1. No category

Dengzhanhua preparations for acute cerebral infarction
(Review)
Cao W, Liu W, Wu T, Zhong D, Liu G
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2008, Issue 4
http://www.thecochranelibrary.com
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Dengzhanhua versus other drugs, Outcome 1 Marked neurologic improvement.
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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i
[Intervention Review]
Dengzhanhua preparations for acute cerebral infarction
Wenzhai Cao2 , Weimin Liu3 , Taixiang Wu4 , Dechao Zhong2 , Guanjian Liu1
1 Department
of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, China.
Zigong No. 1 People’s Hospital, Zigong, China. 3 China Academy of Traditional Chinese Medicine,
Beijing, China. 4 Chinese Cochrane Centre, Chinese EBM Centre, West China Hospital, Sichuan University, Chengdu, China
2 Department of Internal Medicine,
Contact address: Guanjian Liu, Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan
University, No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, China. [email protected].
Editorial group: Cochrane Stroke Group.
Publication status and date: New, published in Issue 4, 2008.
Review content assessed as up-to-date: 9 March 2008.
Citation: Cao W, Liu W, Wu T, Zhong D, Liu G. Dengzhanhua preparations for acute cerebral infarction. Cochrane Database of
Systematic Reviews 2008, Issue 4. Art. No.: CD005568. DOI: 10.1002/14651858.CD005568.pub2.
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Dengzhanhua preparations are widely used in China. Many controlled trials have been undertaken to investigate the efficacy of
dengzhanhua preparations in the treatment of acute cerebral infarction.
Objectives
To assess whether dengzhanhua preparations are effective and safe at improving outcomes in patients with acute cerebral infarction.
Search methods
We searched the Cochrane Stroke Group Trials Register (last searched October 2007), the Chinese Stroke Trials Register (last searched
June 2006), the trials register of the Cochrane Complementary Medicine Field (last searched June 2006), the Cochrane Central Register
of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2 2006), MEDLINE (1966 to June 2006), EMBASE (1980 to June
2006), AMED (the Allied and Complementary Medicine Database, 1985 to June 2006), the China Biological Medicine Database
(CBM-disc, 1979 to June 2006), and Chinese Knowledge Infrastructure (CNKI,1994 to October 2007). We also searched the reference
lists of relevant articles.
Selection criteria
Randomised and quasi-randomised controlled clinical trials of dengzhanhua preparations regardless of duration, dosage and route of
administration in patients with confirmed acute cerebral infarction.
Data collection and analysis
Two review authors independently applied the inclusion criteria, assessed trial quality, and extracted the data.
Main results
We included nine trials, all conducted in China, involving 723 participants. The method of randomisation and concealment was poorly
described. The included trials compared dengzhanhua injection plus routine therapy with routine therapy alone. Patients were enrolled
up to one week after the onset of stroke. No trials reported data on the pre-specified primary or secondary outcomes. In a post-hoc
comparison of dengzhanhua injection plus routine therapy versus routine therapy alone, dengzhanhua injection showed a statistically
significant benefit on the outcome ’marked neurologic improvement’ (relative risk 1.53; 95% confidence interval 1.36 to 1.72). No
serious adverse effects were reported.
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
Authors’ conclusions
Due to the generally low methodological quality and small sample size of the included trials in this systematic review, we could not
draw a firm conclusion.
PLAIN LANGUAGE SUMMARY
Dengzhanhua preparations for acute cerebral infarction
There is no clear evidence that dengzhanhua injections benefit patients with acute cerebral infarction. Dengzhanhua preparations are a
traditional herbal drug that are commonly used in China to treat disorders of the blood supply to the heart and brain, including stroke.
These compounds have a number of actions which might help reduce disability after stroke. The most common type of stroke is cerebral
infarction, which is due to blockage of the blood supply to one part of the brain. This review aimed to include randomised or quasirandomised trials of dengzhanhua preparations in the treatment of patients with recent cerebral infarction. Nine studies involving 723
participants were included. The studies were of poor quality. Although treatment with dengzhanhua injections appeared to improve
neurological function, there was no evidence that treatment improved the chance of being alive and free of disability. This review
therefore did not find evidence to support the routine use of dengzhanhua for patients with recent stroke. Further well-designed trials
are needed.
BACKGROUND
A stroke is an acute impairment of focal brain function which
can be due to a variety of pathologic alterations in intracranial
or extracranial blood vessels and can result in death or physical
disability (Goldman 2000). In China, stroke is the second most
common cause of death in urban areas and the third most common in rural areas (MOH PRC 1999). It is estimated that 15
million new cases of stroke and five million deaths occur each year
worldwide (WHO 2005). In the United States, stroke is the third
most common cause of death, accounting for more than one in
every 15 deaths in 2001. Approximately 700,000 Americans suffer
a new or recurrent stroke each year (AHA 2004). Acute ischaemic
stroke accounts for 80% of all strokes (Jeffrey 2005). Neurological
symptoms and signs evolve after stroke onset in 25% to 40% of
patients. Severe clinical manifestations in the acute phase usually
indicate an increased risk of death and physical disability (Vila
2000).
No medication has yet been confirmed to have neuroprotective effects for acute ischaemic stroke (Adams 2003). Management of patients with acute ischaemic stroke with thrombolytic therapy carries the risk of catastrophic intracerebral haemorrhage (Hommel
1995). Although intravenous recombinant tissue plasminogen activator (rt-PA) in cerebral infarction can improve functional outcome of patients within three hours of stroke onset, it cannot be
used as a routine therapy outside special units (NINDS 1995).
Heparin has no benefit in reducing mortality in patients with acute
ischaemic stroke (Gubitz 2004). Therefore, we have to seek a more
effective therapy for these patients.
Dengzhanhua (Breviscapine) injection is extracted from Erigeron
breviscapus (Vant.) (Erigeron breviscapus is a plant which mainly
grows in southwest China; ’Vant.’ means compositae). Dengzhanhua injection is a traditional herbal drug for cardio-cerebral vascular diseases recorded by the Chinese Drug Dictionary 1977 edition. The main active components of dengzhanhua injection are
Scutellarin and Pyromeconic acid (Yang 2001; Zhang 2000).
Recent pharmacological experiments proved that dengzhanhua
has several possible modes of action. The compound can inhibit
platelet 5-HT release and platelet destruction could be reduced
in vivo (Wang 1989). In addition, dengzhanhua can also reduce
brain oedema, inhibit myeloperoxidase (MPO) activity and the
expression of intercellular adhesion molecule 1 (ICAM-1). Breviscapine attenuates brain oedema and neutrophil infiltration after
cerebral ischaemia reperfusion (He 2004). More important, there
is evidence that dengzhanhua can protect against reperfusion injury after ischaemia through inhibiting protein kinase C (PKC),
raised blood flow and maintaining the activity of Na+, K+ -A TPase
and Ca2+-ATPase in the brain (Chen 1998). Dengzhanhua can
therefore have effects on the occurrence of, and further neuronal
impairment after acute cerebral infarction.
There are several preparations available such as troche (buccal
tablet) (20 mg) and injection (5 mg per 2 ml). It can be taken orally
40 mg three times per day, or 5 mg twice a day intramuscular, or
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2
5 mg to 10 mg in 5% to 10% glucose solution intravenously for
acute ischaemic stroke (Ren 2002).
Though dengzhanhua treatment and its method of manufacture
are widely accepted in China, the constituents of the pharmacological preparations used in the trials cannot be specified precisely.
The main component is Breviscapine, but there may be still other
components which are not clear yet. This is in marked contrast to
industrially manufactured pharmacological agents used in Western
medicine, in which the chemical constituents and their quantities
(and the percentage of any impurities or contaminants) are very
precisely known, and the variation between different production
batches is kept within specified limits. Variation between formulations and batches of treatments is an inevitable consequence of
the nature of Chinese Traditional Medicine; it is a factor that may
contribute to any heterogeneity between different study results.
The effects, both beneficial and adverse, of dengzhanhua on acute
cerebral infarction need to be reviewed systematically and appraised critically to inform current practice and direct the continued search for new treatment regimens.
Types of interventions
We included trials of dengzhanhua regardless of duration, dosage
and route of administration. We compared dengzhanhua with
placebo or no treatment. However, trials of dengzhanhua plus
another treatment versus the other treatment alone in order to
assess dengzhanhua were also included.
Types of outcome measures
Primary outcome measure
(1) Death from any cause at the end of the scheduled follow-up
period.
Secondary outcome measures
(1) Death or dependence at the end of follow-up period.
(2) Quality of life if used in the included trials.
(3) Adverse events: bleeding, nausea, vomiting, abdominal pain,
diarrhoea, allergic reaction, or other serious adverse event caused
by dengzhanhua. We evaluated the number of patients developing
at least one severe adverse event listed above.
OBJECTIVES
To assess the effect of dengzhanhua preparations for acute cerebral
infarction compared with placebo or open control, and to evaluate
the side effects and adverse events of dengzhanhua preparations.
METHODS
Criteria for considering studies for this review
Types of studies
We included randomised and quasi-randomised controlled clinical trials (that is, allocation using alternation, the sequence of admission, case record numbers, dates of birth, or day of the week).
Search methods for identification of studies
See: ’Specialized register’ section in the Cochrane Stroke Group
We searched the Cochrane Stroke Group Trials Register, which
was last searched by the Review Group Co-ordinator in October 2007, the Chinese Stroke Trials Register (last searched June
2006), and the trials register of the Cochrane Complementary
Medicine Field (last searched June 2006). In addition, we searched
the Cochrane Central Register of Controlled Trials (CENTRAL)
(The Cochrane Library, Issue 2, 2006), MEDLINE (1966 to June
2006) (Appendix 1), EMBASE (1980 to June 2006), AMED
(the Allied and Complementary Medicine Database, 1985 to June
2006) and the China Biological Medicine Database (CBM-disc,
1979 to June 2006), which is a database of Chinese biomedical research literature. At the peer review stage of this review, a reviewer
suggested we search the Chinese Knowledge Infrastructure for additional studies. Though this was not included in the protocol, we
searched CNKI (1994 to October 2007).
We also searched the reference lists of relevant articles.
Types of participants
Participants were male or female of any age or ethnic origin with
acute cerebral infarction in either the carotid or vertebral artery territory, defined by brain computerised tomography (CT) or magnetic resonance imaging (MRI) scan. Trials restricted to patients
with transient ischaemic attacks (TIA) or intracranial haemorrhage
were excluded.
Data collection and analysis
Study selection
Two authors independently screened every title, abstract, and full
text of study reports. We included those studies that met the pre-
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3
determined inclusion criteria. We resolved any disagreements on
the selection of studies for inclusion by consensus discussion or
with a third party if necessary. We tried to obtain missing data
from the study authors where possible.
Quality assessment of studies
According to the empirical evidence, we assessed the methodological quality as described by The Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 (Higgins 2005).
Minimisation of selection bias
• Was the randomisation procedure adequate?
• Was the allocation concealment adequate?
Minimisation of performance bias
• Were the patients and people administering the treatment
blind to the intervention?
Minimisation of attrition bias
• Were withdrawals and dropouts completely described?
• Was analysis by intention-to-treat?
(1) General information: published or unpublished, title, authors,
reference or source, contact address, country, urban or rural, language of publication, year of publication, duplicate publications,
sponsor, setting.
(2) Trial characteristics: design, duration of follow up, method of
randomisation, allocation concealment, blinding (patients, people
administering treatment, outcome assessors).
(3) Intervention(s): intervention(s) (dose, route and timing), comparison intervention(s) (dose, route and timing) and co-medication (dose, route and timing).
(4) Patients: exclusion criteria, total number and number in comparison groups, age (adults), baseline characteristics, diagnostic
criteria, similarity of groups at baseline (including any co-morbidity), assessment of compliance, withdrawals and losses to follow
up (reasons, description), subgroups.
(5) Outcomes: outcomes specified above, any other outcomes assessed, other events, length of follow up, quality of reporting of
outcomes.
(6) Results: for outcomes and times of assessment (including a
measure of variation) converted to measures of effect specified
below if necessary, intention-to-treat analysis.
We resolved disagreements in data extraction by consensus, referring to the original article. If necessary, we sought information
from the study authors. If there was continued disagreement we
consultated a third author (Wu).
Minimisation of detection bias
• Were outcome assessors blind to the intervention?
Data analysis
Based on these criteria, we broadly subdivided the studies into the
following three categories.
A - all quality criteria met: low risk of bias.
B - one or more of the quality criteria only partly met: moderate
risk of bias.
C - one or more criteria not met: high risk of bias.
This classification was to be used as the basis of a sensitivity analysis. Since the studies were all of the same poor quality, we did not
perform a sensitivity analysis.
We included data in a meta-analysis if they were available, of sufficient quality and sufficiently similar. We expected both dichotomous data and continuous data. Only dichotomous data were extracted from included studies and expressed as relative risk (RR).
We did not perform combination analyses for overall results since
different comparators were used in variety studies. We assessed
heterogeneity by using the I-square (I2 ) statistic. We used a random-effects model for combination analysis in each subgroup. We
did not perform a publication bias analysis as there were no more
than three studies included in a subgroup.
Two authors (Cao, Liu) assessed each trial independently. We resolved disagreements, if necessary, by recourse to a third author
(Wu). In cases of further disagreement, we consulted the rest of
the group and a judgment was made based on consensus.
Subgroup analyses
Data extraction
For binary outcomes, we extracted the number of events and the
total number in each group. For continuous outcomes, we abstracted or imputed means, standard deviations and sample sizes
for each group. Two authors (Cao, Liu) independently extracted
data concerning details of study population, intervention and outcomes using a data extraction form specifically designed for this
review. The data extraction form included the following items.
We had planned to perform the following subgroup analyses.
• Treatment form (injection, tablet, granules, extract, capsule,
oral liquid, dripping pills, buccal tablets).
• Course of treatment, combined medication, route of
administration, dosage.
• The subgroup analyses were to be the time from stroke
onset to treatment, the duration of follow up (four weeks versus
more than four weeks), patients with Asian ethnic origin
compared with ones non-Asian origin, dose (low, medium, high
based on the data). We planned to explore reasons for
heterogeneity in the included studies and, if necessary, we also
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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planned to do sensitivity analyses to examine the effects of
excluding study subgroups, such as those studies with lower
methodological quality.
However, it was not possible to perform the subgroup analyses
because of the lack of data.
post-hoc analysis on the proportion of patients with marked neurologic improvement after treatment. The measures could concentrate on either specific neurologic dysfunction (such as motor
or cognition deficit) or overall neurologic deficit (such as the National Institute of Health Stroke Scale, which involves consciousness, vision, gaze, motor and other impaired neurological function).
As the studies were all of poor quality, we did not perform a sensitivity analysis.
RESULTS
Risk of bias in included studies
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Through electronic searches and screening of reference lists of articles we identified 43 potentially relevant references. At the peer
review stage of this review, we searched the Chinese Knowledge
Infrastructure for additional studies and found other 30 potentially relevant references. Among these, we excluded 52 irrelevant
references (mainly experimental studies), which left us with 21
potentially eligible trials, of which nine (Feng 2005; Huang 2005;
Li 1996; Liu 2004a; Peng 2005; Wang 2004; Wang 2005; Wen
2003; Yu 2005) were included, containing 723 patients with acute
ischaemic stroke. Details of the included trials can be found in the
Characteristics of included studies section. We excluded 12 studies
(Bai 2002; Chu 2003; Fang 1996; Liu 1999; Li 2000; Liu 2004;
Lu 2002; Sun 2000; Wang 1987; Xu 1999; Yang 2000; Zhang
2002) because they compared dengzhanhua with unproven drugs
(see Characteristics of excluded studies).
The included trials were conducted in China. The average age of
participants ranged from 54 to 85 years. All the trials enrolled more
males than females, except one trial (Li 1996), which included
more females. All the trials described the inclusion criteria. All the
trials routinely performed a CT or MRI head scan in patients to
exclude haemorrhage before randomisation.
All included trials studied dengzhanhua injection to assess the
effect of dengzhanhua, and compared dengzhanhua and routine
therapy in the treatment group with routine therapy alone in the
control group. The doses of dengzhanhua ranged from 16 ml to 40
ml, 30 mg to 75 mg respectively. The course of treatment ranged
from 10 days to 30 days. The dengzhanhua injection used in the
trials was administered once a day for one course of treatment.
None of the trials reported follow up after the termination of the
treatment period. Neither deaths nor adverse events were reported.
None of the trials included quality of life as an outcome measure.
None of the trials reported the outcome measures that we used in
our study protocol. The outcome measures used in the included
trials were the measurement of neurologic deficit using the nationally approved outcome measures which were similar to the National Institute of Health Stroke Scale. We therefore performed a
Two trials (Wang 2005; Liu 2004a) described allocated treatment
according to the sequence of admission and hence were quasirandomised.The remaining seven trials (Feng 2005; Huang 2005;
Li 1996; Peng 2005; Wang 2004; Wen 2003; Yu 2005) did not
describe the method of allocation or allocation concealment. We
tried to contact the original authors to check the randomisation
method in detail, but none of authors were contacted successfully.
Therefore, the overall quality rating of all the included trials was
graded C (high risk of bias). The baseline characteristics of the
patients in the included trials showed no significant imbalance
between groups. The time from stroke onset to randomisation in
all the trials was within one week from onset. No loss to follow up
was reported in any trial.
Effects of interventions
Death from any cause at the end of the scheduled
follow-up period
None of the trials reported the continued follow up after the termination of the treatment period. None of the trials reported any
deaths at all.
Death or dependence at the end of follow-up period
No trials reported any death or dependence at the end of follow-up
period. Therefore, death or dependence at the end of the followup period was not assessed in the included trials.
Quality of life if used in the included trials
None of the included trials undertook the assessment of quality
of life.
Adverse events
None of the trials provided any data regarding adverse events,
and no case of serious adverse events such as major extracranial
bleeding was reported during the treatment period.
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5
Comparison 1.1: Marked neurologic improvement
(post-hoc comparison)
Although we were not able to extract any data on the pre-specified
primary and main secondary outcomes, we were able to extract
data on the proportion of participants with marked neurologic
improvement after treatment. This was a post-hoc outcome, and
this analysis must therefore be interpreted with caution. All nine
trials including randomised data from 723 participants evaluated
neurologic dysfunction (divided into six grades from death or deterioration to cure), and we converted these outcomes to dichotomous data (the proportion of patients with at least 45% neurologic
improvement). The included trials appeared to show a statistically
significant benefit from dengzhanhua compared with control (RR
1.53; 95% CI 1.36 to 1.72); no statistical heterogeneity was detected (I2 = 0%).
DISCUSSION
Though dengzhanhua treatment and its method of manufacture
are widely accepted in China, the effects, both beneficial and adverse, of dengzhanhua on acute cerebral infarction needed to be
appraised critically. We included nine completed randomised or
quasi-randomised controlled trials of dengzhanhua preparations
for acute ischaemic infarction. The result of our meta-analysis
suggests that dengzhanhua could have potential therapeutic value
in the treatment of acute ischaemic infarction. However, due to
the generally poor methodological quality of the included trials,
we could not make firm conclusions. There are several substantial
limitations.
Firstly, published studies from China were found to be different from typical articles published in the Western literature, with
key details concerning randomisation and blinding omitted. In
our meta-analysis, although all included trials reported the use of
randomisation, two described a method of allocation which was
not true randomisation and the other seven did not describe the
method of randomisation or concealment; our overall rating of
the quality of all the included studies was therefore C, that is associated with a high risk of bias. From a recent telephone interview
with the clinical investigators by the Chinese Cochrane Center,
only 7% of them undertook correct randomisation, while most of
them misunderstood the concept of randomisation (Wu 2006).
Through contact with several trialists before inclusion of the trials, we found that some investigators had little knowledge of randomisation design. One trial described as randomised was actually
a case-control study. Therefore we could not determine that allocation was truly random and well concealed. Empirical research
had proved that inadequate allocation concealment is associated
with bias (Moher 1998).The result of this meta-analysis could be
confounded by possible bias.
Secondly, the included trials were generally of small sample size.
None of the trials reported the method of determination of the
sample size. The shortcomings of a small sample size is to imply
low power of a test. However, no trial appeared to apply any power
analysis or mentioned the possibility of a type-II error occurring.
Thirdly, the scheduled treatment period ranged from 10 days to
30 days in the included trials. All the follow ups terminated at the
end of the treatment period. The recovery of neurologic deficit
occurred quickly in the first three months after symptom onset
(Kotila 1984). Three months after the onset of stroke would be an
appropriate time to measure the neurologic outcome. Therefore
we could not determine the long-term effect because of the short
period of follow up.
Fourthly, acute stroke trials should use the outcome measures
which are relevant to patients to influence clinical practice (Roberts
1998). The included trials in this review used the nationally approved outcome measures alone to evaluate the patients neurologic
impairment, which was the least clinically relevant to the patients.
Handicap or even health-related quality of life outcome measures
might be more relevant. However, none of the included trials used
these outcome measures.
Furthermore, we have to mention the effect on death. No deaths at
the end of the scheduled follow-up period were reported in these
trials, which is more important than the neurologic improvement
for the stroke patients. In the recent review of trials of traditional
Chinese medicines in acute stroke (Wu 2007), the frequency of
death was also extremely low. Therefore, this almost certainly is
due to under-reporting, and highlights another major concern
about the inadequate quality of these studies.
Finally, herbal medicine used to be perceived as being natural
and harmless in China, but recent literature on the adverse effect
of herbal medicine, including dengzhanhua injection, reported
allergic reactions, and toxic effects on the liver or renal function
(Zhou 2000). Therefore we tried to review both the beneficial and
adverse effects of dengzhanhua for stroke. However, none of the
included trials reported adverse events, which provided insufficient
data for us to evaluate the safety of dengzhanhua. From the possible
pharmacological action of dengzhanhua, we could not draw a firm
conclusion that it does not cause bleeding.
AUTHORS’ CONCLUSIONS
Implications for practice
Based on this systematic review, we found no clear evidence that
dengzhanhua injection benefits patients with acute cerebral infarction. Even the apparent improvement in neurologic impairment
was not reliable because of inadequate randomisation and other
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
6
methodological weaknesses. Adverse effects were not reported in
the trials, so the safety of dengzhanhua is unclear. Due to the generally poor methodological quality and small sample sizes of the
included trials, we could not draw any reliable implications for
practice.
Implications for research
Clinical trials with both high methodological quality and large
sample sizes are needed. Sample size should be estimated by the
proper statistical method and power or type-II errors should be
evaluated. Trials of dengzhanhua for acute cerebral infarction
should use more clinically relevant outcome measures and suitable end-points identified to undertake outcome measurements.
Furthermore, investigators conducting randomised trials should
receive formal training in clinical trial design. From the results of
this systematic review, it would be necessary to compare dengzhanhua with placebo or no intervention to discover the definite effect
of dengzhanhua for acute cerebral infarction. In addition to the
outcome measures for beneficial effects, it is essential to establish
a clear monitoring and reporting system for the adverse effects of
herbal medicines.
ACKNOWLEDGEMENTS
We extend our thanks to the Cochrane Stroke Group Editorial
Board for their helpful comments.
REFERENCES
References to studies included in this review
Feng 2005 {published data only}
Feng ZW, Hu ZC. Curative effect of dengzhanhua injection
for acute ischemic stroke. Journal of Guangxi Medical
University 2005;22(3):438–9.
Huang 2005 {published data only}
Huang XY, Ding YJ, Fang HW. Investigation on the
curative effect of dengzhanhua for acute cerebral infarction.
Modern Journal of Integrated Traditional Chinese and Western
Medicine 2005;14(15):1964–5.
Wen 2003 {published data only}
Wen TY. Clinical observation on dengzhanhua injection for
39 patients with acute ischemic stroke. China Traditional
Chinese Medicine Emergency 2003;12(3):239.
Yu 2005 {published data only}
Yu XQ, Zhou J. Clinical observation of dengzhanhua
injection for 26 patients with acute ischemic stroke.
Cardiovascular Journal of Chinese Traditional Medicine and
Western Medicine 2005;3(10):925.
References to studies excluded from this review
Li 1996 {published data only}
Li F, Gu DX, Yang SJ, Lu XG. Clinical investigation of
combination therapy of Chinese Traditional Medicine &
Western Medicine for acute cerebral infarction. Zhong Xi
Yi Jie He Shi Yong Lin Chuang Ji Jiu Zha Zhi 1996;3(5):
209–11.
Bai 2002 {published data only}
Bai GH, Li CJ, Xu B. Clinical observation on the effect
of dengzhanhua injection for acute cerebral infarction.
Clinical Medicine 2002;22(12):56.
Liu 2004a {published data only}
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injection for acute ischemic stroke. Journal of Jinzhou
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Chu 2003 {published data only}
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dengzhanhua injection for 60 cases with acute cerebral
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Wang 2004 {published data only}
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acute ischemic stroke. Henan Journal of Practical Nervous
Diseases 2004;7(4):54.
Wang 2005 {published data only}
Wang J, Gu W, Tan F. Effect of erigeron injection on platelet
level of CD62p and serum content of TNF-alpha and IL-6
in patients with acute cerebral infarction. Chinese Journal
of Integrated Traditional and Western Medicine/Chung-kuo
Chung Hsi 2005;25(4):324–6.
Fang 1996 {published data only}
Fang DW. Curative effect of Yunnan dengzhanhua injection
on 106 cases with acute cerebral infarction. Zhejiang Zhong
Yi Za Zhi 1996;8:381.
Li 2000 {published data only}
Li Q, Guo YJ. Curative effect of naloxone plus dengzhanhua
for acute cerebral infarction. Yunnan Zhong Yi Zhong Yao
Za Zhi 2000;21(3):17.
Liu 1999 {published data only}
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dengzhanhua plus citicoline for acute cerebral infarction.
Lin Chuang Yi Xue 1999;19(7):36–7.
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Liu 2004 {published data only}
Liu FR, Bian LZ. Curative effect of dengzhanhua on 106
cases with acute cerebral infarction. Central Plains Medical
Journal 2004;31(12):38–9.
Lu 2002 {published data only}
Lu YF. The clinical observation of erigeron breviscapus
hand-mazz injection in the treatment of cerebral infarction.
Journal of Qiqihar Medical College 2002;23(4):362–4.
Sun 2000 {published data only}
Sun CP, Ma JJ, XU J. Investigation on the curative effect
of dengzhanhua for 93 cases with acute cerebral infarction.
Henan Yi Yao Xin Xi 2000;8(2):50–1.
Wang 1987 {published data only}
Wang H, Shi M, Yang C, Li J. Clinical observation
on the therapeutic effect of deng-zan-hua-su-pian on
cerebrovascular diseases. Journal of Apoplexy and Nervous
Diseases 1987;4(4):247–8.
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dengzhanhua for 34 cases with acute cerebral infarction.
Zhong Guo Xiang Chun Yi Sheng Za Zhi 1999;3:23–4.
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plus shenmai injection for acute cerebral infarction. Journal
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Dengzhanhua preparations for acute cerebral infarction (Review)
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8
Wu 2006
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References to other published versions of this review
Cao 2006
Cao W, Liu W, Wu T. Dengzhanhua preparations for
acute cerebral infarction. (Protocol). Cochrane Database of
Systematic Reviews 2006, Issue 1. [Art. No.: CD005568.
DOI: 10.1002/14651858.CD005568]
∗
Indicates the major publication for the study
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
9
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Feng 2005
Methods
RCT, method of randomisation and concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
108 patients (acute ischaemic stroke)
100% CT scan before entry
Comparability: age similar, more males than females
Numbers of severity of stroke not stated
Interventions
T: dengzhanhua 40 ml once a day for 30 days + routine treatment
C: routine treatment
Outcomes
The proportion of patients with marked neurologic improvement at 30 days
Notes
FU: 30 days
Quality grading: C (high risk of bias)
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Huang 2005
Methods
RCT, method of randomisation and concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
60 patients (acute ischaemic stroke)
100% CT scan before entry
Comparability: age similar, more males than females
Numbers of severity of stroke: mild - 4 participants in each group; moderate - 13 participants in treatment
group,12 participants in control group; severe - 13 participants in treatment group,14 participants in
control group
Interventions
T: dengzhanhua 40 ml once a day for 14 days + routine treatment
C: routine treatment
Outcomes
The proportion of patients with marked neurologic improvement at 14 days
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Huang 2005
(Continued)
Notes
FU: 14 days
Quality grading: C (high risk of bias)
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Li 1996
Methods
RCT, method of randomisation and concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
80 patients (acute ischaemic stroke)
100% CT or MRI scan before entry
Comparability: age similar, more females than males
Numbers of severity of stroke not stated
Interventions
T: dengzhanhua 16 ml once a day for 10 days + routine treatment
C: routine treatment
Outcomes
The proportion of patients with marked neurologic improvement at 10 days
Notes
FU: 10 days
Quality grading: C (high risk of bias)
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Liu 2004a
Methods
Quasi-RCT, method of randomisation: the sequence of admission, concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
106 patients (acute ischaemic stroke)
100% CT or MRI scan before entry
Comparability: age similar, more males than females
Numbers of severity of stroke not stated
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Liu 2004a
(Continued)
Interventions
T: dengzhanhua 75 mg once a day for 14 days + routine treatment
C: routine treatment
Outcomes
The proportion of patients with marked neurologic improvement at 14 days
Notes
FU: 14 days
Quality grading: C (high risk of bias)
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
No
C - Inadequate
Peng 2005
Methods
RCT, method of randomisation and concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
66 patients (acute ischaemic stroke)
100% CT or MRI scan before entry
Comparability: age similar, more males than females
Numbers of severity of stroke not stated
Interventions
T: dengzhanhua 40 ml once a day for 14 days + routine treatment
C: routine treatment
Outcomes
The proportion of patients with marked neurologic improvement at 14 days
Notes
FU: 14 days
Quality grading: C (high risk of bias)
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Wang 2004
Methods
RCT, method of randomisation and concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
120 patients (acute ischaemic stroke)
100% CT scan before entry
Comparability: age similar, more males than females
Numbers of severity of stroke: mild - 20 participants in treatment group,18 participants in control group;
moderate - 32 participants in treatment group, 28 participants in control group; severe - 12 participants
in treatment group,10 participants in control group
Interventions
T: dengzhanhua 30 mg once a day for 30 days + routine treatment
C: routine treatment
Outcomes
The proportion of patients with marked neurologic improvement at 30 days
Notes
FU: 30 days
Quality grading: C (high risk of bias)
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Wang 2005
Methods
Quasi-RCT, method of randomisation: the sequence of admission, concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
68 patients (acute ischaemic stroke)
100% CT or MRI scan before entry
Comparability: age similar, more males than females
Numbers of severity of stroke not stated
Interventions
T: dengzhanhua 40 ml once a day for 15 days + routine treatment
C: routine treatment
Outcomes
The proportion of patients with marked neurologic improvement at 15 days
Notes
FU: 15 days
Quality grading: C (high risk of bias)
Risk of bias
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Wang 2005
(Continued)
Item
Authors’ judgement
Description
Allocation concealment?
No
C - Inadequate
Wen 2003
Methods
RCT, method of randomisation and concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
69 patients (acute ischaemic stroke)
100% CT scan before entry
Comparability: age similar, more males than females
Numbers of severity of stroke: mild - 14 participants in treatment group,11 participants in control group;
moderate - 16 participants in treatment group,12 participants in control group; severe - 9 participants in
treatment group,7 participants in control group
Interventions
T: dengzhanhua 30 ml once a day for 28 days + routine treatment
C: routine treatment
Outcomes
The proportion of patients with marked neurologic improvement at 28 days
Notes
FU: 28 days
Quality grading: C (high risk of bias)
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Yu 2005
Methods
RCT, method of randomisation and concealment not stated
Losses to FU: none
Blinding: not stated
Participants
Country: China
46 patients (acute ischaemic stroke)
100% CT or MRI scan before entry
Comparability: age similar, more females than males
Numbers of severity of stroke not stated
Interventions
T: dengzhanhua 40 ml once a day for 30 days + routine treatment
C: routine treatment
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Yu 2005
(Continued)
Outcomes
The proportion of patients with marked neurologic improvement at 30 days
Notes
FU: 30 days
Quality grading: C (high risk of bias)
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Routine treatment/therapy: mannitol; management of blood glucose, blood pressure, and antibiotics; no thrombolytic therapy was
applied
C: control group
CT: computerised tomography
FU: follow up
MRI: magnetic resonance imaging
RCT: randomised controlled trial
T: treatment group
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Bai 2002
Dengzhanhua compared with unproven drug
Chu 2003
Dengzhanhua compared with unproven drug
Fang 1996
Dengzhanhua compared with unproven drug
Li 2000
Confounded with naloxone
Liu 1999
Dengzhanhua compared with unproven drug
Liu 2004
Dengzhanhua compared with unproven drug
Lu 2002
Dengzhanhua compared with unproven drug
Sun 2000
Dengzhanhua compared with unproven drug
Wang 1987
Dengzhanhua compared with unproven drug
Xu 1999
Dengzhanhua compared with unproven drug
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
15
(Continued)
Yang 2000
Confounded with Shenmai
Zhang 2002
Dengzhanhua compared with unproven drug
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
16
DATA AND ANALYSES
Comparison 1. Dengzhanhua versus other drugs
Outcome or subgroup title
No. of
studies
No. of
participants
9
9
723
1 Marked neurologic improvement
1.1 Dengzhanhua plus routine
therapy versus routine therapy
Statistical method
Effect size
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Subtotals only
1.53 [1.36, 1.72]
Analysis 1.1. Comparison 1 Dengzhanhua versus other drugs, Outcome 1 Marked neurologic improvement.
Review:
Dengzhanhua preparations for acute cerebral infarction
Comparison: 1 Dengzhanhua versus other drugs
Outcome: 1 Marked neurologic improvement
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
1 Dengzhanhua plus routine therapy versus routine therapy
Feng 2005
30/58
15/50
5.6 %
1.72 [ 1.06, 2.82 ]
Huang 2005
22/30
15/30
7.8 %
1.47 [ 0.97, 2.23 ]
Li 1996
25/41
13/39
5.3 %
1.83 [ 1.10, 3.04 ]
Liu 2004a
43/56
19/50
9.3 %
2.02 [ 1.38, 2.96 ]
Peng 2005
20/33
9/33
3.5 %
2.22 [ 1.19, 4.14 ]
Wang 2004
61/64
37/56
35.7 %
1.44 [ 1.19, 1.75 ]
Wang 2005
25/35
13/33
6.1 %
1.81 [ 1.13, 2.91 ]
Wen 2003
36/39
21/30
21.6 %
1.32 [ 1.03, 1.70 ]
Yu 2005
17/26
10/20
5.0 %
1.31 [ 0.78, 2.20 ]
382
341
100.0 %
1.53 [ 1.36, 1.72 ]
Subtotal (95% CI)
Total events: 279 (Treatment), 152 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 7.65, df = 8 (P = 0.47); I2 =0.0%
Test for overall effect: Z = 7.17 (P < 0.00001)
0.1 0.2
0.5
Favours control
1
2
5
10
Favours treatment
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
17
APPENDICES
Appendix 1. MEDLINE search strategy
The following search strategy was used for MEDLINE (Ovid) and was modified to suit the other databases.
1. cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain ischemia/ or exp carotid artery diseases/ or
exp cerebrovascular accident/ or exp hypoxia-ischemia, brain/ or exp intracranial arterial diseases/ or exp “intracranial embolism and
thrombosis”/
2. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial
or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$ or
apoplexy)).tw.
3. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw.
4. 1 or 2 or 3
5. plant extracts/ or drugs, Chinese herbal/
6. phytotherapy/ or plants/ or plants, medicinal/ or asteraceae/
7. (dengzhanhua$ or deng zhan hua$ or deng-zhan-hua$).tw.
8. (dengzhanxixin$ or deng zhan xi xin$ or deng-zhan-xi-xin$).tw.
9. (erigero$ or breviscap$ or yimaikang or scutellarin or fleabane).tw.
10. 5 or 6 or 7 or 8 or 9
11. 4 and 10
WHAT’S NEW
Last assessed as up-to-date: 9 March 2008.
Date
Event
Description
17 April 2008
Amended
Converted to new review format.
HISTORY
Protocol first published: Issue 1, 2006
Review first published: Issue 4, 2008
CONTRIBUTIONS OF AUTHORS
All five authors contributed to this review.
• Search strategy: Liu, Wu
• Study selection: Cao, Liu
• Data extraction: Cao, Liu
• Quality assessment: Cao, Liu, Wu
• Statistical and methodological input: Wu, Liu
• Interpretation of data: Cao, Zhong
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
18
• Providing general advice on the review: Liu
• Writing the review: Cao, Wu
DECLARATIONS OF INTEREST
None known
SOURCES OF SUPPORT
Internal sources
• Chinese Cochrane Center, Chinese Centre of Evidence-Based Medicine, West China Hospital of Sichuan University, China.
• China Medical Board of New York, USA.
External sources
• Cochrane Stroke Group, UK.
INDEX TERMS
Medical Subject Headings (MeSH)
Acute Disease; Anticoagulants [∗ therapeutic use]; Cerebral Infarction [∗ drug therapy]; Flavonoids [∗ therapeutic use]; Randomized
Controlled Trials as Topic
MeSH check words
Humans
Dengzhanhua preparations for acute cerebral infarction (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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