Buyang Huanwu Decoction (BHD) is a well-known traditional Chinese herbal prescription for treating stroke-induced disability. The objective of this study was to evaluate the efficacy and safety of BHD for acute ischemic stroke. A systematic literature search was performed in 6 databases until February 2012. Randomized controlled clinical trials (RCTs) that evaluate efficacy and safety of BHD for acute ischemic stroke were included. Nineteen RCTs with 1580 individuals were identified. The studies were generally of low methodological quality. Only one of the trial included death or dependency as a primary outcome measure. Only 4 trials reported adverse events. Meta-analysis showed the clinical effective rate of neurological deficit improvement favoring BHD when compared with western conventional medicines (WCM),
Stroke is one of the major causes of disability and dependence in the world [
China, as a developing country, has the largest number of stroke cases in the world because it has a population of 1.34 billion in 2011. The most appreciable difference between China and the Western countries in treating stroke is the use of Traditional Chinese Medicine (TCM) therapy including Chinese herbal medicine (CHM), acupuncture, and other nonmedication therapies [
BHD is commonly used in the acute, recovery, and sequelae stages of patients with ischemic stroke in China. However, the most important period of recovery is at the acute and subacute stages during the clinical course of ischemic stroke [
Randomized controlled clinical trials (RCTs) that evaluate efficacy and safety of BHD for ischemic stroke patients were included. Quasi-RCTs were not considered such as using the admission sequence for treatment allocation.
Patients of any gender, age, or race/ethnicity with ischemic stroke within 7 days of onset were considered. The ischemic stroke was diagnosed clinically according to the World Health Organization definition [
The patients of the control group were given western conventional medicines (WCM). WCM refer to the combination of needed therapies of the following aspects: (1) general supportive care mainly includes (A) airway, ventilatory support and supplemental oxygen, (B) cardiac monitoring and treatment, (C) temperature, (D) blood pressure, (E) blood sugar, and (F) nutrition; (2) specialized care mainly includes a variety of measures to improve cerebral blood circulation (such as antiplatelet agents, anticoagulants, fibrinogen-depleting agents, volume expansion, and vasodilators, except thrombolytic agents) and neuroprotective agents; (3) treatment of acute complications mainly includes (A) brain edema and elevated intracranial pressure, (B) seizures, (C) dysphagia, (D) pneumonia, (E) voiding dysfunction and urinary tract infections, and (F) deep vein thrombosis. The intervention for control group included only WCM treatments. Studies comparing BHD therapy to another form of Chinese herbal medicine were excluded. The patients at the treatment groups were given BHD therapy in addition to WCM which was similar to the control group. Modified BHD was (BHD plus few herbal) also included. The clinical trials were included regardless of length of treatment period and dosage of treatment.
The primary outcome measures were death or dependency at the end of followup (at least 3 months). Dependency was defined as need assistance in activity of daily living, such as the Barthel Index
In this paper, the neurologic deficit score criteria were adopted based on the Modified Edinburgh-Scandinavian Stroke Scale, a nationwide accepted scoring system recommended at the Second and revised at the Fourth National Cerebrovascular Diseases Conference in China [
We searched Cochrane library; PubMed; EMBASE; China National Knowledge Infrastructure; VIP Journals Database; Wanfang database until February 2012. The search terms used were (Bu-yang Huan-wu decoction OR Bu-yang-Huan-wu decoction) AND (Ischemic Stroke OR Cerebral infarction OR cerebral embolism); Chinese Databases were also searched using the above search terms in Chinese. We hand-searched Chinese journals that may publish potentially eligible studies and conference proceedings relevant to this topic. The reference lists of all relevant articles were searched for further studies.
All articles were read by two independent reviewers (Hao CZ, Wu F), who extracted data from the articles according to a standardized data extraction form, including patients, methods, interventions, and outcomes. The reasons for the exclusion of studies were recorded accordingly. For eligible studies, two review authors (Hao CZ, Wu F) extracted the data independently. Disagreements were resolved through consultation with a third party author (Zheng GQ or Liao WJ).
The risk of bias was assessed using the twelve criteria recommended by the Cochrane Back Review Group [
We synthesized the results in a meta-analysis. A fixed-effects model or random-effect model was used across the trials, and risk ratios with their 95% confidence intervals (CI) were calculated for dichotomous data. If continuous data were available, weighted mean difference or standardized mean difference was to be calculated using RevMan 5.1 software provided by the Cochrane Collaboration, and Cochrane’s
On the basis of search strategy, we identified 354 potentially relevant articles, and 255 articles were excluded because they were not reporting clinical trials, case report, or lacking comparison group. Of the remaining 99 articles, 80 were excluded because 7 articles were not real RCTs with admission sequence used for treatment allocation, 61 with patients who did not meet the criteria of the types of participants; there are 3 trials used Chinese Herbal Injections in control group and 9 adopted nonstandard efficacy criteria. Finally, 19 studies, involving a total of 1580 participants, met our inclusion criteria [
Flowchart of trials selection process.
The 19 studies included were all conducted in China and published between 1995 and 2012, and all of them were performed in a single center. The sample size was small, with 3 having a size less than 50, and 11 between 50 and 100, the other 5 between 100 and 200, and none reported sample size estimation. All the 19 RCTs based the diagnosis of acute ischemic stroke on both clinical examination and CT or MRI. All the 19 RCTs used BHD combining with conventional western therapy as the treatment group, and conventional western therapy as control group. The duration of studies lasted from 10 days to 30 days. Both clinical effective rate and neurologic deficit scores were observed in 8 studies, while only clinical effective rate was observed in 9 studies, only neurologic deficit scores were observed in 1 studies [
Summary of the characteristics of the included trials.
First author year | Subjects (trial/control) | Age (years) | Intervention | Main outcome measures | Course of disease (d) | Course of treatment (d) | ||
---|---|---|---|---|---|---|---|---|
Trial group | Control group | Trial group+ | Control group | |||||
Zhang 2010 [ |
82/82 | 51–77 | 50–78 | BHD* | WCM** | TER, NDS | <7 | 30 |
Wu 2011 [ |
35/35 | 59.8 ± 7.3 | 60.5 ± 8.1 | BHD* plus two-toothed achyranthes root and syndrome differentiation | WCM** | TER | <1 | 28 |
Zhang 2004 [ |
40/40 | 45–70 | 42–80 | BHD* plus syndrome differentiation | WCM** | TER, NDS | <3 | 15 |
Guo 2009 [ |
57/30 | 48–78 | 47–80 | BHD* plus syndrome differentiation | WCM** | TER, |
<3 | 15 |
Jia 2010 [ |
32/28 | 31–70 | 30–70 | BHD* | WCM** | TER | <3 | 14 |
Fang 2005 [ |
65/72 | 68.7 ± 0.8 | 67.2 ± 0.7 | BHD* plus stiff silkworm | WCM** | TER | <3 | 30 |
Zhang 2012 [ |
34/36 | 64.8 ± 5.6 | 65.2 ± 5.2 | BHD* plus pangolin scales, grassleaf sweetflag rhizome, milkwort root, stiff silkworm, two-toothed achyranthes root, and bile arisaema based on syndrome differentiation | WCM** | TER | <2 | 45 |
Li 2011 [ |
33/33 | 75–81 | 75–80 | BHD* plus syndrome differentiation | WCM** | ESS | <3 | 14 |
Kang 2006 [ |
36/38 | 48–80 | 49–82 | BHD* plus danshen root | WCM** | TER, NDS | <3 | 15 |
Lin 2008 [ |
32/30 | 50–75 | 50–75 | BHD* plus scorpion and leech | WCM** | TER | <3 | nr |
Chen 2007 [ |
33/32 | 61.6 ± 4.7 | 58.7 ± 5.6 | BHD* | WCM** | TER, NDS | <3 | 14 |
Yan 2004 [ |
60/60 | 46–78 | 46–80 | BHD* plus tangshen | WCM** | TER | <7 | 20 |
Cui 2005 [ |
50/30 | 55–71 | 56–68 | BHD* plus tangshen, fragrant solomonseal rhizome, common aucklandia root, bile arisaema, and white mustard seed based on syndrome differentiation | WCM** | TER | <7 | 20 |
Liu 2010 [ |
55/55 | 39–74 | 39–75 | BHD* plus danshen root and plus syndrome differentiation |
WCM** | TER | <3 | 14 |
Shi 1995 [ |
21/20 | 62.9 ± 7.5 | 63.3 ± 11.9 | BHD* plus cassia twig and danshen root |
WCM** | TER | <3 | 10 |
Run 2001 [ |
24/24 | 48–76 | 45–77 | BHD* plus syndrome differentiation | WCM** | TER | <3 | 28 |
Wang 2005 [ |
64/64 | 36–65 | 40–71 | BHD* plus stiff silkworm, cicada slough, bile arisaema, grassleaf sweetflag rhizome, and syndrome differentiation | WCM** | TER, NDS | <7 | 14 |
Lv 2009 [ |
35/35 | 64.71 ± 10.63 | 63.31 ± 10.47 | BHD* plus two-toothed achyranthes root and syndrome differentiation | WCM** | TER, NDS | <3 | 30 |
Zheng 2004 [ |
27/22 | 65.6 ± 6.3 | 62.6 ± 6.8 | BHD* | WCM** | TER, NDS | <3 | 21 |
Notes: BHD: buyang huanwu decoction, WCM: western conventional medicines, TER: total effective rate, NDS: neurological deficit score; +: mean same as the control group treatment. *BHD is composed of seven kinds of Chinese medicine: Huangqi (Radix Astragali seu Hedysari), Danggui (Radix Angelicae Sinensis), Chishao (Radix Paeoniae Rubra), Chuanxiong (Rhizoma Ligustici Chuanxiong), Honghua (Flos Carthami), Taoren (Semen Persicae), and Dilong (Pheretima). **WCM refer to the combination of needed therapies of the following aspects: (1) general supportive care mainly include: (A) airway, ventilatory support, and supplemental oxygen, (B) cardiac monitoring and treatment, (C) temperature, (D) blood pressure, E. blood sugar, and F. nutrition; (2) specialized care mainly include a variety of measures to improve cerebral blood circulation (such as antiplatelet agents, anticoagulants, fibrinogen-depleting agents, volume expansion, and vasodilators, except thrombolytic agents) and neuroprotective agents; (3) treatment of acute complications mainly include: (A) brain edema and elevated intracranial pressure, (B) seizures, (C) dysphagia, (D) pneumonia, E.voiding dysfunction, and urinary tract infections and F. deep vein thrombosis.
All of the studies were described as randomized, but no study reported the method of random sequences generation. No study mention allocation concealment. Only one study mentioned single blinding [
The methodological quality of the included trials.
First author year | A | B | C | D | E | F | G | H | I | J | K | L |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Zhang 2010 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Wu 2011 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Zhang 2004 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Guo 2009 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Jia 2010 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Fang 2005 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Zhang 2012 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Li 2011 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Kang 2006 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Lin 2008 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Chen 2007 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Yan 2004 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Cui 2005 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Liu 2010 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Shi 1995 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Run 2001 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Wang 2005 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
Lv 2009 [ |
? | ? | ? | ? | ? | − | − | ? | + | + | + | + |
Zheng 2004 [ |
? | ? | − | − | ? | − | − | ? | + | + | + | + |
A: adequate sequence generation; B: concealment of allocation; C: blinding (patient); D: blinding (investigator); E: blinding (assessor); F: incomplete outcome data addressed (ITT analysis); G: incomplete outcome data addressed (dropouts); H: free of selective reporting; I: similarity at baseline; J: cointerventions constant; K: compliance acceptable; L: timing outcome assessments. +Yes, −No, ?Unclear.
Based on GRADE system, the evidence of effective rate and neurological deficit scores (Modified Edinburgh-Scandinavian Stroke Scale) was level D, while the evidences of neurological deficit scores (ESS) was level C, and all of them were weak recommendation (Table
Summary of GRADE on evidences of outcomes of Bu-yang Huan-wu decoction for acute ischemic stroke.
Quality assessment | Number of patients | Effect | Quality | Importance | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Number of studies | Design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Trial | Control | Relative |
Absolute | ||
Effective rate | ||||||||||||
| ||||||||||||
17 | Randomized trials | Very serious | No serious inconsistency | No serious indirectness | No serious imprecision | Reporting bias | 696/747 (93.2%) | 535/697 (76.8%) | RR 1.18 |
138 more per 1000 (from 92 more to 184 more) |
|
Important |
75% | 135 more per 1000 (from 90 more to 180 more) | |||||||||||
| ||||||||||||
Neurological deficit scores (Modified Edinburgh–Scandinavian Stroke Scale) | ||||||||||||
| ||||||||||||
9 | Randomized trials | Very serious | No serious inconsistency | No serious indirectness | No serious imprecision | Reporting bias | 409 | 377 | — | MD 4.65 lower (6.57 to 2.72 lower) |
|
Important |
| ||||||||||||
Neurological deficit scores (ESS) | ||||||||||||
| ||||||||||||
1 | Randomized trials | Very serious | No serious inconsistency | No serious indirectness | No serious imprecision | None | 33 | 33 | — | MD 7.99 higher (3.96 to 12.02 higher) |
|
Important |
One study used the Barthel Index to evaluate the dependency rate [
4 studies reported that there were no adverse events [
17 of the included studies which adopted the effective rate to assess the clinical improvement were qualified to perform a meta-analysis, and the random-effect model was used for statistical analysis because of the heterogeneity (
Meta-analyses of the total effective rate of BHD therapy for acute ischemic stroke.
Study or subgroup | Experimental | Control | Weight | Risk ratio | Risk ratio | ||
---|---|---|---|---|---|---|---|
Events | Total | Events | Total | M-H, random, 95% CI | M-H, random, 95% CI | ||
Chen, 2007 [ |
28 | 32 | 21 | 32 | 3.0% | 1.33 [1.00, 1.77] |
|
Cui et al.,2005 [ |
49 | 50 | 25 | 30 | 6.6% | 1.18 [1.00, 1.39] | |
Fang et al.,2005 [ |
58 | 65 | 47 | 72 | 5.5% | 1.37 [1.13, 1.65] | |
Guo, 2009 [ |
56 | 57 | 27 | 30 | 9.1% | 1.09 [0.96, 1.24] | |
Jia et al.,2010 [ |
30 | 32 | 21 | 28 | 4.1% | 1.25 [0.99, 1.58] | |
Kang, 2006 [ |
35 | 36 | 35 | 38 | 10.4% | 1.06 [0.95, 1.18] | |
Lin, 2008 [ |
30 | 32 | 22 | 30 | 4.0% | 1.28 [1.01, 1.61] | |
Liu, 2010 [ |
52 | 55 | 40 | 55 | 6.2% | 1.30 [1.09, 1.55] | |
Lv, 2009 [ |
33 | 35 | 30 | 35 | 7.0% | 1.10 [0.94, 1.29] | |
Run, 2001 [ |
21 | 24 | 14 | 24 | 1.8% | 1.50 [1.04, 2.17] | |
Shi and Zhang,1995 [ |
17 | 21 | 12 | 20 | 1.5% | 1.35 [0.89, 2.04] | |
Wang and Yu,2005 [ |
62 | 64 | 55 | 64 | 10.4% | 1.13 [1.01, 1.26] | |
Wu and Luo,2011 [ |
33 | 35 | 29 | 35 | 6.3% | 1.14 [0.96, 1.35] | |
Yan and Mei,2004 [ |
55 | 60 | 52 | 60 | 9.1% | 1.06 [0.93, 1.20] | |
Zhang, 2004 [ |
36 | 40 | 25 | 40 | 3.4% | 1.44 [1.11, 1.87] | |
Zhang et al.,2010 [ |
77 | 82 | 67 | 82 | 9.7% | 1.15 [1.02, 1.29] | |
Zheng et al.,2004 [ |
24 | 27 | 13 | 22 | 1.8% | 1.50 [1.04, 2.18] | |
|
|
|
|
|
|||
Total events | 696 | 535 | |||||
Heterogeneity: Tau² = 0.00; Chi² = 24.82, df = 16 ( |
|||||||
Test for overall effect: |
Funnel plot of the total effective rate of BHD therapy for acute ischemic stroke.
9 studies which used the neurologic deficit score were qualified to perform a meta analysis, and the random-effect model was used for statistical analysis because of the heterogeneity (
Meta-analyses of the scores of neurological deficit of BHD therapy for acute ischemic stroke.
Study or subgroup | Experimental | Control | Weight | Mean difference | Mean difference | ||||
---|---|---|---|---|---|---|---|---|---|
Events | SD | Total | Events | SD | Total | IV, random, 95% CI | IV, random, 95% CI | ||
Chen, 2007 [ |
13.55 | 9.22 | 32 | 11.9 | 8.89 | 32 | 8.3% | 1.65 [−2.79, 6.09] |
|
Guo, 2009 [ |
5.28 | 7.51 | 57 | 11.25 | 7.59 | 30 | 10.2% | −5.97 [−9.31, −2.63] | |
Kang, 2006 [ |
5.14 | 1.86 | 36 | 8.22 | 2.04 | 38 | 14.3% | −3.08 [−3.97, −2.19] | |
Lv, 2009 [ |
12.86 | 7.92 | 35 | 19.67 | 8.36 | 35 | 9.3% | −6.81 [−10.63, −2.99] | |
Wang and Yu, 2005 [ |
8.82 | 7.92 | 64 | 18.5 | 8.82 | 64 | 11.0% | −9.68 [−12.58, −6.78] | |
Zhang, 2004 [ |
7.12 | 7.45 | 40 | 14.56 | 7.4 | 40 | 10.4% | −7.44 [−10.69, −4.19] | |
Zhang et al., 2010 [ |
12.02 | 6.39 | 82 | 14.39 | 7.29 | 82 | 12.6% | −2.37 [−4.47, −0.27] | |
Zhang et al., 2012 [ |
11.26 | 2.56 | 36 | 17.84 | 3.86 | 34 | 13.5% | −6.58 [−8.12, −5.04] | |
Zheng et al., 2004 [ |
18.08 | 5.16 | 27 | 18.77 | 6.24 | 22 | 10.4% | −0.69 [−3.94, 2.56] | |
|
|
|
|
|
|||||
Heterogeneity: Tau² = 6.54; Chi² = 49.62, df = 8 ( |
|||||||||
Test for overall effect: | |||||||||
Funnel plot of the scores of neurological deficit of BHD therapy for acute ischemic stroke.
Nineteen studies with 1580 individuals suffering from acute ischemic stroke were selected out for this systematic review on the mortality and dependency, clinical efficacy, and safety of BHD treatment for acute ischemic stroke. The main finding of this review was that BHD therapy could improve the neurological deficit of acute ischemic stroke. However, a clinical recommendation cannot be warranted because of the generally low methodological quality of the included studies. Another finding suggested that there was no evidence available about the effect of BHD therapy on the primary outcomes because none of the studies included the rates of death or dependency at the end of followup (at least 3 months). At last, BHD therapy was generally safe for acute ischemic stroke. However, adverse reactions should be rigorously investigated to assess the safety because only 21.1% studies mentioned the safety of BHD therapy.
Firstly, there are also a number of methodological limitations in this systematic review. None of the included trials reported the random method or allocation concealment, which may produce selection bias. Only one study mentioned blinding, but did not mention either subjects or investigator or assessor blinding. None of the studies described intention-to-treat analyses, and no study reported follow-up or dropout data; all of which are likely to show exaggerated treatment effects. Moreover, it is well established that 5 to 6 months after stroke are an appropriate time point at which to measure neurological and functional outcome, for spontaneous recovery does not reach a plateau until 5 to 6 months after stroke [
Secondly, the testified intervention should be compared with placebo-controlled or current “gold standard treatment” rather than randomly chosen unproved treatment [
Thirdly, the outcome measure of most of the trials was defined as an “effective rate,” the validity and reliability of which were uncertain in assessing the outcome. The primary outcome measure should be focused on the level of activities rather than a vague effective rate [
Lastly, we made an effort to identify all relevant studies, including those in the West and the East. However, all the studies met the criteria were from China, and this may limit the generalizability of the findings.
This systematic review provides suggestive evidence for the effectiveness and safety of BHD adjuvant therapy to disability improvement after acute ischemic stroke. However, a clinical recommendation cannot be warranted because of the generally unclear methodological quality of the included studies. We did not find sufficient evidence on the primary measure of efficacy to support the routine use of BHD therapy for ischemic stroke. BHD therapy may have beneficial effects on neurological impairment for ischemic stroke, but this efficacy needs to be further confirmed by methodologically rigorous trials. Therefore, further RCTs with adequate concealment of allocation, double-blinding, placebo-controlled, and long-term followup are needed and should be reported in detail according to the consolidated standards of reporting trials (CONSORT) 2010 statement [
The authors have declared that no conflict of interests exists.
G.-q. Zheng was supported by a grant from the National Natural Science Foundation of China (81173395/H2902).