Abstract
Background and purpose: Buyang Huanwu decoction (BYHWD) is widely used in the treatment of ischemic stroke in the recovery period, and many clinical trials have been reported, but its clinical efficacy and safety have not been fully evaluated. In this study, we conducted a systematic review and meta-analysis to evaluate the clinical efficacy and safety of BYHWD in the recovery period.
Materials and methods: Eight databases, including CNKI, Wanfang Database, VIP Database, China Biomedical Literature Database, PubMed, Cochrane Library, EMBASE, and Web of Science, were searched from the establishment of the database to 13 April 2022. We selected all eligible randomized controlled trials of BYHWD in the treatment of ischemic stroke during the recovery period. Systematic review and meta-analysis were conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. The National Institutes of Health Stroke Score (NIHSS) was the primary outcome, and the Chinese Stroke Scale (CSS), activities of daily living (ADL), and adverse drug reaction (ADR) were the secondary outcomes.
Results: A total of 39 randomized controlled trials were included, and 3,683 patients in the recovery period of ischemic stroke were recruited. Compared with conventional treatment alone, BYHWD combined with conventional treatment significantly decreased the NIHSS score (MD = -1.44, 95% CI: 1.75, -1.12, p < 0.00001), the CSS score (MD = -1.18, 95% CI: 2.02, -0.34, p = 0.006), improved the ADL (MD = 4.33, 95% CI: 3.06, 5.61, p < 0.00001), and did not increase the adverse reactions of patients (OR = 0.88, 95% CI: 0.48, 1.61, p = 0.67).
Conclusion: BYHWD is an effective and safe therapy for the recovery of ischemic stroke. To further determine the efficacy and safety of BYHWD in the treatment of ischemic stroke in the recovery period, more high-quality, multicenter, and prospective RCTs are needed.
1 Introduction
Ischemic stroke is a cerebrovascular disease caused by cerebral ischemia and hypoxia due to cerebral blood supply disorder, resulting in necrosis, softening, and the formation of infarction (). Ischemic stroke is divided into the acute phase, recovery phase, and sequelae phase. The recovery period refers to 2 weeks to 6 months after the onset of the disease. This period is the key period for the recovery of patients, and it is also an important part of clinical treatment (). Patients with ischemic stroke are prone to neurological dysfunction, slow recovery, and many complications, which seriously affect their physical and mental health (). Active and effective treatments for stroke patients during the recovery period can significantly improve their daily living ability. Besides rehabilitation, antiplatelet aggregation and anticoagulant therapy are commonly used western medicine treatments for these patients, but they easily cause drug resistance and adverse reactions (). In recent years, traditional Chinese medicine (TCM) has shown a good effect on ischemic stroke in the recovery period (; ).
Ischemic stroke belongs to the category of “stroke” in TCM. It is mostly caused by deficiency of Qi and blood, lack of nourishment for the brain, block of phlegm and blood stasis, obstruction of brain and collaterals, deficiency of liver and kidney or hyperactivity of liver yang, and disturbance of wind and yang, which in turn causes hemiplegia, skewed tongue, hemianopia, aphasia and other symptoms (1). The main pathogenesis of ischemic stroke is characterized by “wind, fire, phlegm, Qi and blood stasis”. Wang Qingren pioneered the theory of “Qi deficiency and blood stasis” and believed that “the loss of vitality is its source” and “if vitality is deficient, it will not reach the blood vessels. Once the blood vessels have no gas, the blood will stop and become stasis” (). It should be treated by supplementing qi, activating blood circulation, and removing blood stasis (Zhai et al., 2022). BYHWD is a classical prescription for regulating Qi and blood, removing phlegm and blood stasis in TCM (). It is composed of Astragalus trimestris L [Fabaceae, the dried root of Astragalus trimestris L]; Angelica sinensis (Oliv.) Diels [Apiaceae, the dried root of Angelica sinensis (Oliv.) Diels]; Paeonia officinalis subsp. Officinalis [Paeoniaceae, the dried root and rhizome of Paeonia officinalis subsp. Officinalis]; Pheretima aspergillum (E. Perrier) [Megascolecidae, the dried body of Pheretima aspergillum (E. Perrier)]; Oreocome striata (DC.) Pimenov and Kljuykov [Apiaceae, the dried rhizome of Pheretima aspergillum (E. Perrier) ]; Oreocome striata (DC.) Pimenov and Kljuykov]; Curcuma longa L [Zingiberaceae, the dried flower of Curcuma longa L]; Prunus persica (L.) Batsch [the dried seed of Prunus persica (L.) Batsch], according to the ratio 120: 6: 5: 3: 3: 3: 3. In a previous study, an HPLC-DAD-ELSD method was developed for simultaneous determination of 12 bioactive compounds in BYHWD, including calycosin-O-β-D-glucoside ononin, calycosin, astragaloside IV and astragaloside I from Radix Astragalis; tetramethylpyrazine, ferulic acid and Z-ligustilide from Radix Angelicae Sinensis and Rhizoma Ligustici Chuanxiong; hydroxysafflor yellow A and kaempferol from Flos Carthami; paeoniflorin from Radix paeoniae Rubra; and amygdalin from Semen persicae. (). In another study, Wang et al. found that hydroxysafflor yellow A, astragaloside IV, ferulic acid, ligustrazine, Z-ligustilide, and linoleic acid were considered to be bioactive compounds of BYHWD (). Kaempferol, Quercetin, Mairin, Jaranol, Hederagenin and AstragalosideIV are the compounds of Astragalus trimestris L; Baicalein, Quercetagetin,Beta-carotene, and Baicalin are the compounds of Paeonia officinalis subsp. Officinalis and Curcuma longa L; Ferulic acid and Cis-ligustilide are the compounds of Angelica sinensis (Oliv.) Diels; Ligustrazine and Z-ligustilide are the compounds of Oreocome striata (DC.) Pimenov and Kljuykov; Sitosterol alpha1 and Folinic acid are the compounds of Prunus persica (L.) Batsch; Arachidonic acid and Dihydrocapsaicin are the compounds of Pheretima aspergillum (E. Perrier) (Table 1).
TABLE 1
| Scientific name | Family | English name | Chinese name | Part used | Quantity (gram) |
|---|---|---|---|---|---|
| Astragalus trimestris L | Fabaceae | Astragalus membranaceus | Huang Qi | Root | 120 |
| Angelica sinensis (Oliv.) Diels | Apiaceae | Chinses angelica | Dang Gui | Root | 6 |
| Paeonia officinalis subsp. Officinalis | Paeoniaceae | Paeonia rubra | Chi Shao | Root and rhizome | 5 |
| Pheretima aspergillum (E. Perrier) | Megascolecidae | Earthworm | Di Long | Dried Body | 3 |
| Oreocome striata (DC.) Pimenov and Kljuykov | Apiaceae | Sargentgloryvine | Chuan Xiong | Rhizome | 3 |
| Curcuma longa L | Zingiberaceae | safflower | Hong Hua | Flower | 3 |
| Prunus persica (L.) Batsch | Rosaceae | Peach kernel | Tao Ren | Seed | 3 |
Components of buyang huanwu decoction.
Many previous studies have shown that BYHWD has a good therapeutic effect on ischemic stroke. Based on network pharmacology, Wang K et al. found that the active ingredients of Buyang Huanwu Decoction in the treatment of ischemic stroke are baicalein β- Carotene, baicalin, kaempferol, etc. (Wang K, 2021). Cai GX et al. studied the effects of BYHWD on neurological function, quality of life, and serum vascular endothelial growth factor (VEGF) in convalescent patients with cerebral infarction in a randomized controlled trial (RCT), showing that BYHWD can improve the neurological function and quality of life of convalescent patients with cerebral infarction and increase serum VEGF (). Jin C et al. conducted a meta-analysis to evaluate the role of BYHWD in poststroke fatigue patients. The results showed that BYHWD could improve the fatigue severity scale score and the total clinical effective rate (). In recent years, BYHWD has been widely used in the treatment of ischemic stroke in the recovery period, and a large number of clinical trials have described its efficacy and safety, but no rigorous clinical research can provide reliable clinical evidence. The sample size of these trials is generally not large, and it is difficult to convince the public that BYHWD has a significant effect in the treatment of ischemic stroke in the recovery period based on the results of small sample data, which limits the use and promotion of BYHWD to a certain extent. In addition, no systematic review or meta-analysis has focused on the clinical efficacy and safety of BYHWD in the recovery period of ischemic stroke. Therefore, in this study, we conducted a systematic review and meta-analysis to evaluate the clinical efficacy and safety of BYHWD in the recovery period of ischemic stroke.
2 Methods
We conducted this systematic review and meta-analysis in accordance with the PRISMA (preferred Reporting Item for Systematic Reviews and Meta-Analyses) guidelines ().
2.1 Search strategy
Two independent reviewers (Wang and Ren) searched CNKI, Wanfang Database, VIP Database, China Biomedical Literature Database, PubMed, Cochrane Library, EMBASE, and Web of Science. The last search date was 13 April 2022. The search terms used were (“Apoplexy” OR “Stroke” OR “Cerebral Infarction” OR “Brain Infarction” OR “Ischemic Stroke” OR “Ischemic Apoplexy” OR “Cerebrovascular accident” AND “Buyang Huanwu Decoction” AND “random” OR “randomized controlled trial” OR “controlled clinical trial” OR (RCT) OR (RCT) OR (RCTs). No restrictions were imposed on language or publication status.
2.2 Type of study
2.2.1 Inclusion criteria
1) Type of study: A randomized controlled trial using integrated traditional Chinese and Western medicine in the recovery period of ischemic stroke. The languages are limited to Chinese and English. 2) Research subjects: patients were diagnosed with ischemic stroke in the recovery period (2 weeks to 6 months after onset). 3) Interventions: The control group received conventional treatment (including controlling blood pressure, improving microcirculation, expanding cerebral vessels, using neurotrophic agents and physical therapy, etc. The experimental group was given BYHWD on the basis of conventional treatment. 4) Outcomes: Studies including the National Institute of Health Stroke Scale (NIHSS), Chinese Stroke Scale (CSS), Activities of daily living (ADL), and Adverse drug reaction (ADR).
2.2.2 Exclusion criteria
1) Nonrandomized controlled trials or studies that do not indicate the type of study. 2) The included literature can only extract part of the original data, which makes the data impossible to extract. 3) Animal experiments, literature reviews, conference papers. 4) Outcomes studies that did not include NIHSS, CSS, ADL, and ADR. 5) Studies where interventions did not meet the requirements.
2.3 Participant characteristics
Age, sex, and race were not the limiting conditions for the inclusion criteria. As long as the ischemic stroke patients in the recovery period who met the above criteria were considered to meet the inclusion criteria.
2.4 Interventions
This study selected all RCTs comparing BYHWD with conventional methods in the treatment of ischemic stroke in the recovery period, regardless of language, publication status, or blinding method. Nonrandomized trials, reviews, case reports, and animal studies were excluded. The experimental group used both BYHWD and CT, and the control group used CT alone for comparison. Conventional treatment was the same in both groups.
2.5 Outcome measures
The NIHSS was the primary outcome measure, and CSS, ADL, and ADR were the secondary outcomes.
NIHSS (National Institute of Health Stroke Scale) score, which is a quantitative indicator of the severity of AIS disease, is often used as a surrogate endpoint in clinical research and stratifies patients according to the NIHSS score to guide clinical decision-making (). It is divided into 11 items, including consciousness, gaze, visual field, facial paralysis, upper limb movement, lower limb movement, ataxia, sensation, language, dysarthria, and neglect, with a score of 0–42. The lower the score, the better the neurological function. The Chinese Stroke Scale (CSS) is based on the standard evaluation of clinical efficacy revised by the fourth national Cerebrovascular Disease Conference (). Efficacy standards: A sensory test is performed on the big toe. Symptom score: yes = 1, no = 0; reflex score: none = 2, diminished = 1L, normal = 0; sensory test score: abnormal = 1, normal = 0. Among them, six points are from symptoms, eight points are from the reflexes of both lower extremities, and five points are from the sensation of the thumbs. The total score is added up, from normal = 0 points to the highest score of 19 points. The patient’s ability to do daily living (ADL) was assessed by the Basel index, with a total score of 0–100. A score <40 points indicated that the patient had severe activity disorder; 41–60 points, indicated that the patient needed help to complete daily activities. 60 points meant that the patient needed some help to complete daily activities. The higher the score, the stronger the ADL (). Adverse drug reaction (ADR) mainly referred to gastrointestinal reactions after taking drugs, such as nausea and retching. The internal consistency reliability of NIHSS, CSS, and ADL was high, and the three scales had common validity, but the predictive validity of CSS and ADL was not as comprehensive as NIHSS (; ; ).
2.6 Data extraction
Two researchers (Wang and ren) independently screened the literature in strict accordance with the inclusion and exclusion criteria. First, the literature was initially screened by reading the title and abstract and then further screened by reading the full text. In case of disagreement, a third party (Wu and Zhang) judged, and finally decided to include or exclude through discussion. Then, two researchers (Li and Bai) independently extracted and included relevant research data, including title, author, year, country, diagnosis method of ischemic stroke, the sample size of each group, age, sex, treatment method, treatment time, outcome indicators and evaluation methods, and main research results.
2.7 Methodological quality assessment
The authenticity of the RCTs was assessed by two investigators (Guo and Bai) according to the Cochrane Handbook, and the risk of bias in the literature was assessed according to the Cochrane Risk of Bias Tool. In case of disagreement, a third party (Zhang and Yang) was consulted. The risk of bias was assessed using seven criteria, including random sequence generation, concealed assignment, blinding of participants and personnel, incomplete outcome data, selective reporting, and other biases. The risk of bias was classified into three categories: “low” (+), “high” (-), and “unclear” (?). The Jadad scale quality score was used to evaluate the methodological quality of the literature, with one to two points for low quality and three to five points for high quality.
2.8 Data synthesis and analysis
Revman 5.4 software was used for meta-analysis (Copenhagen: the Nordic Cochrane Centre, the Cochrane Collaboration, 2014). Pooled effect size: Count data and measurement data were analyzed by odds ratio (OR), relative risk (RR), mean difference (MD), or standard mean difference (SMD). Heterogeneity analysis: I2 was used to assess the heterogeneity of the studies. When I2 < 50%, p > 0.1, it indicated that the heterogeneity was not significant, and a fixed effect model was used; when I2 ≥ 50%, p ≤ 0.1, it indicated that the heterogeneity was substantial, and the source of heterogeneity needed to be analyzed. If there was substantial heterogeneity, a random effect model was used (; ; ; ); if the heterogeneity still existed, the source of heterogeneity was analyzed from both methodological and clinical aspects, and subgroup analysis was used.
2.9 Risk of bias across trials
Funnel plots and Egger’s test were carried out to examine the potential bias in the included trials when the number of RCTs was ≥10 (; ).
2.10 Quality of evidence
Two independent reviewers (Wang and Ren) used the GRADE (grading of recommendations, assessment, development, and evaluations) method () to evaluate the risk of bias in each included trial. If there was disagreement on the downgrade or upgrade evaluation, it was evaluated and decided by the third party (Wu and Zhang). Evidence evaluation adopts four grades of “high”, “medium”, “low” and “extremely low”.
3 Results
3.1 Study identification and selection
After searching major databases, a total of 4,241 articles were retrieved. A total of 2294 duplicates were excluded, and 1948 remained; 1868 were excluded after reading the title and abstract, and 60 remained; 21 were excluded after reading the full text, and 39 were finally included in the study. Figure 1 shows the general flow of the study selection process. Table 2 summarizes the general characteristics of the 39 studies.
FIGURE 1
TABLE 2
| Serial number | References | Race | Design | Sample size (T/C) | Age (years) (T/C) | Male/female ratio (T; C) | Outcome measure(s) | Interventions | Treatment duration | |
|---|---|---|---|---|---|---|---|---|---|---|
| Treatment group | Control group | |||||||||
| 1 | Zuo and Lin (2020) | East Asia | RCT | 50 (25/25) | 67.01 ± 2.13/67.21 ± 2.21 | 14/11; 15/10 | NIHSS, CSS, ADL | BYHWD plus CT | CT | 2 weeks |
| 2 | Zhen Jia Quan, 2016 | East Asia | RCT | 98 (49/49) | 56.4 ± 7.6/56.8 ± 7.2 | 28/21; 29/20 | CSS, ADL | BYHWD plus CT | CT | 4 weeks |
| 3 | Zhang (2017) | East Asia | RCT | 100 (50/50) | 59.87 ± 4.64/60.46 ± 4.92 | 30/20; 31/19 | NIHSS, ADR | BYHWD plus CT | CT | 3 months |
| 4 | Zhang (2013) | East Asia | RCT | 100 (50/50) | 62.7 (45–76) | 53/43 | NIHSS | BYHWD plus CT | CT | 2months |
| 5 | Zhang (2018) | East Asia | RCT | 180 (90/90) | 71.4 ± 4.7 | Not reported | TCM, ADL | BYHWD plus CT | CT | 4 weeks |
| 6 | Zhang and Xiong (2020) | East Asia | RCT | 78 (39/39) | 65.32 ± 5.74/65.67 ± 5.21 | 21/18; 20/19 | NIHSS | BYHWD plus CT | CT | 3 months |
| 7 | Yu (2013) | East Asia | RCT | 102 (49/53) | Not reported | Not reported | ADL | BYHWD plus CT | CT | 6months |
| 8 | Yang (2018) | East Asia | RCT | 60 (30/30) | 56.14 ± 3.18/55.31 ± 2.27 | 17/13; 16/14 | NIHSS | BYHWD plus CT | CT | 4 weeks |
| 9 | Yang (2020) | East Asia | RCT | 80 (40/40) | 63.25 ± 4.68/63.99 ± 4.71 | 24/16; 23/17 | NIHSS | BYHWD plus CT | CT | 4 weeks |
| 10 | Yang et al. (2021) | East Asia | RCT | 90 (45/45) | 58.69 ± 7.52/58.72 ± 7.58 | 30/15; 28/17 | NIHSS | BYHWD plus CT | CT | 2months |
| 11 | Xue and Xue (2015) | East Asia | RCT | 74 (36/38) | Not reported | Not reported | CSS | BYHWD plus CT | CT | 15d |
| 12 | Xu et al. (2017) | East Asia | RCT | 170 (85/85) | 65.33 ± 6.72/65.16 ± 7.05 | 45/40; 47/38 | TCM, ADL, NIHSS | BYHWD plus CT | CT | 6 weeks |
| 13 | Xu (2014) | East Asia | RCT | 110 (60/50) | 62.1 ± 11.6/62.3 ± 10.6 | 37/23; 31/19 | CSS, ADL | BYHWD plus CT | CT | 3 weeks |
| 14 | Xiang (2019) | East Asia | RCT | 60 (30/30) | 64.18 ± 3.44/64.24 ± 3.53 | 18/12; 17/13 | NIHSS, ADL | BYHWD plus CT | CT | Not reported |
| 15 | Wu (2021) | East Asia | RCT | 66 (33/33) | 63.35 ± 4.20/63.42 ± 4.25 | 18/15; 20/13 | NIHSS, ADL, ADR | BYHWD plus CT | CT | 1month |
| 16 | Wang et al. (2021) | East Asia | RCT | 92 (46/46) | 56.70 ± 5.33/56.39 ± 5.50 | 26/20; 27/19 | NIHSS, ADL | BYHWD plus CT | CT | 4 weeks |
| 17 | Wang et al. (2012) | East Asia | RCT | 96 (54/42) | 61.2 ± 11.7/62.5 ± 9.6 | 35/19; 22/20 | CSS, ADL | BYHWD plus CT | CT | 4 weeks |
| 18 | Sui (2014) | East Asia | RCT | 120 (60/60) | 63.89 ± 7.05/64.06 ± 8.73 | 33/27; 34/26 | NIHSS | BYHWD plus CT | CT | 60d |
| 19 | Shi (2016) | East Asia | RCT | 60 (30/30) | 61.84 ± 3.13/61.25 ± 3.22 | 17/13; 18/12 | ADR | BYHWD plus CT | CT | 4 weeks |
| 20 | Shang (2021) | East Asia | RCT | 72 (36/36) | 59.63 ± 7.32/58.76 ± 7.45 | 23/13; 20/16 | NIHSS, ADL | BYHWD plus CT | CT | 14d |
| 21 | Meng et al. (2014) | East Asia | RCT | 120 (60/60) | 64.58 ± 7.63/65.37 ± 7.80 | 36/24; 33/27 | ADL | BYHWD plus CT | CT | 3 weeks |
| 22 | Liu (2018) | East Asia | RCT | 30 (15/15) | 62.7 ± 4.5/63.1 ± 4.2 | 8/7; 9/6 | NIHSS | BYHWD plus CT | CT | 21d |
| 23 | Lin (2014) | East Asia | RCT | 84 (41/43) | Not reported | Not reported | ADL, ADR | BYHWD plus CT | CT | 12 weeks |
| 24 | Li (2012) | East Asia | RCT | 130 (65/65) | 61.3 ± 10.8/61.1 ± 11.2 | 35/15; 36/14 | CSS | BYHWD plus CT | CT | 4 weeks |
| 25 | Li (2018) | East Asia | RCT | 70 (35/35) | 61.8 ± 5.3/62.3 ± 5.1 | 19/16; 18/17 | NIHSS | BYHWD plus CT | CT | 30d |
| 26 | Li and Wei (2021) | East Asia | RCT | 78 (39/39) | 69.32 ± 5.66/68.95 ± 5.53 | 29/10; 28/11 | NIHSS, ADL | BYHWD plus CT | CT | 2 weeks |
| 27 | Li (2014) | East Asia | RCT | 84 (41/43) | Not reported | Not reported | ADL, ADR | BYHWD plus CT | CT | 12 weeks |
| 28 | Li (2011) | East Asia | RCT | 61 (31/30) | 45–70/47–72 | 21/10; 19/11 | NIHSS | BYHWD plus CT | CT | 14d |
| 29 | Li (2019) | East Asia | RCT | 84(42/42) | 54.34 ± 8.22/54.52 ± 8.16 | 23/19; 24/18 | NIHSS, ADL, ADR | BYHWD plus CT | CT | 4 weeks |
| 30 | Li and Li (2010) | East Asia | RCT | 112(56/56) | 59.1 ± 5.1/57.9 ± 6.5 | 31/25; 30/26 | NIHSS, ADL, ADR | BYHWD plus CT | CT | 30d |
| 31 | Jin and Xu (2019) | East Asia | RCT | 60(30/30) | 60.3 ± 7.2/58.6 ± 7.5 | 18/12; 16/14 | NIHSS | BYHWD plus CT | CT | 2months |
| 32 | Jiang (2019) | East Asia | RCT | 100(50/50) | 57.9 ± 1.1/57.8 ± 1.2 | 28/22; 29/21 | NIHSS | BYHWD plus CT | CT | 4 weeks |
| 33 | Ji (2016) | East Asia | RCT | 60(30/30) | 73.1 ± 11.9/72.5 ± 1.25 | 17/13; 18/12 | ADL,ADR | BYHWD plus CT | CT | 4 weeks |
| 34 | Han (2014) | East Asia | RCT | 80(40/40) | 64.58 ± 7.63/65.37 ± 7.80 | 36/24; 33/27 | CSS, ADL | BYHWD plus CT | CT | 4 weeks |
| 35 | Fang et al. (2019) | East Asia | RCT | 76 (38/38) | 66.5 ± 4.5/65.9 ± 5.2 | 20/18; 24/14 | NIHSS | BYHWD plus CT | CT | 4 weeks |
| 36 | Du (2018) | East Asia | RCT | 90(45/45) | 65.18 ± 2.24/65.12 ± 2.13 | 23/22; 24/21 | CSS, ADR | BYHWD plus CT | CT | 4 weeks |
| 37 | Diao (2017) | East Asia | RCT | 60(30/30) | 64.15 ± 5.65/63.45 ± 5.15 | 20/10; 20/10 | NIHSS | BYHWD plus CT | CT | 2months |
| 38 | Chen Yan, 2016 | East Asia | RCT | 70(35/35) | 42–75 | 39/31 | ADL | BYHWD plus CT | CT | 8 weeks |
| 39 | Chen Xiao Bing, 2018 | East Asia | RCT | 376(188/188) | 60.2 ± 8.3/111 ± 77 | 112/76 | NI HSS, ADL | BYHWD plus CT | CT | Not reported |
Characteristics of studies included in the meta-analysis.
Notes: 1. RCT: randomized controlled trial; 2. T/C: Treatment group/control group; 3. NIHSS: national institute of health stroke scale; CSS: cincinnati stroke scale; ADL: activities of daily living; ADR: adverse drug reaction; 4. INTERVENTION STUDY; treatment group; BYHWD, buyang huanwu decoction or modified buyang huanwu decoction; 5. Control group: CT, conventional treatment (including controlling blood pressure, improving microcirculation, expanding cerebral vessels, using neurotrophic agents and physical therapy).
3.2 Risk of bias
The risks of bias in the trials are shown in Table 3 and Figure 2, and Figure 3. All 39 trials included in this study explicitly used random sequence generation, of which 18 described the randomization methods in detail (random number table method for 16 trials: ; ; Zuo and Lin, 2020; Zhang, 2018; Xu et al.,2017; Xiang, 2019; Wu, 2021; Wang et al., 2021; Sui, 2014; Shi, 2016; Li and Wei, 2021; Li, 2019; Jiang, 2019; Ji, 2016; Han, 2014; Fang et al., 2019; ; random alphabet method for one trial: (Meng et al., 2014); random envelope method for one trial: (Du, 2018). The other 21 articles described the use of randomization but did not provide detailed information on the methods of randomization.
TABLE 3
| Serial number | References | Random sequence generation | Allocation concealment | Blinding of participants and personnel | Blinding of outcome assessment | Incomplete outcome data | Selective reporting | Other bias |
|---|---|---|---|---|---|---|---|---|
| 1 | Zuo and Lin (2020) | + | + | ? | ? | + | + | + |
| 2 | Zhen Jia Quan, 2016 | ? | + | ? | ? | + | + | + |
| 3 | Zhang (2017) | ? | + | ? | ? | + | + | + |
| 4 | Zhang (2013) | ? | + | ? | ? | + | + | + |
| 5 | Zhang (2018) | + | + | ? | ? | + | + | + |
| 6 | Zhang and Xiong (2020) | ? | + | ? | ? | + | + | + |
| 7 | Yu (2013) | ? | + | ? | ? | - | + | + |
| 8 | Yang (2018) | ? | + | ? | ? | + | + | + |
| 9 | Yang (2020) | + | + | ? | ? | + | + | + |
| 10 | Yang et al. (2021) | ? | + | ? | ? | + | + | + |
| 11 | Xue and Xue (2015) | ? | + | ? | ? | + | + | + |
| 12 | Xu et al. (2017) | + | + | ? | ? | + | + | + |
| 13 | Xu (2014) | ? | + | ? | ? | + | + | + |
| 14 | Xiang (2019) | + | + | ? | ? | + | + | + |
| 15 | Wu (2021) | + | + | ? | ? | + | + | + |
| 16 | Wang et al. (2021) | + | + | ? | ? | + | + | + |
| 17 | Wang et al. (2012) | ? | + | ? | ? | + | + | + |
| 18 | Sui (2014) | + | + | ? | ? | + | + | + |
| 19 | Shi (2016) | + | + | ? | ? | + | + | + |
| 20 | Shang (2021) | ? | + | ? | ? | + | + | + |
| 21 | Meng et al. (2014) | + | + | ? | ? | + | + | + |
| 22 | Liu (2018) | ? | + | ? | ? | + | + | + |
| 23 | Lin (2014) | ? | + | ? | ? | - | + | + |
| 24 | Li (2012) | ? | + | ? | ? | + | + | + |
| 25 | Li (2018) | ? | + | ? | ? | + | + | + |
| 26 | Li and Wei (2021) | + | + | ? | ? | + | + | + |
| 27 | Li (2014) | ? | + | ? | ? | - | + | + |
| 28 | Li (2011) | ? | + | ? | ? | + | + | + |
| 29 | Li (2019) | + | + | ? | ? | + | + | + |
| 30 | Li and Li (2010) | ? | + | ? | ? | + | + | + |
| 31 | Jin and Xu (2019) | ? | + | ? | ? | + | + | + |
| 32 | Jiang (2019) | + | + | ? | ? | + | + | + |
| 33 | Ji (2016) | + | + | ? | ? | + | + | + |
| 34 | Han (2014) | + | + | ? | ? | + | + | + |
| 35 | Fang et al. (2019) | + | + | ? | ? | + | + | + |
| 36 | Du (2018) | + | + | ? | ? | + | + | + |
| 37 | Diao (2017) | ? | + | ? | ? | + | + | + |
| 38 | + | + | ? | ? | + | + | + | |
| 39 | ? | + | ? | ? | + | + | + |
The methodological quality of the included trials assessed using the Cochrane Risk of Bias Tool.
+ = low risk of bias; ? = unclear risk of bias; - = high risk of bias.
FIGURE 2
FIGURE 3
Based on the information from the included literature, all the studies performed allocation concealment. The blinding of participants or personnel and the blinding of outcome assessments were not mentioned in any of the studies. Detection bias on complete outcome data was considered low in all trials. All data were also considered to be at low risk of selective reporting and other biases.
In addition, the Jadad scale quality score is shown in Table 4. The final scores of 39 articles were all three or above, belonging to high-quality literature.
TABLE 4
| Serial number | References | Random sequence generation | Double-blind method | Withdrawals and missed visits | Score |
|---|---|---|---|---|---|
| 1 | Zuo and Lin (2020) | 2 | 1 | 1 | 4 |
| 2 | Zhen Jia Quan, 2016 | 1 | 1 | 1 | 3 |
| 3 | Zhang (2017) | 1 | 1 | 1 | 3 |
| 4 | Zhang (2013) | 1 | 1 | 1 | 3 |
| 5 | Zhang (2018) | 2 | 1 | 1 | 4 |
| 6 | Zhang and Xiong (2020) | 1 | 1 | 1 | 3 |
| 7 | Yu (2013) | 1 | 1 | 1 | 3 |
| 8 | Yang (2018) | 1 | 1 | 1 | 3 |
| 9 | Yang (2020) | 2 | 1 | 1 | 4 |
| 10 | Yang et al. (2021) | 1 | 1 | 1 | 3 |
| 11 | Xue and Xue (2015) | 1 | 1 | 1 | 3 |
| 12 | Xu et al. (2017) | 2 | 1 | 1 | 4 |
| 13 | Xu (2014) | 1 | 1 | 1 | 3 |
| 14 | Xiang (2019) | 2 | 1 | 1 | 4 |
| 15 | Wu (2021) | 2 | 1 | 1 | 4 |
| 16 | Wang et al. (2021) | 2 | 1 | 1 | 4 |
| 17 | Wang et al. (2012) | 1 | 1 | 1 | 3 |
| 18 | Sui (2014) | 2 | 1 | 1 | 4 |
| 19 | Shi (2016) | 2 | 1 | 1 | 4 |
| 20 | Shang (2021) | 1 | 1 | 1 | 3 |
| 21 | Meng et al. (2014) | 2 | 1 | 1 | 4 |
| 22 | Liu (2018) | 1 | 1 | 1 | 3 |
| 23 | Lin (2014) | 1 | 1 | 1 | 3 |
| 24 | Li (2012) | 1 | 1 | 1 | 3 |
| 25 | Li (2018) | 1 | 1 | 1 | 3 |
| 26 | Li and Wei (2021) | 2 | 1 | 1 | 4 |
| 27 | Li (2014) | 1 | 1 | 1 | 3 |
| 28 | Li (2011) | 1 | 1 | 1 | 3 |
| 29 | Li (2019) | 2 | 1 | 1 | 4 |
| 30 | Li and Li (2010) | 1 | 1 | 1 | 3 |
| 31 | Jin and Xu (2019) | 1 | 1 | 1 | 3 |
| 32 | Jiang (2019) | 2 | 1 | 1 | 4 |
| 33 | Ji (2016) | 2 | 1 | 1 | 4 |
| 34 | Han (2014) | 2 | 1 | 1 | 4 |
| 35 | Fang et al. (2019) | 2 | 1 | 1 | 4 |
| 36 | Du (2018) | 2 | 1 | 1 | 4 |
| 37 | Diao (2017) | 1 | 1 | 1 | 3 |
| 38 | 2 | 1 | 1 | 4 | |
| 39 | 1 | 1 | 1 | 3 |
The methodological quality of the included trials assessed using the Jadad scale quality score.
1–2 points for low quality; three to five points for high quality.
3.3 Outcome measures
The summary of the meta-analysis is presented in Table 5.
TABLE 5
| Outcome or subgroup | No. Of studies | No. Of participants | Statistical method | Effect size | p |
|---|---|---|---|---|---|
| Adverse drug reaction | 12 | 956 | RR (fixed), 95% CI | 0.88 [0.50, 1.57] | 0.67 |
| OR (fixed), 95% CI | 0.88 [0.48, 1.61] | 0.67 | |||
| RD (fixed), 95% CI | -0.01 [-0.03, 0.02] | 0.68 | |||
| Activities of daily living | 20 | 2194 | SMD (fixed), 95% CI | 0.27 [0.19, 0.36] | <0.00001a |
| WMD (fixed), 95% CI | 4.33 [3.06, 5.61] | <0.00001a | |||
| National Institute of Health Stroke Scale | 23 | 2121 | SMD (fixed), 95% CI | -0.38 [-0.47, -0.29] | <0.00001a |
| WMD (fixed), 95% CI | -1.44 [-1.75, -1.12] | <0.00001a | |||
| Cincinnati Stroke Scale | 6 | 568 | SMD (fixed), 95% CI | -0.23 [-0.39, -0.06] | 0.007a |
| WMD (fixed), 95% CI | -1.18 [-2.02, -0.34] | 0.006a |
Summary of the meta-analysis.
The treatment group had significantly improved outcomes.
OR, odds ratio; RD, risk difference; RR, relative ratio; SMD, standardized mean difference; WMD, weighted mean difference.
3.4 Primary outcome
3.4.1 NIHSS
Twenty-three articles reported the NIHSS scores of patients after BYHWD combined with conventional treatment or conventional treatment alone. Due to the results of the heterogeneity test among the studies (p = 1.00, I2 = 0%), a fixed effect model was used. The results of the meta-analysis showed that the NIHSS score of the experimental group was significantly lower than that of the control group (MD = -1.44%, 95% CI: 1.75, -1.12, p < 0.00001) (Figure 4).
FIGURE 4
3.5 Secondary outcomes
3.5.1 CSS
Six articles reported the CSS of patients after different treatments with BYHWD plus conventional treatment or conventional treatment alone. There was no heterogeneity among the studies (p = 0.95, I2 = 0%), and a fixed effect model was used. The results of the meta-analysis showed that the CSS score of the experimental group was statistically lower than that of the control group (MD = -1.18, 95% CI: 2.02, -0.34, p = 0.006) (Figure 5).
FIGURE 5
3.6 ADL
The results of the meta-analysis showed that compared with the control group, the ADL of patients in the experimental group was significantly improved (MD = 4.33, 95% CI: 3.06, 5.61, p < 0.00001) (Figure 6).
FIGURE 6
3.8 ADR
The results of the meta-analysis showed that compared with conventional treatment alone, BYHWD plus conventional treatment did not increase the adverse reactions of patients (OR = 0.88, 95% CI: 0.48, 1.61, p = 0.67) (Figure 7).
FIGURE 7
3.9 Publication bias
The funnel plots of the NIHSS suggested that there was a possible publication bias in small trials (Figure 8). Egger’s test also indicated there was significant publication bias (p = 0.672).
FIGURE 8
3.10 Quality of evidence
Using GRADE, we assessed the certainty of the evidence to be moderate to low for outcomes for which data were available. In all 39 trials, the quality of evidence was downgraded by one level because of the unclear risk of method bias in some trials. The total number of patients was enough for each outcome, and the statistical heterogeneity of the results was small, so the quality of evidence for these outcomes was upgraded by one level. Consequently, the quality of evidence was moderate for the NIHSS, ADL, and ADR scores (Table 6).
TABLE 6
| Outcome (no. Of trials) | Quality assessment | Sequelae of stroke | Clinical efficacy and safety | Quality | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | BYHWD and CT | CT | 95% CI | Adverse reactions | ||||
| NIHSS | Noneb | No | No | No | Noneb | 1063/2121 (50.1%) | 1058/2121 (49.9%) | -1.75 to -1.12 | None | ⊕⊕⊕Ο | ||
| Moderate | ||||||||||||
| CSS | Noneb | No | No | No | Noneb | 294/568(51.8%) | 274/568(48.2%) | -2.02 to -0.34 | None | ⊕⊕⊕Ο | ||
| Moderate | ||||||||||||
| ADL | Noneb | No | No | No | Noneb | 1104/2194 (50.3%) | 1090/2194 (49.7%) | 3.06 to 5.61 | None | ⊕⊕⊕Ο | ||
| Moderate | 474/956(49.6%) | |||||||||||
| ADR | Noneb | No | No | No | Noneb | 482/956(50.4%) | 0.88 to 1.61 | None | ⊕⊕⊕Ο | |||
| Moderate | ||||||||||||
Evidence GRADE profile.
NIHSS: national institute of health stroke scale; CSS: cincinnati stroke scale; ADL: activities of daily living; ADR: adverse drug reaction.
Most trials had an unclear risk of methodological bias. Evidence was therefore downgraded by one level.
Publication bias was not presented. The results were robust. Therefore, the evidence was not downgraded.
4 Discussion
Stroke is the main cause of disability and the second leading cause of death in the world (). Ischemic stroke has become a global health problem that seriously threatens human life and health (). With the continuous development of medicine, the methods of treating ischemic stroke are also increasing, and TCM treatment has always played an important role in it. BYHWD is a classical Chinese medicine prescription for the treatment of ischemic stroke in the recovery period and has a good clinical effect on ischemic stroke in the recovery period (). Therefore, this meta-analysis aimed to evaluate the clinical efficacy and safety of BYHWD in the recovery period of ischemic stroke patients.
A total of 39 studies involving 3,683 patients were included in this meta-analysis, and BYHWD combined with conventional treatment and conventional treatment alone were compared in patients with ischemic stroke in the recovery period. Under normal circumstances, clinical ischemic stroke patients often leave symptoms of different degrees of neurological deficits. Improving the symptoms of this neurological deficit and improving the activities of daily living have always been the top priorities in the treatment of cerebral infarction (). Therefore, in this study, the NIHSS was the primary outcome measure, and CSS, ADR, and ADL were the secondary outcomes. The above indicators were used as clinical trial observation and efficacy evaluation indicators. The National Institute of Health Stroke Scale (NIHSS) score (), which is a quantitative indicator of the severity of the stroke, is often used as a surrogate endpoint in clinical research and stratifies patients according to the NIHSS score to guide clinical decision-making. Effective treatment was defined as a decrease in the NIHSS score by more than four points or complete disappearance of symptoms after treatment. The CSS score includes horizontal gaze, level of consciousness, speech, limb flexibility, and walking ability. The higher the score, the worse the patient’s condition and the worse the neurological function (). The results of this study show that, compared with conventional treatment alone, BYHWD combined with conventional treatment can reduce the NIHSS score and CSS score of patients, suggesting that BYHWD can improve the neurological function of ischemic stroke patients in the recovery period. In terms of activities of daily living, the activities of daily living in the experimental group were stronger than those in the control group. Moreover, the results of the meta-analysis indicated that compared with the control group, the treatment of the experimental group in the recovery period of ischemic stroke did not increase the adverse reactions of patients. All the results prove that BYHWD is an effective therapy to improve the recovery period of ischemic stroke, which is beneficial for relieving the patient’s condition, promoting the improvement of the patient’s neurological function, and improving the quality of life without increasing adverse reactions.
BYHWD comes from Wang Qingren’s “Yilin Correction” in the Qing Dynasty. It is a commonly used prescription for the treatment of ischemic stroke. “This prescription treats hemiplegia, crooked eyes, slurred speech, salivation at the corners of the mouth, dry stools, frequent urination, and incontinence of enuresis” (). This prescription has the compatibility characteristics of “not to remove blood stasis to activate blood, but to invigorate Qi to activate blood” (). Astragalus trimestris L is the monarch drug in BYHWT, which has the effects of nourishing vitality, promoting blood circulation, and removing blood stasis; Angelica sinensis (Oliv.) Diels is the ministerial drug of the formula, which can activate blood and nourish blood and remove blood stasis; Other botanical drugs have activities of expectorating phlegm and dredging collaterals. The combination of the above drugs can have a synergistic effect and achieve the effects of nourishing Qi and promoting blood circulation, removing blood stasis, and dredging collaterals. As a popular traditional Chinese medicine formula, BYHWD was widely used for treating ischemic diseases. However, there are few studies focused on the effects of BYHWD on neurodegenerative diseases, and the underlying molecular mechanisms are largely elusive. Li Z et al. established a neurotoxic model in PC12 cells and adopted an innovative experimental grouping method to investigate the neuroprotective effects of BYHWD on neurotoxicity induced by 6-Hydroxydopamine (6-OHDA) exposure. They found that BYHWD had neuroprotective effects against the 6-OHDA-induced neurotoxicity via Akt/GSK3β pathway based on serum pharmacology methodology. (). Another study found that BYHWD could modulate multiple signaling pathways including the Jak/Stat3/cyclin D1 signaling pathway, EGFR/PI3K/Akt/Bad/14–three to three signaling pathway, caveolin-1, and Hes1. The modulations of these cellular signaling pathways contributed to the anti-apoptotic cell death, improvement of the neural stem cell proliferation, astrogenesis, and neurogenesis in post-ischemia brains, subsequently inducing the recovery of the neurological functions in the post-ischemic brains (). In addition, modern studies have shown that BYHWD can reduce cerebral infarct size and improve neurological deficits in ischemic stroke rats and attenuate neuronal damage in rats with cerebral ischemia/reperfusion (I/R) injury (); BYHWD can promote neurogenesis and angiogenesis in rats with cerebral ischemia (); BYHWD can protect the integrity of the neurovascular unit and improve the permeability of the blood-brain barrier, thereby improving stroke caused by cerebral ischemia (). Therefore, BYHWD can effectively treat ischemic stroke and can be widely used in the clinical treatment of ischemic stroke.
Limitations of this study: 1) Although the included trials were described as “random grouping”, most of the trials did not describe specific grouping methods, blinding, allocation concealment, etc., so the possibility of selection bias cannot be ruled out; 2) Samples of most included studies were relatively small; 3) The efficacy evaluation of most studies was subject to a certain degree of subjectivity, and there was a lack of standard quantitative research; 4) Due to generally low quality of the included trials, this study can only draw very limited conclusions. There is an urgent need to improve the quality of the design and report of such studies.
5 Conclusion
Compared with conventional treatment alone, BYHWD combined with conventional treatment contributed to a significant improvement in clinical efficacy, neurological function, and activities of daily living, while it did not increase adverse reactions. Due to the limitations of this study, the quality of the included trials was generally low. In the future, more clinical trials with standardized designs, strict implementations, and large samples are needed to further verify the clinical efficacy and safety of BYHWD in the treatment of ischemic stroke in the recovery period and provide a more reliable evidence-based basis for clinical application.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Author contributions
RW, JR, SL, XB, and WG are equal contributors and co-first authors.
Funding
This work was financially supported by the Science and Technology Development Fund, Macau SAR (File No: 0077/2019/A2, 0040/2021/AGJ and SKL-QRCM(MUST)-2020-2022); Sichuan Academy of traditional Chinese medicine reserve candidate project (File No: Sichuan Chinese Medicine Letter (2020) No. 85).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
CT, conventional treatment; NIHSS, National Institute of Health Stroke Scale; CSS, Chinese Stroke Scale; TCM, traditional Chinese medicine; ADL: activities of daily living; ADR, adverse drug reaction; RCT, randomized controlled trial; T/C, treatment group/control group.
References
1
BelovaA. N.BogdanovE. I.ZhadnovV. A.KamchatnovP. R.KurushinaO. V. (2021). [Therapy of moderate cognitive impairment in the early recov ery period of ischemic stroke].Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova121 (5), 33–39. 10.17116/jnevro202112105133
2
BoulangerJ. M.LindsayM. P.GubitzG.SmithE. E.StottsG.FoleyN.et al (2018). Canadian stroke best practice recommendations for acute stroke management: Prehospital, emergency department, and acute inpatient stroke care, 6th edition, update 2018. Int. J. Stroke13 (9), 949–984. 10.1177/1747493018786616
3
CaiG. X.LiuB. Y. (2010). Effect of ultra-micronized Buyang Huanwu decoction on neurological function, quality of life, and serum vascular endothelial growth factor in patients convalescent from cerebral infarction. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue22 (10), 591–594.
4
CaiZ.ZhangL. (2022). The effect of combined treatment with ginkgo diterpene lactone meglumine and ozagrel in patients with acute cerebral infarction and its influence on CSS score[J]. Guizhou Med.46 (02), 251–252.
5
ChalosV.van der EndeN. A. M.MulderM. J. H. L.VenemaE.DijklandS. A. (2020). National Institutes of health stroke scale: An alternative primary outcome measure for trials of acute treatment for ischemic stroke. Stroke51 (1), 282–290. 10.1161/STROKEAHA.119.026791
6
ChenH.YaoX.LiT.LamC. W. K.ZhangR.ZhangH.et al (2020a). Compound kushen injection combined with platinum-based chemotherapy for stage III/IV non-small cell lung cancer: A meta-analysis of 37 RCTs following the PRISMA guidelines. J. Cancer11 (7), 1883–1898. 10.7150/jca.40267
7
ChenX.ChenH.HeY.FuS.LiuH.WangQ.et al (2020b). Proteomics-guided study on Buyang huanwu decoction for its neuroprotective and neurogenic mechanisms for transient ischemic stroke: Involvements of EGFR/PI3K/Akt/Bad/14-3-3 and jak2/stat3/cyclin D1 signaling cascades. Mol. Neurobiol.57 (10), 4305–4321. 10.1007/s12035-020-02016-y
8
ChenX.ZhaoD. (2018). Analysis of the effect of Buyang Huanwu Decoction on 188 patients with cerebral infarction in convalescence. Chin. Community Physician34 (26), 115117. 10.3969/j.issn.1007-614x.2018.26071
9
ChenY.CaoJ. (2016). Clinical observation on 35 cases of cerebral infarction in recovery period treated with combination of traditional Chinese and western medicine. Pract. Integr. Chin. West. Med. Clin.16 (5), 16–18. 10.13638/j.issn.1671-4040
10
CumpstonM.LiT.ChandlerJ.WelchV. A.HigginsJ. P. (2019). Updated guidance for trusted systematic reviews: A new edition of the Cochrane Handbook for systematic reviews of interventions. Cochrane Database Syst. Rev.10, ED000142. 10.1002/14651858.ED000142
11
DiaoL. (2017). Study on clinical efficacy of Buyang Huanwu Decoction in treating 30 patients with cerebral infarction in convalescence. China CME9 (18), 180–181. 10.3969/j.issn.1674-9308.2017.18.099
12
DuQ. (2018). Observation on the therapeutic effect of Buyang Huanwu Decoction on stroke recovery. J. Chronic Dis.7, 1. 10.16440/j.cnki.1674-8166.20180517.001
13
EggerM.Davey SmithG.SchneiderM.MinderC. (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ315, 629–634. 10.1136/bmj.315.7109.629
14
Encephalopathy Emergency Collaborative Group of the State Administration of Traditional Chinese Medicine (1995). Stroke diagnosis and efficacy evaluation criteria (trial version) [M]. Beijing: China Traditional Chinese Medicine Press, 1–240.
15
FangT.WangG.ZhaoJ. (2019). Effect of Buyang Huanwu Decoction on serum IGF-1 level and cognitive function of patients with cerebral infarction in convalescence. Hainan Med. J.30 (23), 3027–3029. 10.3969/j.issn.1003-6350.2019.23.010
16
FeskeS. K. (2021). Ischemic stroke. Am. J. Med.134 (12), 1457–1464. 10.1016/j.amjmed.2021.07.027
17
GuoQ.YangS.YangD.ZhangN.LiX.ChenT.et al (2020). Differential mRNA expression combined with network pharmacology reveals network effects of Liangxue Tongyu Prescription for acute intracerebral hemorrhagic rats. J. Ethnopharmacol.246, 112231. 10.1016/j.jep.2019.112231
18
GuyattG. H.OxmanA. D.VistG. E.KunzR.Falck-YtterY.Alonso-CoelloP.et al (2008). Grade: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ336 (7650), 924–926. 10.1136/bmj.39489.470347.AD
19
HanS. (2014). Effect of Buyang Huanwu Decoction on the recovery of neurological function and daily living ability of patients with cerebral infarction in the recovery period (Qi deficiency and blood stasis syndrome). Chin. J. Disabil. Med.11, 193–194. 10.13214/j.cnki.cjotadm.2014.11.184
20
JiX. (2016). Clinical observation on the treatment of cerebral infarction of qi deficiency and blood stasis type with modified Buyang huanwu decoction. Dis. Monit. Control10 (6), 458–459.
21
JiangC. T.WuW. F.DengY. H.GeJ. W. (2020). Modulators of microglia activation and polarization in ischemic stroke (Review). Mol. Med. Rep.21 (5), 2006–2018. 10.3892/mmr.2020.11003
22
JiangP. (2019). Quantitative evaluation and analysis of therapeutic effect of Buyang Huanwu Decoction on qi deficiency and blood stasis syndrome in stroke recovery. Health Care Guide29, 252.
23
JinC.KwonS.ChoS. Y.ParkS. U.JungW. S.MoonS. K.et al (2021). A systematic review and meta-analysis of the effects of herbal medicine Buyang huanwu tang in patients with poststroke fatigue. Evid. Based. Complement. Altern. Med.2021, 4835488. 10.1155/2021/4835488
24
JinD.XuQ. (2019). Study on the improvement of nerve function and quality of life of patients with cerebral infarction in the recovery period by Buyang Huanwu Decoction. Electron. J. Clin. Med. Literature6 (A1), 174.
25
LiC.LiZ. (2010). The effect of supplementing qi and activating blood circulation on the quality of life and curative effect of patients with cerebral infarction in the recovery period. J. Traditional Chin. Med.16 (6), 41–43. 10.3969/j.issn.1672-951X.2010.06.021
26
LiD. (2019). Prognostic analysis of patients with cerebral infarction in convalescence treated with Buyang Huanwu Decoction. China Pract. Med.14 (13), 127–128. 10.14163/j.cnki.11-5547/r.2019.13.068
27
LiG. (2011). Clinical observation on modified Buyang huanwu decoction in treating cerebral infarction in recovery period[J]. Med. Inf. late issue24 (1), 2. 10.3969/j.issn.1674-7860.2014.35.033
28
LiH.PengD.ZhangS. J.ZhangY.WangQ.GuanL. (2021). Buyang Huanwu Decoction promotes neurogenesis via sirtuin 1/autophagy pathway in a cerebral ischemia model. Mol. Med. Rep.24 (5), 791. 10.3892/mmr.2021.12431
29
LiR. (2014). Clinical observation on Buyang huanwu decoction in the treatment of cerebral infarction in the recovery period. Inn. Mong. J. Traditional Chin. Med.33 (17), 10–11.
30
LiS.WeiZ. (2021). Effect of Buyang Huanwu Decoction on neurological function and serum oxLDL, MDA, SOD of stroke patients in recovery period. Guangming Tradit. Chin. Med.36 (19), 3296–3298. 10.3969/j.issn.1003-8914.2021.19.032
31
LiT. (2018). Clinical observation of Buyang Huanwu decoction in treating cerebral infarction in convalescence Oriental. food Ther. health care1, 267.
32
LiX. (2012). Analysis of the clinical efficacy of Buyang Huanwu Decoction in the recovery period of cerebral infarction. China Med. Eng.20 (12), 125.
33
LiZ.WangH.WangQ.SunJ. (2016). Buyang huanwu decoction vigorously rescues PC12 cells against 6-OHDA-induced neurotoxicity via akt/gsk3β pathway based on serum pharmacology methodology. Rejuvenation Res.19 (6), 467–477. 10.1089/rej.2015.1798
34
LiangR.TangQ.WangL.YueP.ZhuL. (2021). Buyang huanwu decoction combined with probiotics or prebiotics for functional recovery from stroke: A meta-analysis protocol for systematic review. Med. Baltim.100 (51), e28371. 10.1097/MD.0000000000028371
35
LiberatiA.AltmanD. G.TetzlaffJ.MulrowC.GotzscheP. C.IoannidisJ. P. A.et al (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ339, b2700. 10.1136/bmj.b2700
36
LinX. (2014). Buyang Huanwu Decoction in the treatment of 41 patients with cerebral infarction in the recovery period. Modern Distance Education of Chinese Med.12 (11), 129–130. 10.3969/j.issn.1672-2779.2014.11.082
37
LiuD. (2018). Clinical observation on Buyang huanwu decoction in treating patients with qi deficiency and blood stasis syndrome in the recovery period of cerebral infarction. Electron. J. Cardiovasc. Dis. Integr. Traditional Chin. West. Med.6 (15), 143.
38
LiuE. H.QiL. W.ChengX. L.pengY. B.LiP. (2010). Simultaneous determination of twelve bioactive constituents in Buyang Huanwu decoction by HPLC-DAD-ELSD and HPLC-TOF/MS. Biomed. Chromatogr.24 (2), 125–131. 10.1002/bmc.1269
39
LiuM.PuY.GuJ.HeQ.LiuY.ZengY.et al (2021). Evaluation of zhilong huoxue tongyu capsule in the treatment of acute cerebral infarction: A systematic review and meta-analysis of randomized controlled trials. Phytomedicine.86, 153566. 10.1016/j.phymed.2021.153566
40
LiuW.ZhangY.ZhouX.ZengK. (2022). Research progress on the mechanism of Buyang Huanwu Decoction against cerebral ischemia[J]. New Chin. Med. Clin. Pharmacol.33 (03), 411–418.
41
MengW.LiJ.ZhangL. (2014). Clinical observation on modified Buyang huanwu decoction in the treatment of cerebral infarction recovery (qi deficiency and blood stasis syndrome). J. Yunnan Univ. Traditional Chin. Med.2, 74–76.
42
PaulS.Candelario-JalilE. (2021). Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Exp. Neurol.335, 113518. 10.1016/j.expneurol.2020.113518
43
ShangH. (2021). Effect of Buyang huanwu decoction on cerebral infarction recovery. Big Vis. Health9, 85.
44
ShaoL.SheY.YongS.ChenB.YiJ.LiY.et al (2022). An evidence-based evaluation of Buyang huanwu decoction for the treatment of the sequelae of stroke: A PRISMA-compliant systematic review and meta-analysis of randomized controlled trials. Phytomedicine.104, 154312. 10.1016/j.phymed.2022.154312
45
ShiW. (2016). Observation on the clinical efficacy of traditional Chinese medicine in treating patients with stroke in convalescence. Health Care Guide32, 23.
46
StinearC. M.LangC. E.ZeilerS.ByblowW. D. (2020). Advances and challenges in stroke rehabilitation. Lancet. Neurol.19 (4), 348–360. 10.1016/S1474-4422(19)30415-6
47
StriniV.PiazzettaN.GalloA.SchiavolinR. (2020). Barthel index: Creation and validation of two cut-offs using the BRASS index. Acta Biomed.91 (2-S), 19–26. 10.23750/abm.v91i2-S.9226
48
SuiW. (2014). Li aiping clinical study on Buyang huanwu decoction to improve neurological function defects in the recovery period of ischemic stroke. New Chin. Med.46 (7), 40–42. 10.13457/j.cnki.jncm.2014.07.19
49
TaoZ. (2009). Reliability, validity and sensitivity of Chinese scale for clinical neurological deficit of stroke patients. Acad. J. Sec. Mil. Med. Univ.30 (03), 283–285. 10.3724/sp.j.1008.2009.00283
50
The Fourth National Academic Conference on cerebrovascular disease (1996). sScoring criteria for clinical neurological deficits of stroke patients [J]. Chin. J. Neurology29 (6), 381–382.
51
WangH.MaZ.ShiZ. (2012). Observation on the therapeutic effect of Buyang Huanwu Decoction on 54 cases of cerebral infarction in the recovery period. Yunnan J. Traditional Chin. Med.6 (6), 47–48. 10.3969/j.issn.1007-2349.2012.06.027
52
WangK.LeiL.QiaoY.LiangR.DuanJ. (2021). Network pharmacology-based prediction of the active compounds and mechanism of Buyang Huanwu Decoction for ischemic stroke.Exp. Ther. Med.22 (4), 1050. 10.3892/etm.2021.10484
53
WangQ. (1999). Yilin correction. Tianjin Science and Technology Press, 32.
54
WangX.LiuZ.SuiX.WuQ.WangJ.XuC. (2019). Elemene injection as adjunctive treatment to platinum-based chemotherapy in patients with stage III/IV non-small cell lung cancer: A meta-analysis following the PRISMA guidelines. phytomedicine59, 152787. 10.1016/j.phymed.2018.12.010
55
WangX.WangY.LiuZ.QuL. (1999). A comparative study on the reliability and validity of four stroke scales. Chin. J. Phys. Med. rehabilitation3, 13–16.
56
WangX.WangR.XieC. (2021). The clinical effect of Buyang Huanwu Decoction on stroke of qi deficiency and blood stasis in convalescence. J. Clin. Ration. Drug Use14 (26), 51–53. 10.15887/j.cnki.13-1389/r.2021.26.018
57
WuJ. (2007). Study on reliability and validity of four stroke scales. Master’s Electronic Journal. Tianjin (China): Tianjin Medical University.
58
WuJ. (2021). Analysis of the clinical effect of Buyang Huanwu Decoction on patients with qi deficiency and blood stasis syndrome in the recovery period of cerebral infarction. Zhonghua Health Care39 (17), 17–18.
59
WuQ.YaoX.ChenH.LiuZ.LiT.FanX.et al (2020). Long-term aspirin use for primary cancer prevention: An updated systematic review and subgroup meta-analysis of 29 randomized clinical trials. J. Cancer11 (21), 6460–6473. 10.7150/jca.49001
60
WuW. (2019). Study on the mechanism of Buyang Huanwu Decoction in the treatment of ischemic stroke [J]. Electron. J. Clin. Med. Literature6 (17), 193. 10.21203/rs.3.rs-24632/v1
61
XiangJ. (2019). Clinical observation on the treatment of cerebral infarction in the recovery period with modified Buyang huanwu decoction. Guangming Tradit. Chin. Med.34 (20), 3149–3150. 10.3969/j.issn.1003-8914.2019.20.034
62
XingY.BaiY. (2020). A review of exercise-induced neuroplasticity in ischemic stroke: Pathology and mechanisms. Mol. Neurobiol.57 (10), 4218–4231. 10.1007/s12035-020-02021-1
63
XuH.ZouY.ZhouH.LvJ. (2017). Evaluation of therapeutic effect of Buyang Huanwu Decoction on patients with ischemic stroke in the recovery period. World J. Integr. Traditional West. Med.12 (08), 1155–1157+1176. 10.13935/j.cnki.sjzx.170832
64
XuG. (2014). Observation on the therapeutic effect of Buyang Huanwu Decoction on 60 cases of cerebral infarction in the recovery perio. Med. Inf.37, 426. 10.3969/j.issn.1006-1959.2014.37.668
65
XueL.XueJ. (2015). Clinical observation on 36 cases of cerebral infarction in recovery period treated with Buyang huanwu decoction. Pharmacol. Clin. Med. Traditional Chin. Med.31 (2), 179–180.
66
YamalJ. M. (2021). National Institutes of health stroke scale as an outcome measure for acute stroke trials. Stroke52 (1), 142–143. 10.1161/STROKEAHA.120.032994
67
YangJ.WenY.ZhouH. (2021). Clinical observation of Buyang Huanwu Decoction in the treatment of cerebral infarction in convalescence. J. Pract. Chin. Med.37 (12), 2034–2035.
68
YangS. (2020). Observation on the therapeutic effect of Buyang Huanwu Decoction on the syndrome of qi deficiency and blood stasis in the recovery period of ischemic stroke. Electron. J. Cardiovasc. Dis. Integr. Traditional Chin. West. Med.8 (24), 164167.
69
YangY. (2018). Observation on the application of Buyang Huanwu Decoction in the recovery period of stroke. Diet health care5 (41), 114–115. 10.3969/j.issn.2095-8439.2018.41.138
70
YangZ. (2022). Based on the "brain-gut axis" to explore the research progress of traditional Chinese medicine in the treatment of ischemic stroke [J]. J. Liaoning Univ. Traditional Chin. Med.24 (04), 130–134.
71
YuF. (2013). Analysis of clinical efficacy of Buyang Huanwu Decoction in treating cerebral infarction in convalescence. Chin. Med. Guide22, 263–264.
72
ZhangG.XiongC. (2020). Observation on the effect of integrated traditional Chinese and Western medicine in treating sequelae of cerebral apoplexy of qi deficiency and blood stasis type and analysis on the influence of neurological recovery. Health Compuls.11, 165.
73
ZhangJ. (2018). The improvement effect of Buyang Huanwu Decoction on the depressive state of patients with stroke in the recovery period. China Higher Medical Education, 134. 10.3969/j.issn.1002-1701.2018.10.070.
74
ZhangL. (2013). Effect of buyang huanwu decoction on neurological function and quality of life of patients with cerebral infarction in recovery period. China Pharmaceutical. 22, 106. 10.3969/j.issn.1006-4931.2013.20.059.
75
ZhangM. (2017). 50 cases of cerebral infarction of qi deficiency and blood stasis type in convalescence were treated with integrated traditional Chinese and Western medicine. Chin. Folk. Med.26 (23), 111–112119.
76
ZhengJ. (2016). Observation on the therapeutic effect of Buyang Huanwu Decoction in the recovery period of cerebral infarction. Electron. J. Clin. Med. Literature3 (28), 5590–55905592.
77
ZhaoX.ZhouM. (2021). Research progress of traditional Chinese medicine in the treatment of ischemic stroke[J]. Med. Rev.27 (22), 4548–4552.
78
ZhengX. Y.ZhangY. H.SongW. T.CaoH.LiuJ. X. (2021). Effects of Buyang huanwu decoction on neurovascular units after cerebral ischemia: A review. Zhongguo Zhong Yao Za Zhi46 (20), 5226–5232. 10.19540/j.cnki.cjcmm.20210610.706
79
ZhugeL.FangY.JinH.LiL.YangY.HuX.et al (2020). Chinese medicine Buyang Huanwu decoction promotes neurogenesis and angiogenesis in ischemic stroke rats by upregulating miR-199a-5p expression. Zhejiang Da Xue Xue Bao Yi Xue Ban.49 (6), 687–696. 10.3785/j.issn.1008-9292.2020.12.03
80
ZuoQ.JinL. (2020). Observation on therapeutic effect of Buyang Huanwu Decoction combined with Western medicine in the recovery period of cerebral infarction. Grassroots Med. Forum24 (13), 1890–1892. 10.19435/j.1672-1721.2020.13.071
Summary
Keywords
Buyang Huanwu Decoction, ischemic stroke, recovery period, systematic review, meta-analysis, traditional Chinese medicine
Citation
Wang R, Ren J, Li S, Bai X, Guo W, Yang S, Wu Q and Zhang W (2022) Efficacy evaluation of Buyang Huanwu Decoction in the treatment of ischemic stroke in the recovery period: A systematic review of randomized controlled trials. Front. Pharmacol. 13:975816. doi: 10.3389/fphar.2022.975816
Received
22 June 2022
Accepted
22 September 2022
Published
14 October 2022
Volume
13 - 2022
Edited by
Jiangang Shen, The University of Hong Kong, Hong Kong SAR China
Reviewed by
Guo-Qing Zheng, Zhejiang Chinese Medical University, China
Zeyan Li, Shandong University, China
Updates
Copyright
© 2022 Wang, Ren, Li, Bai, Guo, Yang, Wu and Zhang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sijin Yang, ysjimn@sina.com; Qibiao Wu, qbwu@must.edu.mo; Wei Zhang, ysjimn@sina.com
† These authors have contributed equally to this work
This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.