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Valery L. FeiginHerbal Medicine in Stroke : Does It Have a Future?

ISSN: 1524-4628

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Herbal Medicine in StrokeDoes It Have a Future?

Valery L. Feigin, MD, MSc, PhD, FAAN

See related article, pages 19731979.

The 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 billionannually 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 properties3,4 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 ofStroke, Wu and colleagues11 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 usedin 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 theremaining 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 thesetrials 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 orof 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 TrialsResearch Unit, University of Auckland, Private Bag 92019, Auckland,New Zealand. E-mail [email protected]

(Stroke. 2007;38:1734-1736.) 2007 American Heart Association, Inc.

Stroke is available at http://www.strokeaha.orgDOI: 10.1161/STROKEAHA.107.487132

*Chinese patent medicines refer to finished or formulated products(eg, capsules) made from crude herbs.2

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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 ofacceptable 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 TCPMdrugs 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 thewidespread 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 interventionthat 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 byCampbell and colleagues for complex health-related interven-

tions.18 Recently developed CONSORT guidelines19,20 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 inHerbal 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 herhelpful comments on the draft of the manuscript.

DisclosuresNone.

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KEY WORDS: drug trials herbal medicines stroke

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