published locally in non-
English languages, thus making their retrieval and appraisal
very difficult for specialists outside that region. Therefore,
any efforts to systematically analyze and present the existing
clinical evidence on the efficacy of herbal medicines to
English-speaking audiences should be welcome.
In this issue of Stroke, Wu and colleagues
11
present the first
systematic review of the efficacy and safety of 59 Traditional
Chinese Patent Medicine* (TCPM) drugs listed in the Chi-
nese National Essential Drug list (2004) and commonly used
in China for ischemic stroke patients. The authors tried to
apply Cochrane systematic review methodology to their
review, and chose death/dependency and adverse events at 3
months of follow-up as the primary outcome measures. Six
reviewers independently selected the studies and extracted
the data, which reduced the potential for bias and errors. Their
thorough literature search (19662005) of both published and
unpublished Chinese and non-Chinese language literature
yielded 5 definitely randomized, 115 possibly randomized
and 71 nonrandomized controlled clinical trials (19 338
patients in total) conducted in China to evaluate the efficacy
of 22 TCPM drugs (no eligible trials were identified for the
remaining 37 TCPM drugs). The authors correctly stress the
poor methodological quality of almost all (97%) the clinical
trials selected for the review. The pooled analysis of trials
(randomized and nonrandomized combined) showed a strik-
ingly large and significant (odds ratio [OR] 3.4, 95% CI 3.1
to 3.6) positive effect of almost all TCPM treatments (21 of
22) analyzed in improving neurological impairment (over
3-fold improvement compared with controls) and an ex-
tremely low (3%) case-fatality in 10 trials that reported death
outcome, again, in favor of the treatment group (OR 0.5, 95%
CI 0.2 to 0.9). However, only 2 trials (both with adequate
concealment of randomization) reported primary outcomes
(death or dependency), and no difference was found in these
trials between treatment and control groups. The extremely
low case-fatality is most likely to be explained by a highly
selected group of patients included in these trials, although
reporting bias (underreporting) cannot be excluded. No sta-
tistically significant difference in adverse events between
treatment and control groups on 14 TCPM analyzed was
found in 38 trials that reported adverse events, although it
remains unclear whether adverse events were registered but
not reported in the remaining 57 trials included in the analysis
of adverse events.
The opinions in this editorial are not necessarily those of the editors or
of the American Heart Association.
From the Clinical Trials Research Unit, School of Population Health,
The University of Auckland, New Zealand.
Correspondence to Associate Professor Valery Feigin, Clinical Trials
Research Unit, University of Auckland, Private Bag 92019, Auckland,
New Zealand. E-mail v.feigin@ctru.auckland.ac.nz
(Stroke. 2007;38:1734-1736.)
2007 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/STROKEAHA.107.487132
*Chinese patent medicines refer to finished or formulated products
(eg, capsules) made from crude herbs.
2
1734
Editorial
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The authors have reached 4 major conclusions, only 2 of
which seem reasonably supported by the evidence they
provided. First, based on the overall poor methodological
quality of trials included in the review they conclude that
there is insufficient evidence on the effects of TCPM in
ischemic stroke. This conclusion seems reasonable and is in
line with results of 2 recent Cochrane systematic reviews that
analyzed 2 TCPM drugs (Ginkgo biloba and Dan Shen
agents),
6,7
which are listed among 59 TCPM included in the
current review. However, it would have been methodologi-
cally better if the authors had not analyzed all clinical trials
irrespective of their methodological quality but instead ana-
lyzed trials of acceptable methodological quality alone or at
least separately. The authors also did not provide references
to trials and TCMP drugs listed in their Table 1 and Figures
1 and 2, thus making the interpretation of the results difficult.
It is unclear why they did not include in the analysis some
TCPM drugs currently analyzed by the Cochrane Collabora-
tion for the treatment of acute ischemic stroke.
1214
Second,
based on the existence of 2 randomized controlled trials of
acceptable methodological quality the authors argue that
TCPM can be evaluated in a randomized controlled trial
setting. This conclusion also seems reasonable, although the
authors did not provide clear guidelines for the desirable
design of future trials that would address some important
issues specifically pertaining to the proper evaluation of
herbal medicines in ischemic stroke patients, such as com-
plexity of the components of herbal medicines, or dosage and
timing of the intervention. Third, the authors conclude that
data concerning adverse events associated with TCPM drugs
were reassuring. Given the very high likelihood of multiple
biases in the trials analyzed (eg, selection, measurement, and
reporting biases) and the fact that adverse events for 6 TCPM
drugs analyzed (2 of which were tested in randomized
controlled trials of acceptable methodological quality) were
significantly higher than in controls, this conclusion seems
overstated. The absence of analysis for publication bias and
the authors inability to obtain missing data from relevant
trialists make this and other conclusions of the review less
certain. Fourth, the authors recommend 8 TCPM drugs (Milk
vetch, Mailuoning, Ginkgo biloba, Ligustrazine, Danshen
agents, Xuesetong, Puerarin, and Acanthopanax) for further
research, justifying their selection by the number of studies
and patients in which these drugs have been studied com-
pared with other drugs. This justification is not convincing.
The choice of TCPM drugs for further clinical testing should
be largely based on their efficacy and safety profiles estab-
lished in preclinical and early clinical (phase I and IIa trials)
research, evidence which is not yet available for most of these
herbal medicines.
So, what lessons can we learn from this systematic review?
There are at least 2 important and inter-related lessons. First
of all, it is clear that there is great interest among Chinese
researchers in studying efficacy of TCPM drugs in ischemic
stroke patients. Therefore it is important to develop statutory
regulations and approval process that would allow the devel-
opment of scientifically sound and locally applicable guide-
lines to study these medicines appropriately. Given the
widespread use of traditional medicines across the world, it is
important to regulate and establish educational and practice
standards for practitioners practicing these medicines.
15
Ef-
forts should be made to extract and study active components
from allegedly efficient herbs that may be a basis for new
pharmacological agents for ischemic stroke patients.
16
Sec-
ondly, existing evidence is insufficient to either refute or
support the use of TCPM as a treatment in acute and subacute
ischemic stroke patients. It should be noted that these drugs
are not side-effect free (including direct toxic reactions to the
herbs, interactions with other medicines, allergic reactions,
and idiosyncratic reactions) and caution should be exercised
in their use, especially outside of clinical research and
clinically monitored settings. Only properly designed clinical
research will be able to reliably address questions regarding
the efficacy, efficiency and safety of these drugs in ischemic
stroke patients. The widespread and increasing use of herbal
medicines throughout the world cannot be ignored any longer
by Western medicine. This is reflected in some newly
available funds for studying traditional medicine (eg, funds
and research projects of the National Center for Complemen-
tary and Alternative Medicine of the National Institutes of
Health). This, together with the ever increasing burden of
stroke in the world, especially in low- and middle-income
countries,
17
justifies the urgent need to evaluate herbal
medicines in properly designed randomized controlled trials,
followed by appropriate meta-analysis. However, there are
several issues specifically pertaining to clinical testing of
herbal medicines in stroke patients that need to be addressed
in the design of such trials. These include, for example, the
difficulty of using placebo-controlled design in countries
where herbal-based treatments are regarded as a standard,
such as China; difficulty of developing a placebo intervention
that would not be different from active herbal intervention in
terms of its taste, smell, and appearance; reluctance to report
adverse events for fear of individual blame attributable to
cultural beliefs in some Eastern countries or attributable to
belief that some adverse effects (eg, diarrhea) are part of the
normal response to herbal treatment; uncertainty and multi-
component structure of active ingredients and other chemic
compounds of herbal medicines that can be considered as
complex interventions of varying dosages and interactions,
especially in the context of differences in treatment concepts
between Western and traditional medicines; timing, dosage
and duration of the interventions. One possible approach to
these issues may be to use study design options suggested by
Campbell and colleagues for complex health-related interven-
tions.
18
Recently developed CONSORT guidelines
19,20
should
be used for reporting randomized, controlled trials of herbal
interventions and which can form the basis for planning and
conducting of such trials.
20
Until scientifically sound evi-
dence of the efficacy and safety of herbal medicine in
ischemic stroke patients is available, efforts should be made
throughout the world to continue implementing treatment
strategies of proven effectiveness.
Acknowledgments
I would like to thank Dr Joanne Barnes, Associate Professor in
Herbal Medicines at the School of Pharmacy, Faculty of Medical and
Feigin Herbal Medicine in Stroke 1735
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Health Sciences, University of Auckland, New Zealand for her
helpful comments on the draft of the manuscript.
Disclosures
None.
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KEY WORDS: drug trials

herbal medicines

stroke
1736 Stroke June 2007
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