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Comparative efficacy of Chinese herbal injections for treating acute cerebral infarction: a network meta-analysis of randomized controlled trials

BMC Complementary and Alternative MedicineBMC series – open, inclusive and trusted201818:120

https://doi.org/10.1186/s12906-018-2178-9

Received: 12 October 2017

Accepted: 19 March 2018

Published: 3 April 2018

Abstract

Background

Chinese herbal injections (CHIs) are prepared by extracting and purifying effective substances from herbs (or decoction pieces) using modern scientific techniques and methods. CHIs combined with aspirin + anticoagulants + dehydrant + neuroprotectant (AADN) are believed to be effective for the treatment of acute cerebral infarction (ACI). However, no randomized controlled trial (RCT) has been performed to directly compare the efficacies of different regimens of CHIs. Therefore, we performed a systematic review and network meta-analysis (NMA) to compare the efficacies of different regimens of CHIs for ACI.

Methods

We conducted an overall and systematic retrieval from literature databases of RCTs focused on the use of CHIs to treat ACI up to June 2016. We used the Cochrane Handbook version 5.1.0 and CONSORT statement to assess the risk of bias. The data were analyzed using STATA 13.0 and WinBUGS 1.4.3 software.

Results

Overall, 64 studies with 6225 participants involving 15 CHIs were included in the NMA. In terms of the markedly effective rate, Danhong (DH) + AADN had the highest likelihood of being the best treatment. In terms of the improvement of neurological impairment, Shuxuening (SXN) + AADN had the highest likelihood of being the best treatment. Considering two outcomes, injections of SXN, Yinxingdamo (YXDM), DH, Shuxuetong (SXT), HongHuaHuangSeSu (HHHSS), DengZhanXiXin (DZXX) and Shenxiong glucose (SX) plus AADN were the optimum treatment regimens for ACI, especially SXN + AADN and YXDM + AADN.

Conclusions

Based on the NMA, SXN, YXDM, DH, SXT, HHHSS, DZXX and SX plus AADN showed the highest probability of being the best treatment regimens. Due to the limitations of the present study, our findings should be verified by well-designed RCTs.

Keywords

  • Network meta-analysis
  • Acute cerebral infarction
  • Chinese herbal injection

Background

Acute cerebral infarction (ACI) is one of the most common cerebral vascular diseases, also referred to as ischemic stroke, which is result from ischemia, hypoxia and cerebral blood circulation [13]. ACI has the characteristics of high disability and recurrence [46]. Besides, it is a major disease leading to serious damage of central nervous system or death [4, 7]. It was estimated that ACI cause 6.2 million mortalities annually worldwide [8]. In traditional Chinese medicine (TCM) theories, ACI refers to “apoplexy”, majorly due to blood stasis syndrome [3]. Therefore, promoting blood flow is of primary importance. It has been proven that TCM is an effective complementary intervention for stroke, especially in the treatment of ischemic stroke [913].

Currently, therapies for ACI include thrombolytics, antithrombotics, anticoagulants, and neuroprotectants [14]; this was the Grade-I recommendation in the guidance of diagnosis and treatment of acute ischemic stroke in China 2010, which fully considered the national conditions and clinical experience. Among them, thrombolytic has a short therapeutic time window. Thus, many patients easily miss the effective time window of thrombolysis. ACI patients who are not eligible for thrombolysis therapy should be given oral aspirin, which was approved by the US Food and Drug Administration (FDA), at a dose ranging from 150 to 300 mg/d as soon as possible (level of evidence: A) [15, 16]. And patients with brain edema could use a mannitol intravenous drip. Although more high-quality clinical trials are needed to further demonstrate the efficacy and safety of neuroprotective agents, a number of RCTs have suggested that edaravone and cerebroprotein hydrolysate improve functional outcomes and the safety of patients with ACI [1720]. Additionally, the therapeutic principle of invigorating blood circulation for removing blood stasis of TCM holds a significant position for ACI. Chinese herbal injections (CHIs) have the characteristics of rapid efficacy and high bioavailability [2123].Presently, 37 injections are often used in the treatment of cerebral infarction, such as Xueshuantong injection, Shuxuening injection, Mailuoning injection, and Danshenchuanxiongqin injection [2427]. Clinical data [2832] from systematic reviews of RCTs have demonstrated the beneficial effects of CHIs for inhibiting platelet aggregation, improving blood microcirculation and nerve function, enhancing the tolerance of ischemic tissue to hypoxia, and protecting against ischemic reperfusion injury.

Hence, this study systematically evaluated the clinical effectiveness of CHIs combined with an aspirin + anticoagulants + dehydrant + neuroprotectant (AADN) regimen in ACI patients that conformed to the standardized treatment of ischemic cerebrovascular disease: integration, individualization and sequencing. However, there is no direct head-to-head evidence revealing the best CHIs for ACI treatment. Determining the superiority of a treatment based on a pairwise comparison meta-analysis is difficult. A network meta-analysis (NMA), which is an extension of a traditional meta-analysis, synthesizes the available evidence to enable simultaneous comparisons of different treatment options that lack direct head-to-head evaluations [3335]. Therefore, the present study performed a NMA to compare the clinical efficacy of 37 CHIs combined with the AADN regimen to reveal the best CHIs for ACI, aiming to provide more sights for selection of ACI.

Methods

Eligibility criteria

Studies meeting the following criteria were included: (1) Clinical randomized controlled trials (RCTs) using CHIs + AADN to treat ACI regardless of blinding. (2) Cerebrovascular disease was diagnosed according to the standards revised by the Fourth National Conference on Cerebrovascular Disease by the Chinese Medical Association in 1995 [36]. The acute phase of ACI generally refers to 2 weeks after the onset of disease. Thus, this NMA enrolled patients with the course of disease within 2 weeks. No cerebral hemorrhage was detected using cranial computed tomography (CT) or magnetic resonance imaging (MRI). There were no limits on age, gender, race or disease severity. (3) Eligible comparisons were CHIs + AADN regimens versus the AADN regimen alone and CHIs + AADN regimens versus other CHIs + AADN regimens. There was no limitation on the dosages or treatment courses. (4) Outcome measures included the markedly effective rate, improvement of neurological impairment, activities of daily living function, and death from all causes within the treatment and during the entire follow-up period. The following formula was used: the markedly effective rate (%) = (number of recovered patients + number of patients with significant progress) / total number × 100%. The efficacy criteria were predominantly based on the reduction of the neurological deficit score and could be divided into four grades: recovery, significant progress, progress, and no change or deterioration. Recovery, significant progress, progress, and no change or deterioration were determined when the neurological deficit score decreased from 91% to 100%, between 46% and 90%, between 18% and 45%, and < 17%, respectively. The improvement of neurological impairment is expressed as the mean ± standard deviation.

The following studies were excluded: (1) studies that did not refer to the acute phase; (2) studies that did not meet the curative effect valuation standard; (3) studies involving patients who had a severe cognitive disorder, hemorrhagic tendency, or serious complications, such as atrial fibrillation, severe heart failure, severe liver and kidney diseases, undergoing surgery, acupuncture or other physical therapy; (4) data that were incorrect, incomplete or unavailable; (5) reviews or meta-analyses, experimental research, retrospective studies, case reports, and conference abstracts.

Data sources and search strategy

A systematic literature search was performed using the following databases from inception to June 2016: PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure Database (CNKI), Wanfang Database, and Chinese Biomedical Literature Database (CBM). The medical subject headings (MeSH) and free text words were used. No language or other restrictions were imposed. Furthermore, we hand searched the reference lists of all retrieved studies. The specific Chinese and English search terms for each CHIs are shown in Additional file 1: Table S1 and the detailed search strategy is shown in Additional file 2.

Literature selection and data extraction

Two reviewers independently read the titles and abstracts of the literature to exclude literature that was obviously not relevant as well as reviews and pharmacological experiments. We retrieved the full text of the articles to determine whether they were eligible.

The data of interest from each included RCT were collected using a standard data abstraction form created in Microsoft Excel 2013 (Microsoft Corp, Redmond, WA, USA). The main components of the extracted data were as follows: (1) General information: author names and publication data; (2) Patient information: median age, number of patients, gender, and acute phase; (3) Intervention: names, dosages, and treatment; (4) Outcomes: the markedly effective rate, improvement of neurological deficit score, adverse drug reactions/adverse drug events (ADRs/ADEs), activities of daily living function, and death from all causes within the treatment and during the entire follow-up period.

Quality assessment

The methodological quality of each included study was evaluated using the Cochrane Risk of Bias tool [37] and the CONSORT statement [38]. The items included randomization, blinding, dropout, eligibility criteria for participants, adverse events, and statistical methods. The judgments for each entry involved were divided into 3 grades: “high”, “unclear”, and “low”. A quality assessment was performed by two independent reviews, and disagreements were resolved by consensus.

Statistical analysis

We performed a pairwise meta-analysis using STATA 13.0 software (Stata Corporation, College Station, TX, USA). The pooled odds ratios (ORs) were calculated for dichotomous data and standardized mean differences (SMDs) were calculated for continuous variables, both with 95% confidence interval (95% CI). The Chi-squared test was used to evaluate the heterogeneity between studies, and I 2 was used to show the extent of heterogeneity. When P was ≥0.1 and I 2 was ≤50%, no statistical heterogeneity was suggested and the Mantel-Haenszel fixed-effects model was used for the meta-analysis. When P < 0.1 and I 2 was > 50%, we explored the sources of heterogeneity using a subgroup analysis and meta-regression. When there was no clinical heterogeneity, the Mantel-Haenszel random-effects model was used to perform the meta-analysis [37].

A Bayesian NMA was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK). The random-effects model with vague priors for multi-arm trials was used [39]. The model parameters were estimated using a Markov chain Monte Carlo method called Gibbs sampling. Convergence was found to be adequate after running 1000 samples. These samples were discarded as “burn-in,” and posterior summaries were based on 100,000 subsequent simulations. The results are reported as the OR and SMD with 95% CI. To evaluate the inconsistency between direct and indirect effect estimates for the same comparison, we evaluated each closed loop in the network. In a closed loop, we employed the inconsistency factor (IF) to evaluate heterogeneity among the included studies. If the 95% CIs of the IF values were truncated at zero, it indicated that the 2 sources were in agreement [39]. To rank the treatments, we used the surface under the cumulative ranking probabilities (SUCRA); a SUCRA value of 100% is assigned to the best treatment and 0% for the worst treatment [39]. A comparison-adjusted funnel plot was used to assess the presence of small-study effect [40]. Egger’s test was used to assess the symmetry of the funnel plot [41].

To account for both the markedly effective rate and neurological deficits, we used multivariate methods to determine the dependency between outcomes. Clustering methods and 2-dimensional plots were used to produce clusters of treatments [42]. Using the clusterank command, clustered ranking plots can be obtained using the STATA program. The markedly effective rate and neurological deficits became the data variable containing the SUCRA scores for all treatments in this network. The different colors correspond to the estimated clusters and were utilized for grouping the treatments according to their similarity for both outcomes.

Results

Literature search and characteristics of the included studies

Figure 1 shows the PRISMA flow diagram. A total of 13,764 articles were identified from electronic databases. After the exclusion of duplications, reviews, and obviously irrelevant studies by reading titles and abstracts, 3493 papers were downloaded for additional review. A total of 3429 RCTs were excluded for the following reasons: non-RCTs, non-acute phase, not meeting intervention and the curative effect valuation standard, incorrect data, no treatment time, and no outcomes of interest. Hence, 64 studies and 15 CHIs were included in the NMA. All studies were published in Chinese from 2006 to 2015.
Figure 1
Fig. 1

Flow diagram of the study search

Characteristics of the included studies

The 64 RCTs [28, 43105] included 6225 participants, with sample sizes varying from 26 to 300 participants. All RCTs were conducted among Chinese populations in China. All participants were evaluated using cranial CT or NMRI. The rang of participants was approximately 35 to 87 years. There were more male patients (59.4%) than females. This study included 16 treatments for ACI: AADN, Shuxuening injection(SXN) + AADN, Shuxuetong injection (SXT) + AADN, Shenxiong injection (SX) + AADN, Mailuoning injection (MLN) + AADN, Honghuahuangsesu injection (HHHSS) + AADN, Fufangdanshen injection (FFDS) + AADN, Dengzhanhuasu injection (DZHS) + AADN, Dengzhanxixin injection (DZXX) + AADN, Danshenchuanxiongqin injection (DSCXQ) + AADN, Danshen injection (DS) + AADN, Danhong injection (DH) + AADN, Yinxingdamo injection (YXDM) + AADN, Ligustrazine injection (LI) + AADN, Xuesaitong injection (XST2) + AADN, and Xueshuantong injection (XST1) + AADN; to concisely express the results of this research, we used the abbreviations of the TCM injections to replace the treatments. The treatment abbreviations are shown in Table 1. The acute phase was no more than 30 days, with 62.5% of the cases having an acute phase of less than 72 h. The duration of treatment for both the experimental and control groups was no more than 30 days. Figure 2 shows a network graph comparing fifteen CHIs. There were 120 pairwise comparisons including 40 direct comparisons. Table 2 provides a summary of the included studies. Additional file 3 showed the more details of included CHIs.
Table 1

Treatment abbreviations

Full name

Abbreviations

Aspirin + Anticoagulants + Dehydrant + Neuroprotectant

AADN

Ligustrazine injection

LI

Xueshuantong injection

XST1

Xuesaitong injection

XST2

Shuxuening injection

SXN

Dengzhanxixin injection

DZXX

Dengzhanhuasu injection

DZHS

Shuxuetong injection

SXT

Danhong injection

DH

Fufangdanshen injection

FFDS

Yinxingdamo injection

YXDM

Mailuoning injection

MLN

Honghuahuangsesu injection

HHHSS

Shenxiong glucose injection

SX

Danshen Chuanxiongqin injection

DSCXQ

Danshen injection

DS

Figure 2
Fig. 2

Network of the included comparisons. Note: Nodes are proportional to the number of patients included in the corresponding treatments, and edges are weighted according to the number of studies included in the respective comparisons

Table 2

Characteristics of the studies included in this meta-analysis

Study

Acute phase

Sex (M/F)

Age

Experimental group

Control group

Course

Outcomes

ADRs/ADEs

N

T1

Dosage

N

T2

Dosage

Yu YC 2014

72 h

38/30

62.5 (44–76)

34

XST1

500 mg

34

AADN

14d

(1)

None

Yu YM 2009

72 h

71/45

62.5 (40–72)

58

DH

20 ml

58

FFDS

20 ml

15d

(1)(2)

Unclear

Yu Y 2015

72 h

35/21

54.3 (38–71)

28

XST1

500 mg

28

FFDS

20 ml

14d

(1)(2)

6

Zhang ZJ 2008

74 h

41/30

64.3

35

SX

100 ml

36

FFDS

20 ml

14d

(1)

None

Zheng XD 2007

72 h

39/21

66.4

30

YXDM

20 mL

30

FFDS

30 ml

14d

(1)

None

Zhou SJ 2011

1 M

46/34

62 (42–75)

40

SX

100 ml

40

AADN

14d

(1)(2)

None

Zhou SF 2009

48 h

52/42

65.6 (62–86)

48

SX

200 ml

46

FFDS

20 mL

21d

(1)(2)

10

Zhou SH 2013

72 h

50/40

62

45

SXN

20 ml

45

AADN

14d

(1)(4)

None

Xu XY 2011

12 h

40/20

55.9 (45–73)

30

YXDM

20 ml

30

DS

20 ml

21d

(1)(2)(3)

Unclear

Xie S 2011

24 h

42/30

61.4 (53–78)

36

SXT

6 ml

36

FFDS

20 ml

14d

(1)

None

Xie YG 2010

48 h

39/31

61.6 (50–76)

35

SXT

6 ml

35

DZHS

50 mg

14d

(1)(2)

None

Xu LL 2011

72 h

48/34

63.0 (55–81)

42

LI

120 mg

42

AADN

14d

(1)(2)

Unclear

Xu XQ 2012

72 h

64/44

57.9

54

YXDM

20 ml

54

FFDS

20 ml

14d

(1)(2)

1

Yang HJ 2007

24 h

50/34

53.6 (39–75)

48

DSCXQ

10 ml

36

FFDS

10 ml

30d

(1)(2)

1

Yang YF 2012

48 h

68

112

DH

30 ml

101

AADN

21d

(1)(2)

Unclear

Yao QY 2010

72 h

64/40

70.8 (54–82)

56

SXT

6 ml

48

LI

12 ml

14d

(1)(2)

2

Yao J 2010

72 h

37/27

60.5 (49–76)

32

YXDM

20 ml

32

DZHS

50 mg

14d

(1)(2)

None

Xie RP 2010

72 h

52/28

42–80

40

SXN

20 ml

40

FFDS

20 mL

15d

(1)

None

Tan SY 2016

72 h

49/37

39–82

43

DH

30 ml

43

AADN

14d

(1)(2)

None

Wang WP 2015

72 h

49/41

68.2 (60–78)

45

SXN

20 mL

45

FFDS

20 mL

14d

(1)(2)

Unclear

Ren HM 2009

72 h

38/26

40–78

32

SX

100 ml

32

AADN

14d

(1)(2)

None

Sun HJ 2013

72 h

42/36

60.9 (40–70)

39

LI

120 mg

39

AADN

14d

(1)(2)

Unclear

Tang JP 2013

72 h

47/45

51.8 (43–73)

46

HHHSS

100 mg

46

AADN

14d

(1)(2)

None

Tang FY 2009

72 h

39/33

64.0 (50–78)

36

DZHS

50 mg

36

AADN

14d

(1)(2)

None

Tang XJ 2013

72 h

45/33

58

39

YXDM

20 mg

39

AADN

14d

(1)(2)

None

Wang L 2010

48 h

26/22

65.6 (62–86)

40

SX

200 mL

40

FFDS

20 mL

21d

(1)(2)

Unclear

Wang YL 2013

168 h

33/23

32–88

28

SXT

6 ml

28

DZHS

40 ml

14d

(2)

Unclear

Lan Y 2015

72 h

41/39

54–72

40

DSCXQ

10 ml

40

AADN

14d

(1)(2)

3

Li M 2014

24 h

63/17

48–76

40

DH

30 ml

40

AADN

14d

(2)

Unclear

Liu YP 2010

72 h

45/35

51–71

40

DH

40 ml

40

AADN

15d

(1)

1

Ma J 2010

24 h

29/31

59.1 (50–68)

30

DZHS

20 mg

30

AADN

14d

(1)(2)

Unclear

Ma J 2015

72 h

49/41

65.5 (45–79)

45

DH

20 ml

45

AADN

28d

(1)(4)

Unclear

Chen H 2015

24 h

74/60

59.4 (46–87)

67

SXT

6 ml

67

AADN

14d

(1)(2)

5

Luan T 2014

48 h

52/43

57.5

50

XST2

0.4 g

45

DS

20 ml

15d

(1)(4)

7

Huang ML 2012

72 h

158/142

62.6 (42–71)

150

XST1

500 mg

150

DS

25 ml

14d

(1)

1

Li X 2015

72 h

129/71

62.9

100

HHHSS

0.1 g

100

AADN

14d

(1)(2)

Unclear

Ma ZL 2011

72 h

74/46

62.8 (45–84)

60

HHHSS

0.1 g

60

AADN

14d

(1)(2)

None

Zhang Y 2012

48 h

52/28

57.5 (35–80)

40

DSCXQ

100 mg

40

AADN

14d

(1)(2)

1

Liu M 2014

48 h

79/57

60.2 (40–76)

68

DSCXQ

10 mL

68

AADN

14d

(1)(2)

2

Chen YC 2011

72 h

44/24

57.9

34

YXDM

20 ml

34

FFDS

20 ml

14d

(1)(2)

1

Yang RF 2013

48 h

52/48

60.8 (30–83)

50

SXT

6 g

50

AADN

14d

(1)

Unclear

Lin YF 2008

72 h

39/21

66.5

30

YXDM

20 ml

30

FFDS

20 ml

14d

(1)(3)

None

Peng T 2006

48 h

51/48

68

49

SXT

7 ml

50

FFDS

20 ml

14d

(1)(3)

1

Li XH 2011

168 h

63.5(40–78)

120

SXN

20 ml

120

AADN

14d

(1)(2)

Unclear

Liu L 2015

6-72 h

74/46

61.4 (39–76)

60

DH

20 ml

60

SXN

20 ml

14d

(1)

None

Zhang YH 2010

6-72 h

62/34

58.9 (39–81)

48

DH

30 ml

48

XST2

400 mg

14d

(1)(2)

5

Fan J 2006

72 h

56/32

64 (41–82)

44

YXDM

20 ml

44

FFDS

20 ml

14d

(2)

Unclear

Liu HY 2014

96 h

67/57

61.9 (38–83)

64

XST2

0.4 g

60

FFDS

30 ml

15d

(1)

None

Li FQ 2010

72 h

74/46

64

60

YXDM

30 ml

60

FFDS

40 ml

15d

(1)

Unclear

Lian CL 2013

360 h

49/43

62 (43–77)

46

LI

120 mg

46

AADN

30d

(1)

None

Chen S 2006

72 h

81/53

67.9

70

XST2

800 mg

64

XST1

10 ml

14d

(1)(2)

None

Cao LZ 2012

72 h

71/9

59.3

40

XST2

500 mg

40

FFDS

1.0 g

14d

(1)(2)

Unclear

Liu Y 2009

72 h

79/43

65.1 (43–73)

62

SXT

6 ml

60

XST2

8 ml

14d

(1)

1

Luo XD 2011

72 h

35/25

61.8

30

XST2

0.4 g

30

AADN

14d

(1)(2)

3

Liao MJ 2014

6-72 h

43/17

62.5 (36–80)

30

HHHSS

100 ml

30

XST2

400 mg

14d

(1)

Unclear

Shi JL 2010

72 h

51/33

62

42

YXDM

20 ml

42

LI

200 mg

30d

(2)

Unclear

Ni H 2010

24 h

61/55

62.7 (54–74)

59

SXN

20 ml

57

AADN

14d

(1)

Unclear

Li CP 2007

8-72 h

106/54

63.8 (42–85)

80

SXN

10-20 ml

80

AADN

14d

(1)

Unclear

Zhou ZP 2011

24 h

48/33

62.2

42

DZXX

30 ml

39

AADN

15d

(1)

Unclear

Chen C 2015

72 h

37/31

67.5

34

SXT

6 ml

34

XST2

400 mg

14d

(1)(2)

14

Chen JY 2012

72 h

73/35

67 (40–76)

54

SXT

6 ml

54

FFDS

20 ml

14d

(1)(2)

Unclear

Luo QY 2007

72 h

54/36

63.6 (37–81)

45

SXN

6 ml

45

AADN

20 ml

14d

(1)

None

Chen J 2007

72 h

45/35

61

40

YXDM

20 ml

40

MLN

20 ml

15d

(1)(2)(3)

Unclear

Zhang XL 2005

6d

37/13

35–80

26

MLN

20 ml

24

FFDS

20 m l

21d

(2)

None

M male, F female, AVG average, E experimental group, C control group, W week, D day, AADN aspirin + anticoagulants + dehydrant + neuroprotectant, DH Danhong injection + AADN, DS Danshen injection + AADN, DSCXQ Danshenchuangxiongqin injection + AADN, DZHS Dengzhanhuasu injection + AADN, DZXX Dengzhanxixin injection + AADN, FFDS Fufangdanshen injection + AADN, HHHSS Honghuahuangsesu injection + AADN, SX Shenxiong glucose injection + AADN, SXT Shuxuetong injection + AADN, XST1 Xueshuantong injection + AADN, XST2 Xuesetong injection + AADN, LI Ligustrazine injection + AADN, YXDM Yinxingdamo injection + AADN, SXN Shuxuening injection + AADN, MLN Mailuoning injection + AADN, ADRs adverse drug reactions, ADEs adverse drug events; (1): markedly effective rate; (2): neurological impairment; (3): death; (4): activities of daily living function; N: sample size; T1: therapy of experiment; T2: Therapy of control; N:Number of studies; −: No report

Quality of the included studies

We used the Cochrane Handbook version 5.1.0 and CONSORT statement to conduct a quality evaluation of the included studies. All studies mentioned the use of random distribution, while ten studies [44, 64, 68, 73, 75, 82, 9597, 101] described a satisfactory method of randomization including random number tables or the envelope method. Two studies [60, 85] reported information about blinding. All studies provided information on patients who were lost to follow-up or dropped out. All studies reported the eligibility criteria for participants and statistical methods. Approximately 74.6% of the studies provided information about adverse events. Details on risk of bias are shown in Additional file 4: Figure S1.

Pairwise meta-analysis

Pairwise meta-analysis of the markedly effective rate

Fifty-nine RCTs reported markedly effective rates; in these RCTs, 5864 patients were involved and 34 regimens were included. Table 3 summarizes the results of the pairwise meta-analysis regarding the markedly effective rates. There was no significant heterogeneity in the pooled analysis of all included studies (P > 0.1; I 2  < 50%); the results of the heterogeneity test are shown in Table 2. The direct comparison showed that DH and SXN were more beneficial in improving the markedly effective rate than AADN (AADN versus DH: OR = 0.61, 95% CI = 0.45–0.84; versus SXN: OR = 0.57, 95% CI = 0.44–0.73). SX and XST2 were more beneficial than FFDS (FFDS versus SX: OR = 0.61, 95% CI = 0.38–0.98; versus XST2: OR = 0.54, 95% CI = 0.34–0.86). Other treatment comparisons failed to reach statistical significance (the 95% CI included 1). The detailed results are shown in Fig. 3.
Table 3

A summary of the meta-analysis for the markedly effective rate

AADN

0.61(0.45,0.84) P = 0.96 i2  = 0%

 

0.75(0.48,1.16) P = 0.97 l 2  = 0%

0.72(0.42,1.23) P = 0.82 I 2  = 0%

0.56(0.26,1.17)

0.74(0.54,1.01) P = 0.91 I 2  = 0%

0.67(0.40,1.14) P = 0.92 I 2  = 0%

0.90(0.61,1.32) P = 0.71 I 2  = 0%

0.93(0.46, 1.90)

0.72(0.33, 1.59)

0.81(0.54, 1.21) P = 0.79 I 2  = 0%

0.61(0.30,1.26)

0.57(0.44,0.73) P = 0.19 I 2  = 35.4%

3.89 (2.26, 6.26)

DH

1.53

(0.84,2.80)

1.73

(0.89, 3.34)

1.22

(0.69,2.16)

0.8 (0.29, 1.8)

0.22

(0.07,0.52)

DS

0.79

(0.53,1.19)

0.75

(0.41, 1.36)

0.64

(0.28,1.47)

2.14 (1.02, 3.99)

0.59

(0.23,1.23)

3.3

(0.91,8.58)

DSCXQ

1.70

(0.81,3.59)

2.22 (0.95, 4.47)

0.61

(0.22,1.35)

3.38

(0.92,8.96)

1.16

(0.37,2.82)

DZHS

0.70

(0.32,1.48)

0.75

(0.33,1.72)

 

5.36 (1.06,16.68)

1.47

(0.26,4.87)

8.32

(1.12,30.55)

2.82

(0.44,9.73)

2.82

(0.42,9.88)

DZXX

0.94 (0.57, 1.46)

0.25

(0.13,0.44)

1.41

(0.51,3.11)

0.49

(0.21,0.96)

0.48

(0.19,1.01)

0.29

(0.05,0.93)

FFDS

0.61(0.38, 0.98) P = 0.89 I 2  = 0%

0.74(0.51,1.07)P = 0.86 I 2  = 0%

0.76(0.33, 1.76)

0.54(0.34,0.86)P = 0.70 I 2  = 0%

0.75(0.53,1.06)P = 0.98 I 2  = 0%

0.81(0.50,1.31)P = 0.65 I 2  = 0%

3.34 (1.66, 6.14)

0.91

(0.37,1.91)

5.14

(1.48,13.28)

1.75

(0.62,4)

1.75

(0.56,4.22)

1.02

(0.16,3.51)

3.76

(1.61,7.65)

HHHSS

1.85

(0.79, 4.29)

2.9 (1.36, 5.46)

0.79

(0.32,1.65)

4.43

(1.29,11.37)

1.52

(0.53,3.47)

1.51

(0.49,3.6)

0.89

(0.14,3.03)

3.18

(1.56,5.83)

0.97

(0.34,2.21)

SX

3.27 (1.86, 5.35)

0.89

(0.42,1.66)

4.96

(1.68,11.54)

1.71

(0.68,3.58)

1.68

(0.67,3.51)

1

(0.17,3.27)

3.6

(2.03,5.97)

1.09

(0.44,2.23)

1.25

(0.52,2.55)

SXT

1.38(0.86, 2.22) P = 0.86 I 2  = 0%

1.47

(0.79, 2.78)

1.27 (0.53, 2.6)

0.34

(0.13,0.76)

1.78

(0.7,3.81)

0.66

(0.21,1.62)

0.66

(0.2,1.63)

0.39

(0.06,1.38)

1.39

(0.59,2.84)

0.42

(0.14,1)

0.49

(0.16,1.16)

0.41

(0.16,0.87)

XST1

0.65

(0.37, 1.15)

2.24 (1.23, 3.77)

0.61

(0.29,1.12)

3.31

(1.25,7.23)

1.17

(0.46,2.51)

1.16

(0.43,2.56)

0.68

(0.12,2.28)

2.47

(1.36,4.14)

0.74

(0.31,1.5)

0.86

(0.35,1.77)

0.71

(0.38,1.25)

1.99

(0.85,3.94)

XST2

1.64 (0.78, 3.09)

0.45

(0.18,0.96)

2.54

(0.7,6.6)

0.86

(0.29,2.01)

0.86

(0.27,2.06)

0.5

(0.08,1.73)

1.85

(0.76,3.8)

0.55

(0.19,1.25)

0.64

(0.22,1.48)

0.53

(0.22,1.07)

1.52

(0.47,3.66)

0.79

(0.31,1.68)

LI

2.99 (1.53, 5.34)

0.81

(0.36,1.6)

4.43

(1.57,10.1)

1.56

(0.59,3.4)

1.52

(0.59,3.24)

0.91

(0.15,3.1)

3.24

(1.85,5.34)

1

(0.37,2.17)

1.14

(0.46,2.36)

0.96

(0.45,1.82)

2.69

(1.01,5.84)

1.41

(0.65,2.69)

2.05

(0.74,4.58)

YXDM

1.32

(0.67,2.61)

3.3 (2, 5.14)

0.9

(0.46,1.59)

5.09

(1.64,12.18)

1.73

(0.71,3.61)

1.73

(0.64,3.79)

1.01

(0.18,3.3)

3.69

(1.97,6.31)

1.1

(0.45,2.25)

1.28

(0.53,2.61)

1.08

(0.52,1.98)

3.04

(1.12,6.65)

1.59

(0.75,2.97)

2.27

(0.91,4.75)

1.21

(0.54,2.33)

SXN

1.33 (0.2, 4.65)

0.36

(0.05,1.3)

1.98

(0.24,7.46)

0.69

(0.09,2.61)

0.68

(0.09,2.47)

0.41

(0.03,1.84)

1.45

(0.23,4.95)

0.44

(0.06,1.65)

0.51

(0.07,1.86)

0.43

(0.06,1.52)

1.2

(0.15,4.48)

0.63

(0.09,2.24)

0.91

(0.11,3.45)

0.45

(0.08,1.44)

0.42

(0.06,1.51)

MLN

The upper right corner is the Meta-analysis results. The bottom left corner is the network Meta-analysis results. Results are the odds ratios (OR) and related 95% credibility interval (95% CI) in the row-defining treatment compared with the column -defining treatment. OR higher than 1 favor the row-defining treatment, and vice versa. Significant effects are printed in bold. AADN aspirin + anticoagulants + dehydrant + neuroprotectant, DH Danhong injection + AADN, DS Danshen injection + AADN, DSCXQ Danshenchuangxiongqin injection + AADN, DZHS Dengzhanhuasu injection + AADN, DZXX Dengzhanxixin injection + AADN, FFDS Fufangdanshen injection + AADN, HHHSS Honghuahuangsesu injection + AADN, SX Shenxiong glucose injection + AADN, SXT Shuxuetong injection + AADN, XST1 Xueshuantong injection + AADN, XST2 Xuesetong injection + AADN, LI Ligustrazine injection + AADN, YXDM Yinxingdamo injection + AADN, SXN Shuxuening injection + AADN, MLN Mailuoning injection + AAD

Figure 3
Fig. 3

Forest graph of Meta-analysis on the markedly effective rate

Pairwise meta-analysis of the improvement of neurological impairment

Forty-one RCTs reported an improvement of neurological impairment; in these RCTs, 3828 patients were involved and 29 regimens were included. When P was ≥0.1 and I 2 was ≤50%, the Mantel-Haenszel fixed-effects model was used for the meta-analysis and vice versa. The results of the heterogeneity test are shown in Table 4. Table 4 summarizes the results of the pairwise meta-analysis regarding the improvement of neurological impairment. The direct comparison showed that DH, DZHS, HHHSS, SX, SXT, XST2, LI, YXDM, and SXN were more effective than AADN alone in the reduction of the neurological impairment score (AADN versus DH: SMD = 0.54, 95% CI = 0.33–0.75; versus DZHS: SMD = 1.01, 95% CI = 0.04–1.98; versus HHHSS: SMD = 0.64, 95% CI = 0.44–0.84; versus SX: SMD = 0.77, 95% CI = 0.43–1.11; versus SXT: SMD = 0.79, 95% CI = 0.44–1.14; versus XST2: SMD = 0.53, 95% CI = 0.01–1.04; versus LI: SMD = 0.83, 95% CI = 0.51–1.16; versus YXDM: SMD = 1.03, 95% CI = 0.56–1.50; versus SXN: SMD = 0.41, 95% CI = 0.15–0.66). DH was more effective than FFDS (SMD = − 1.01, 95% CI = − 1.40 to − 0.62) and XST2 (SMD = − 0.61, 95% CI = − 1.02 to − 0.20). DSCXQ was more effective than FFDS (SMD = − 0.82, 95% CI = − 1.27 to − 0.37). YXDM and SXT were more effective than DZHS (DZHS versus YXDM: SMD = 0.75, 95% CI = 0.24–1.26; versus SXT: SMD = 0.84, 95% CI = 0.35–1.33). SX, XST1, XST2, and SXN were more effective than FFDS (FFDS versus SX: SMD = 0.79, 95% CI = 0.45–1.13; versus XST1: SMD = 1.15, 95% CI = 0.58–1.71; versus XST2: SMD = 0.95, 95% CI = 0.49–1.41; versus SXN: SMD = 2.41, 95% CI = 1.85–2.97). SXT was more effective than LI (SMD = − 0.79, 95% CI = − 1.19 to − 0.39). YXDM was more effective than LI (LI versus YXDM: SMD = 0.96, 95% CI = 0.51–1.42). MLN was more effective than YXDM (YXDM versus MLN: SMD = 0.51, 95% CI = 0.06–0.95). Other treatment comparisons failed to reach statistical significance (the 95% CI included 0). The detailed results are shown in Fig. 4.
Table 4

A summary of the meta-analysis for the improvement of neurological impairment

AADN

0.54(0.33, 0.75) I 2  = 13.4% P = 0.32

0.51(− 0.02, 1.03) I2 = 79.8% P = 0.007

1.01(0.04, 1.98) I 2  = 85.2% P = 0.009

0.64(0.44, 0.84) I 2  = 87.2% P = 0.000

0.77(0.43, 1.11) I 2  = 0%

P = 0.60

0.79(0.44,1.14)

0.53(0.01, 1.04)

0.83

(0.51, 1.16) I 2  = 80.4%

P = 0.02

1.03(0.56, 1.50)

0.41(0.15, 0.66)

− 0.71 (− 1.28,-0.13)

DH

− 1.01 (− 1.40,-0.62)

− 0.61

(− 1.02,-0.20)

 

− 0.83 (− 2.21,0.56)

−0.12 (− 1.58,1.3)

DS

0.31 (− 0.20, 0.81)

− 0.52 (− 1.15,0.1)

0.19 (− 0.64,1.01)

0.31 (− 1.18,1.8)

DSCXQ

− 0.82 (− 1.27,-0.37)

−0.59 (− 1.26,0.07)

0.12 (− 0.74,0.96)

0.24 (− 1.23,1.69)

−0.07 (− 0.96,0.8)

DZHS

0.84 (0.35, 1.33)

0.75 (0.24, 1.26)

−0.78 (− 2.19,0.63)

−0.07 (− 1.57,1.41)

0.05 (− 1.88,1.97)

−0.26 (− 1.78,1.2)

−0.19 (− 1.68,1.2)

DZXX

0.03 (− 0.49, 0.55)

0.22 (− 0.3,0.73)

0.92 (0.26,1.58)

1.05 (− 0.32,2.4)

0.74 (0.01,1.47)

0.81 (0.05,1.58)

1.00 (− 0.43,2.43)

FFDS

0.79 (0.45,1.13) I 2  = 0% P = 1

0.07 (−0.03, 0.45)

1.15 (0.58, 1.71)

0.95 (0.49, 1.41)

1.31 (−0.05,2.66) I 2  = 95.7% P = 0

2.41 (1.85, 2.97)

0.44 (−0.12, 1.01)

−0.78 (− 1.47,-0.09)

− 0.07 (− 0.97,0.83)

0.05 (− 1.49,1.58)

−0.26 (− 1.19,0.6)

−0.19 (− 1.16,0.7)

0 (− 1.57,1.57)

− 1 (− 1.86,-0.13)

HHHSS

− 0.67 (− 1.34,0)

0.04 (− 0.8,0.87)

0.16 (− 1.34,1.64)

−0.14 (− 1.03,0.7)

−0.08 (− 0.99,0.8)

0.11 (− 1.41,1.64)

−0.88 (− 1.55,-0.21)

0.11 (− 0.85,1.08)

SX

− 0.81 (− 1.44,− 0.18)

-0.1 (− 0.89,0.69)

0.02 (− 1.44,1.47)

−0.29 (− 1.14,0.5)

−0.22 (− 0.99,0.5)

−0.03 (− 1.29,1.23)

−1.03 (− 1.7,-0.36)

−0.03 (− 0.97,0.91)

−0.14 (− 1,0.72)

SXT

− 0.20 (− 0.68,0.28)

0.79 (− 1.19,-0.39)

− 0.6 (− 1.61,0.39)

0.11 (− 0.97,1.16)

0.23 (−1.41,1.85)

−0.08 (− 1.22,1.0)

−0.01 (− 1.16,1.1)

0.18 (− 1.48,1.83)

−0.82 (− 1.76,0.12)

0.18 (−1.05,1.39)

0.06 (− 1.06,1.18)

0.21 (− 0.87,1.28)

XST1

0.24 (− 0.10,0.58)

−0.56 (− 1.22,0.09)

0.14 (− 0.59,0.88)

0.27 (− 1.22,1.75)

−0.04 (− 0.92,0.8)

0.03 (− 0.85,0.9)

0.22 (−1.25,1.69)

−0.78 (− 1.44,-0.12)

0.22 (− 0.74,1.17)

0.1 (− 0.77,0.97)

0.25 (− 0.5,1)

0.04 (− 0.88,0.97)

XST2

−0.47 (− 1.13,0.19)

0.24 (− 0.61,1.08)

0.36 (−1.09,1.82)

0.05 (− 0.84,0.9)

0.12 (− 0.74,0.9)

0.31 (− 1.16,1.79)

−0.69 (− 1.43,0.07)

0.31 (− 0.65,1.27)

0.2 (− 0.71,1.1)

0.34 (− 0.42,1.1)

0.13 (−1.01,1.28)

0.09 (− 0.78,0.96)

LI

0.96 (0.51, 1.42)

−1.14 (− 1.74,-0.54)

−0.43 (− 1.19,0.34)

−0.31 (− 1.57,0.94)

−0.61 (− 1.43,0.2)

−0.55 (− 1.3,0.22)

−0.36 (− 1.82,1.12)

−1.35 (− 1.89,-0.81)

−0.36 (− 1.27,0.56)

−0.47 (− 1.28,0.33)

−0.33 (− 1.08,0.42)

−0.53 (− 1.59,0.52)

−0.57 (− 1.36,0.21)

−0.67 (− 1.42,0.08)

YXDM

0.51 (0.06,0.95)

−1.25 (− 2.14,-0.37)

− 0.54 (− 1.56,0.47)

−0.41 (− 2.01,1.18)

−0.72 (− 1.79,0.3)

−0.65 (− 1.73,0.4)

−0.46 (− 2.09,1.17)

− 1.46 (− 2.36,-0.58)

−0.47 (− 1.6,0.65)

−0.58 (− 1.63,0.48)

−0.43 (− 1.48,0.59)

−0.64 (− 1.9,0.62)

−0.68 (− 1.73,0.36)

−0.77 (− 1.86,0.29)

−0.11 (− 1.1,0.88)

SXN

− 0.44 (− 1.45,0.57)

0.27 (− 0.84,1.37)

0.39 (− 1.16,1.94)

0.09 (− 1.06,1.2)

0.16 (− 0.98,1.2)

0.35 (− 1.32,2.02)

−0.65 (− 1.58,0.27)

0.34 (− 0.89,1.57)

0.23 (− 0.9,1.36)

0.37 (− 0.73,1.48)

0.17 (− 1.14,1.48)

0.13 (− 0.99,1.24)

0.03 (− 1.1,1.17)

0.7 (− 0.22,1.62)

0.81 (− 0.45,2.08)

MLN

The upper right corner is the Meta-analysis results. The bottom left corner is the network Meta-analysis results. Results are the SMD and related 95% credibility interval (95% CI) in the row-defining treatment compared with the column -defining treatment. SMD higher than 0 favor the column-defining treatment, and vice versa. Significant effects are printed in bold. AADN aspirin + anticoagulants + dehydrant + neuroprotectant, DH Danhong injection + AADN, DS Danshen injection + AADN, DSCXQ Danshenchuangxiongqin injection + AADN, DZHS Dengzhanhuasu injection + AADN, DZXX Dengzhanxixin injection + AADN, FFDS Fufangdanshen injection + AADN, HHHSS Honghuahuangsesu injection + AADN, SX Shenxiong glucose injection + AADN, SXT Shuxuetong injection + AADN, XST1 Xueshuantong injection + AADN, XST2 Xuesetong injection + AADN, LI Ligustrazine injection + AADN, YXDM Yinxingdamo injection + AADN, SXN Shuxuening injection + AADN, MLN Mailuoning injection + AADN

Figure 4
Fig. 4

Forest graph of Meta-analysis on the neurological impairment

Pairwise meta-analysis of the death

Most studies did not report any deaths during the treatment period or during follow up after the treatment ended in all trials. Four studies [50, 81, 82, 102] reported no death during the treatment period. This result may mean that CHIs plus AADN is an effective approach in the treatment of ACI or short follow-up time.

Pairwise meta-analysis of the activities of daily living function

Three studies [46, 67, 71] assessed the activities of daily living function using the Barthel Index. Due to the limited quantity of the included studies, the Mantel-Haenszel random-effects model was used. There was a significant difference between the treatment group and the control group (SX versus AADN: SMD = 0.83, 95% CI = 0.41–1.25; DSCXQ versus AADN: SMD = 0.73, 95% CI = 0.28–1.18; DH versus AADN: SMD = 1.69, 95% CI = 1.21–2.17).

Results of the Bayesian network meta-analysis

In the original analysis, most studies did not mention the activities of daily living function or death from all causes within the treatment period or during the entire follow-up period. Therefore, the present study did not compare death or the activities of daily living function among different treatments; we only performed a NMA to compare the markedly effective rate and the improvement of neurological impairment among the different regimens of CHIs for ACI.

Bayesian network meta-analysis of the markedly effective rate

According to the network of comparisons (Table 3), DH, DSCXQ, DZXX, HHHSS, SX, SXT, XST2, YXDM, and SXN improved the markedly effective rate more significantly than AADN alone (DH: OR = 3.89, 95% CI = 2.26–6.26; DSCXQ: OR = 2.14, 95% CI = 1.02–3.99; DZXX: OR = 5.36, 95% CI = 1.06–16.68; HHHSS: OR = 3.34, 95% CI = 1.66–6.14; SX: OR = 2.90, 95% CI = 1.36–5.46; SXT: OR = 3.27, 95% CI = 1.86–5.35; XST2: OR = 2.24, 95% CI = 1.23–3.77; YXDM: OR = 2.99, 95% CI = 1.53–5.34; SXN: OR = 3.3, 95% CI = 2–5.14). Moreover, DZXX, HHHSS, SX, SXT, XST2, YXDM, and SXN were better than DS (DZXX: OR = 8.32, 95% CI = 1.12–30.55; HHHSS: OR = 5.14, 95% CI = 1.48–13.28; SX: OR = 4.43, 95% CI = 1.29–11.37; SXT: OR = 4.96, 95% CI = 1.68–11.54; XST2: OR = 3.31, 95% CI = 1.25–7.23; YXDM: OR = 4.43, 95% CI = 1.57–10.1; SXN: OR = 5.09, 95% CI = 1.64–12.18). Additionally, HHHSS, SX, SXT, XST2, YXDM, and SXN were more effective than FFDS (HHHSS: OR = 3.76, 95% CI = 1.61–7.65; SX: OR = 3.18, 95% CI = 1.56–5.83; SXT: OR = 3.60, 95% CI = 2.03–5.97; XST2: OR = 2.47, 95% CI = 1.36–4.14; YXDM: OR = 3.24, 95% CI = 1.85–5.34; SXN: OR = 3.69, 95% CI = 1.97–6.31). YXDM and SXN were more effective than XST1 (YXDM: OR = 2.69, 95% CI = 1.01–5.84; SXN: OR = 3.04, 95% CI = 1.12–6.65).

Additional file 5: Figure S2 shows the inconsistency plot used to identify heterogeneity among studies in the closed loop of this NMA. Eleven triangular loops and 25 quadratic loops were present in the NMA; 83% of IF values with 95% CIs were truncated at zero, suggesting no significant inconsistency.

Rank probability

Figure 5 shows the cumulative probabilities (SUCRA results) of CHIs that were the most effective when combined with AADN. DH had the highest likelihood of being the best treatment for the markedly effective rate (SUCRA-85.2%), followed by DZXX (SUCRA-80.4%), SXN (SUCRA-76.3%), SXT (SUCRA-75.9%), HHHSS (SUCRA-74.4%), YXDM (SUCRA-69.2%), SX (SUCRA-66.3%), XST2 (SUCRA-51.9%), DZHS (SUCRA-50.3%), DSCXQ (SUCRA-49.2%), LI (SUCRA-36.0%), XST1 (SUCRA-24.4%), MLN (SUCRA-22.9%), FFDS (SUCRA-12.9%), and DS (SUCRA-8.2%).
Figure 5
Fig. 5

SUCRA for the markedly effective rate

Assessment of publication bias

The comparison-adjusted funnel plots (Additional file 6: Figure S3) for the markedly effective rate were asymmetric near the zero line. The result from Egger’s test was P = 0.047. Therefore, this study may have a small sample effect and publication bias.

Bayesian network meta-analysis of the improvement of neurological impairment

According to the network of comparisons (Table 4), DH, HHHSS, SXT, YXDM, and SXN improved neurological impairment more significantly than AADN alone (DH: SMD = − 0.71, 95% CI = − 1.28 to − 0.13; HHHSS: SMD = − 0.78, 95% CI = − 1.47 to − 0.09; SXT: SMD = − 0.81, 95% CI = − 1.44 to − 0.18; YXDM: SMD = − 1.14, 95% CI = − 1.74 to − 0.54; SXN: SMD = − 1.25, 95% CI = − 2.14 to − 0.37). Moreover, DH, DSCXQ, DZHS, HHHSS, SX, SXT, XST2, YXDM, and SXN were more effective than FFDS (FFDS versus DH: SMD = 0.92, 95% CI = 0.26–1.58; versus DSCXQ: SMD = 0.74, 95% CI = 0.01–1.47; versus DZHS: SMD = 0.81, 95% CI = 0.05–1.58; HHHSS: SMD = − 1, 95% CI = − 1.86 to − 0.13; SX: SMD = − 0.88, 95% CI = − 1.55 to − 0.21; SXT: SMD = − 1.03, 95% CI = − 1.7 to − 0.36; XST2: SMD = − 0.78, 95% CI = − 1.44 to − 0.12; YXDM: SMD = − 1.35, 95% CI = − 1.89 to − 0.81; SXN: SMD = − 1.46, 95% CI = − 2.36 to − 0.58). There was no statistical significance in other treatment comparisons.

As shown in Additional file 7: Figure S4, 9 triangular loops and seventeen quadratic loops were present in the NMA; 81% of IF values with 95% CIs were truncated at zero, suggesting no significant inconsistency.

Rank probability

The cumulative probability analysis (SUCRA results) showed that SXN + AADN had the highest likelihood of improving the neurological impairment scores (SUCRA-84.7%), followed by YXDM (SUCRA-84.4%), SXT (SUCRA-63.8%), HHHSS (SUCRA-60.7%), DS (SUCRA-60.6%), DZXX (SUCRA-58.1%), DH (SUCRA-56.3%), SX (SUCRA-53.2%), XST1 (SUCRA-49.0%), DZHS (SUCRA-47.7%), XST2 (SUCRA-45.5%), DSCXQ (SUCRA-43.1%), LI (SUCRA-39.2%), MLN (SUCRA-38.9%), and FFDS (SUCRA-3.9%). The results are shown in Fig. 6.
Figure 6
Fig. 6

SUCRA for the improvement of neurological impairment

Simultaneous ranking of the interventions for two outcomes

Clustered ranking plots of the network for the markedly effective rate and the improvement of neurological impairment score are shown in Fig. 7. Each color represents a group of treatments that belong to the same cluster. Treatments lying in the upper right corner are more effective than the other treatments. The upper right corner in Fig. 7 shows that SXN, YXDM, DH, SXT, HHHSS, DZXX and SX produce significantly better outcomes in ACI patients.
Figure 7
Fig. 7

Clustered ranking plot of the networks

Discussion

Considerable evidence exists regarding the clinical effectiveness of CHIs in ACI patients. Some CHIs have been widely used to strengthen clinical effectiveness, reduce neurological impairments and improve the patient’s quality of life. However, the majority of these findings have not been analyzed in head-to-head comparisons. Clinicians must decide among several therapeutic options for ACI patients. To address the absence of comparative data, we conducted an NMA to comprehensively estimate the effectiveness of different CHIs combined with AADN for ACI.

This NMA consisted of 64 RCTs that included 6225 participants; fifteen CHIs were identified in the treatment of ACI, including injections of SXN, SXT, SX, MLN, HHHSS, FFDS, DZHS, DZXX, DSCXQ, DS, DH, YXDM, LI, XST1, and XST2. In terms of the improvement of the markedly effective rate, DH had the highest likelihood of being the best treatment in terms of the markedly effective rate. On account of improvement of neurological impairment, SXN had the highest probability of being the best treatment.

The clustered ranking according to two outcomes revealed that the markedly effective rate and the improvement of the neurological impairment cluster were best for SXN, YXDM, DH, SXT, HHHSS, DZXX and SX. SXN and YXDM are shown at the top right corner. Previous meta-analyses [106108] found that SXN and YXDM as adjuvant treatments for ACI were beneficial compared to AADN alone. SXN and YXDM are Ginkgo biloba extracts (GBEs), both of which are extracted from Ginkgo biloba leaves. Ginkgo biloba leaves, the TCM for activating blood circulation, mainly contain ginkgo flavonoids, ginkgolides, and bilobalide and have been used as a therapeutic agent for managing cerebrovascular and neurological disorders [109, 110]. GBE exhibits a wide variety of biological activities, including anti-inflammation and antioxidant effects [111, 112]. ACI is the process whereby artery stenosis or blockage causes brain tissue hypoxic ischemia, resulting in brain dysfunction [6]. There is considerable evidence suggesting the active repair and recovery mechanisms following stroke, and neurogenesis is one of them [113]. GBE not only has antioxidant, anti-atherogenesis and angiogenic properties but can also strengthen repair and regeneration mechanisms and prevent cell death, protect the brain from further damage and improve neurological deficits following stroke [113115]. The neuroprotective mechanism has been attributed to the heme oxygenase 1 (HO1)/Wnt canonical pathway as well as neuritogenic and angiogenic effects [113, 116]. HO1, a key component of the EGb 761 neuroprotective signaling pathway, activates the signaling pathway mechanisms of angiogenesis, cell survival and neuroplasticity, and neurogenesis [113]. Thus, GBE could enhance the post-stroke regeneration process to improve treatments for stroke recovery. Further research is desirable to shed more light on the mechanism underlying the effects of GBE on ACI.

A NMA was used to compare the effectiveness of different CHIs to identify the best CHIs for ACI. This study is the first indirect comparison using a network approach to compare the effectiveness of CHIs, which is valuable for clinicians selecting CHIs for ACI treatment. However, some limitations existed in this NMA.

First, all trials reported random distribution, while ten studies described the randomization methods including random number tables or the envelope method. Information about allocation concealment and blinding was not clear in the majority of trials and may have therefore affected the reliability of the results. Second, the systematic review included only published studies in the database, with no relevant gray literature, which likely caused a selection bias in the literature. Third, the study aimed to use a NMA to evaluate the clinical effectiveness of 37 CHIs combined with an AADN regimen; however, only 15 CHIs were included in the NMA. Thus, more rigorously designed RCTs focused on the 22 additional CHIs are needed to confirm the effectiveness of CHIs for ACI. Fourth, due to the original research limitation, we failed to evaluate the long-term effect of CHIs. Additionally, with the limited data extracted from the original research, we failed to evaluate the ability of CHIs to improve the activities of daily living function and reduce mortality. Fifth, our results might have limited generalizability because all of the included RCTs were conducted in China among Chinese populations. Therefore, it is uncertain whether the effect may change when CHIs are used in populations of other ethnicities and in different geographical locations. In addition, though acute phases were limited, the severities of patient were various. This point may influence the results. Sixth, a NMA compares multiple treatments by incorporating direct and indirect evidence into a general statistical framework. One issue with the validity of a NMA is the inconsistency between direct and indirect evidence. Hence, to improve the reliability of our results, we used a random-effects model within a Bayesian framework. Although, head-to-head trials provide the highest level of evidence when comparing interventions, the quantity of data for some CHI direct trials was small, such as DH versus FFDS, SXN, and XSTT. Large RCTs are needed to specifically compare CHIs with one another.

Conclusions

In summary, our evidence suggested that DH injection plus AADN was the optimum treatment regimen for patients with ACI to improve the markedly effective rate. SXN injection plus AADN was the optimum treatment regimen for ACI to improve the neurological impairment score. Considering both the markedly effective rate and the improvement of neurological impairment, SXN, YXDM, DH, SXT, HHHSS, DZXX and SX plus AADN were the optimum treatment regimens for ACI, especially SXN + AADN and YXDM + AADN. In terms of limitations, highest levels of evidence need to support our conclusions.

Abbreviations

AADN: 

Aspirin + anticoagulants + dehydrant + neuroprotectant

ACI: 

Acute cerebral infarction

CBM: 

Chinese biomedical literature database

CHIs: 

Chinese herbal injections

CNKI: 

China national knowledge infrastructure database

CI: 

Credible interval

CT: 

Computed tomography

DH: 

Danhong injection

DS: 

Danshen injection

DSCXQ: 

Danshenchuanxiongqin injection

DZHS: 

Dengzhanhuasu injection

DZXX: 

Dengzhanxixi injection

FFDS: 

Fufangdanshen injection

GBEs: 

Ginkgo biloba extracts

HHHSS: 

Honghuahuangsesu injection

IF: 

Inconsistency factor

LI: 

Ligustrazine injection

MeSH: 

Medical subject heading

MLN: 

Mailuoning injection

MRI: 

Magnetic resonance imaging

NMA: 

Network meta-analysis

ORs: 

Odds ratios

RCTs: 

Randomized controlled trials

SMDs: 

Standardized mean differences

SUCRA: 

Surface under the cumulative ranking probabilities

SX: 

Shenxiong injection

SXN: 

Shuxuening injection

SXT: 

Shuxuetong injection

TCM: 

traditional Chinese medicine

XST1: 

Xueshuantong injection

XST2: 

Xuesaitong injection

YXDM: 

Yinxingdamo injection

Declarations

Funding

National Natural Science Foundation of China (Nos. 81473547 and 81673829).

Availability of data and materials

All data generated or analyzed during this study are included in the published article.

Authors’ contributions

Conception and design of the network meta-analysis: SL, JRW. Performance of the network meta-analysis: SL, DZ, and KHW. Quality assessment of the network meta-analysis: JRW, DZ, and BZ. Analysis of study data: XMZ, DT, and XJD. Writing of the paper: SL, YYC, and XKL. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Ethical approval was not necessary in the current meta-analysis because our meta-analysis only gathered RCTs from a literature search; hence, this procedure did not require any personal data and did not harm any patient.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China

References

  1. Luo JN. New progress on treating acute cerebral infarction. Pract J card Cereb Pneumal. Vasc Dis. 2010;18:1546–7.Google Scholar
  2. Hui Z, Sha DJ, Wang SL, et al. Panaxatriol saponins promotes angiogenesis and enhances cerebral perfusion after ischemic stroke in rats. BMC Complement Altern Med. 2017;17:70.PubMedPubMed CentralView ArticleGoogle Scholar
  3. Wang K, Zhang D, Wu J, et al. A comparative study of Danhong injection and Salvia miltiorrhiza injection in the treatment of cerebral infarction: a systematic review and meta-analysis. Med. 2017;96:e7079.View ArticleGoogle Scholar
  4. Inoue T, Kobayashi M, Uetsuka Y, Uchiyama S. Pharmacoeconomic analysis of cilostazol for the secondary prevention of cerebral infarction. Circ J. 2006;70:453–8.PubMedView ArticleGoogle Scholar
  5. Sun W, Ou Q, Zhang Z, et al. Chinese acute ischemic stroke treatment outcome registry (CASTOR): protocol for a prospective registry study on patterns of real-world treatment of acute ischemic stroke in China. BMC Complement Altern Med. 2017;17:357.PubMedPubMed CentralView ArticleGoogle Scholar
  6. Wei J, Yang W, Yin S, et al. The quality of reporting of randomized controlled trials of electroacupuncture for stroke. BMC Complement Altern Med. 2016;16:512.PubMedPubMed CentralView ArticleGoogle Scholar
  7. Wang KH, Wu JR, Liu S, Zhang D, Duan XJ, Zhang B. Meta-analysis on randomized controlled trials of xingnaojing injection for treating acute cerebral infarction. Chin J Pharmacoepidemiol. 2017;15:471–6.Google Scholar
  8. You YN, Cho MR, Kim JH, et al. Assessing the quality of reports about randomized controlled trials of scalp acupuncture combined with another treatment for stroke. BMC Complement Altern Med. 2017;17:452.PubMedPubMed CentralView ArticleGoogle Scholar
  9. Sun K, Fan J, Han J. Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage. Acta Pharm Sin B. 2015;5:8–24.PubMedPubMed CentralView ArticleGoogle Scholar
  10. Cao W, Liu W. Wu T, Zhong D, Liu G. Dengzhanhua preparations for acute cerebral infarction. Cochrane Database Syst Rev. 2008;63:CD005568.Google Scholar
  11. Liao P, Wang L, Guo L, Zeng R, Huang J, Zhang M. Danhong injection (a traditional Chinese patent medicine) for acute myocardial infarction: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2015;2015:646530.PubMedPubMed CentralGoogle Scholar
  12. Xie CL, Wang WW, Xue XD, Zhang SF, Gan J, Liu ZG. A systematic review and meta-analysis of Ginsenoside-Rg1 (G-Rg1) in experimental ischemic stroke. Sci Rep. 2015;5:7790.PubMedPubMed CentralView ArticleGoogle Scholar
  13. Li B, Wang Y, Lu J, Liu J, Yuan Y, Yu Y, et al. Evaluating the effects of Danhong injection in treatment of acute ischemic stroke: study protocol for a multicenter randomized controlled trial. Trials. 2015;16:561.PubMedPubMed CentralView ArticleGoogle Scholar
  14. Yu YC, Wu SZ, Hou Q. Clinical study on Xueshuantong combined with aspirinon in treatment of senium acute cerebral infarction. Drugs & Clinic. 2014;7:782–5.Google Scholar
  15. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997;349:1641–9.View ArticleGoogle Scholar
  16. The International Stroke Trial (IST). A randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International stroke trial collaborative group. Lancet. 1997;349:1569–81.View ArticleGoogle Scholar
  17. Edaravone Acute Infarction Study Group. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis. 2003;15:222–9.View ArticleGoogle Scholar
  18. Gu XL, Ding XS, Di Q. Clinical study on edaravone injection in treatment of acute cerebral infarction. Chinese J New Drugs Clin Remedies. 2005;24:113–6.Google Scholar
  19. Zhang M, Xu LJ, Deng LY. Efficacy and safety of Edaravone injection in the treatment of acute cerebral infarction: a randomized, double blind, multicenter study. Chinese J New Drugs Clin Remedies. 2007;26:105–8.Google Scholar
  20. Davalos A, Castillo J, Alvarez-Sabin J, Secades JJ, Mercadal J, López S, et al. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke. 2002;33:2850–7.PubMedView ArticleGoogle Scholar
  21. National Pharmacopoeia Committee. Chinese pharmacopoeia, part 1, Appendix 13. Beijing, China: Chemical Industry Press; 2005.Google Scholar
  22. Xie YY, Xiao X, Luo J-M, Fu C, Wang Q-W, Wang Y-M, et al. Integrating qualitative and quantitative characterization of traditional Chinese medicine injection by high-performance liquid chromatography with diode array detection and tandem mass spectrometry. J Sep Sci. 2014;37:1438–47.PubMedView ArticleGoogle Scholar
  23. Liu J, Liu F, Li PH. Analysis of the adverse reaction of traditional Chinese medicine injections activating blood stasis. China Pharmacy. 2011;22:646–8.Google Scholar
  24. Tan D, Wu JR, Liu S, Zhang B. Meta-analysis of efficacy of shuxuening injection in the treatment of cerebral infarction. J Pharmacoepidemiol. 2016;8:492–8.Google Scholar
  25. Wang X, Wu JR, Zhang D, Wang KH, Zhang B. Meta-analysis of efficacy of xueshuantong injection in the treatment of acute cerebral infarction. J Pharmacoepidemiol. 2016;10:616–22.Google Scholar
  26. Wang KH, Wu JR, Zhang D, Liu S, Zhang XM, Zhang B. Meta-analysis of efficacy of mailuoning injection in the treatment of acute cerebral infarction. J Pharmacoepidemiol. 2016;9:544–8. 590Google Scholar
  27. Duan XJ, Wu JR, Liu S, Zhang D, Fang J, Zhang B. Meta-analysis of efficacy of danshenchuanxiongqin injection in the treatment of acute cerebral infarction. J Pharmacoepidemiol. 2017;1:27–32.Google Scholar
  28. Liu X-T, Ren P-W, Peng L, Kang D-Y, Zhang T-L, Wen S, et al. Effectiveness and safety of ShenXiong glucose injection for acute ischemic stroke: a systematic review and GRADE approach. BMC Complement Altern Med. 2016;16:68.PubMedPubMed CentralView ArticleGoogle Scholar
  29. Wu J, Zhang XM, Zhang B. Qingkailing injection for the treatment of acute stroke: a systematic review and meta-analysis. J Tradit Chin Med. 2014;34:131–9.PubMedView ArticleGoogle Scholar
  30. Zhang X, Wu J, Zhang B. Xuesaitong injection as one adjuvant treatment of acute cerebral infarction: a systematic review and meta-analysis. BMC Complement Altern Med. 2015;15:36.PubMedPubMed CentralView ArticleGoogle Scholar
  31. Peng W, Yang J, Wang Y, Wang W, Xu J, Wang L, et al. Systematic review and meta-analysis of randomized controlled trials of Xingnaojing treatment for stroke. Evid Based Complement Altern Med. 2014;2014:210851.Google Scholar
  32. Wu B, Liu M, Liu H, Li W, Tan S, Zhang S, et al. Meta-analysis of traditional Chinese patent medicine for ischemic stroke. Stroke. 2007;38:1973–9.PubMedView ArticleGoogle Scholar
  33. Jinatongthai P, Kongwatcharapong J, Foo CY, Phrommintikul A, et al. Comparative efficacy and safety of reperfusion therapy with fibrinolytic agents in patients with ST-segment elevation myocardial infarction: a systematic review and network meta-analysis. Lancet. 2017;390:747–59.PubMedView ArticleGoogle Scholar
  34. Sun F, Chai SB, Li LS, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. J Diabetes Res. 2015;2015:157201.PubMedPubMed CentralView ArticleGoogle Scholar
  35. Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004;23:3105–24.PubMedView ArticleGoogle Scholar
  36. The fourth session of the National Cerebrovascular Conference. The norm of clinical neurologic deficit score. Chin J Neurol. 1996;29:381–3.Google Scholar
  37. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [EB/OL]. The Cochrane collaboration (2011). http://training.cochrane.org/handbook. Accessed 16 May 2013.
  38. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63:e1–37.PubMedView ArticleGoogle Scholar
  39. Salanti G, Ades AE, Ioannidis JPA. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64:163–71.PubMedView ArticleGoogle Scholar
  40. Riley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analyses. BMJ. 2011;342:d549.PubMedView ArticleGoogle Scholar
  41. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedPubMed CentralView ArticleGoogle Scholar
  42. Chaimani A, Higgins JPT, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One. 2013;8:e76654.PubMedPubMed CentralView ArticleGoogle Scholar
  43. Yu YM, Ran ZJ. Clinical study on 58 cases acute cerebral infarction treated by Danhong injection. Pract J Card Cereb Pneum Vasc Dis. 2009;17:477–8.Google Scholar
  44. Yu Y. Clinical study on Xueshuantong in treatment of acute cerebral infarction. Chinese Foreign Med Res. 2015;13:32–3.Google Scholar
  45. Zhang ZJ, Cao CY. Clinical study on Shenxiong glucose injection in treatment of acute cerebral infarction and its effect on plasma endothelin. J Guangdong Med Coll. 2008;26:408–9.Google Scholar
  46. Zheng XD. Curative effect with dipyridamole plus aspirin therapy in acute cerebral infarction. J Mod Clin Med. 2007;33:171–3.Google Scholar
  47. Zhou SJ. Study on Shenxiong glucose injection in treatment of acute cerebral infarction. Mod. Prev Med. 2011;38:2656–9.Google Scholar
  48. Zhou SF, Huo Y. Study on Ginkgo dipyridolum injection combined with aspirinon in treatment of acute cerebral infarction. J Mudanjiang Med Univ. 2009;20:56–8.Google Scholar
  49. Zhou SH. Effect of Shu Xue Ning injection on serum IL - 6 and its efficacy in patients with acute cerebral infarction. Zhejiang J Tradit Chin Med. 2013;48:923.Google Scholar
  50. Xu XY. Study on Ginkgo dipyridolum injection in treatment of acute cerebral infarction. In: Shandong province, the third integrated traditional Chinese medicine and western medicine academic symposium. Jinan; 2011. p. 268–270.Google Scholar
  51. Xie S, Cao C. Effect of Shuxuening injection in patients with acute cerebral infarction. J Med Theory Pract. 2011;24:1891–2.Google Scholar
  52. Xie YG, Zhou JH. Observation of effect of Suxuetong injection on acute cerebral infarction. China Trop Med. 2010;10:352–92.Google Scholar
  53. Xu LL, Meng QY, Tian L, Liu XH, Liu T. Curative effection of tetramethylpyrazine on acute cerebral infarction. J Pract Tradit Chinese Intern Med. 2011;25:57–8.Google Scholar
  54. Xu XQ. The observation of aplication of Ginkgo leaf extract and diphyridamole injection in the treatment of acute cerebral infarction. Chinese J Exp Tradit Med Formulae. 2012;18:211–3.Google Scholar
  55. Yang HJ. Effect of Xuetong injection in patients with acute cerebral infarction. J Pract Med Tech. 2007;14:2157.Google Scholar
  56. Yang YF. Study on Danhong injection combined with aspirinon in treatment of acute cerebral infarction. J Psychol Doctor. 2012;3:30.Google Scholar
  57. Yao QY, Gong SJ. Effect of Shuxuetong injection in patients with acute cerebral infarction. Mod J Integr Tradit Chinese Western Med. 2010;19:3389–90.Google Scholar
  58. Yao J, Lu XR. The observation of aplication of Ginkgo leaf extract and diphyridamole injection in the treatment of acute cerebral infarction. Clin Med. 2010;30:44–5.Google Scholar
  59. Xie RP. Clinical study on Shuxuening in treatment of acute cerebral infarction. Proc Clin Med. 2010;19:758–9.Google Scholar
  60. Tan SY, Tan ZL. Clinical study of Danhong injection in the treatment of cerebral infarction caused by branch atheromatous disease. J Shenyang Med Coll. 2016;18:18–20.Google Scholar
  61. Wang WP. Study on Ginkgo dipyridolum injection combined with Fufangdanshen injection in treatment of acute cerebral infarction. Shenzhen J Integr Tradit Chinese and Western Med. 2015;25:21–2.Google Scholar
  62. Ren HM. The observation of aplication of Shenxiong injection in the treatment of acute cerebral infarction. China Healthcare Innov. 2009;4:27.Google Scholar
  63. Sun HJ, Zheng MH, Liang TS. Effects of Chuangxiongqin injection on serum sCD40L and the level of hs-CRP in patients with angina pectoris. J Shanghai Univ Tradit Chin Med. 2013;27:39–41.Google Scholar
  64. Tang JP, Jiang P, Yang XY. Clinical efficacy and safety of safflower yellow pigment injection in the treatment of acute cerebral infarction. J Mod Med Health. 2013;29:2524–5.Google Scholar
  65. Tang FY, Zhang GW. Clinical study on 36 cases acute cerebral infarction treated by breviscapine injection. Chinese J Pract Med. 2009;36:51–2.Google Scholar
  66. Tang XJ. Study on Ginkgo damole injection combined with aspirinon in treatment of acute cerebral infarction. Hebei Med J. 2013;35:1188–9.Google Scholar
  67. Wang L. Clinical study on 48 cases acute cerebral infarction treated by Shenxiong glucose injection. China Foreign Med Treat. 2010;29:116.Google Scholar
  68. Wang YL, Zou XH, Dang LH. Expression of TNF-a and IL-6 in patients with acute cerebral infarction after clinical intervention of Shuxuetong injection and clinical significance. J Yunnan UnivTradit Chin Med. 2013;36:70–2.Google Scholar
  69. Lan Y, Xiao JX, Zheng TY, ZX L. Effect of salvia ligustrazin injection on lysophospholipids acid, P selection and its efficacy in patients with acute cerebral infarction. Mod J Integr Tradit Chinese Western Med. 2015;24:840–2.Google Scholar
  70. Li M, Li Q, Zhang M, Zhang XL, Hu Q, Pang Y. Effect of Dan Hong injection on serum S100B protein and neuron specific alcohol in patients with acute cerebral infarction. Herald Med. 2014;33:1596–9.Google Scholar
  71. Liu YP, Wang ZG, Wu H. Effect of Dan Hong injection on C-reactive protein and its efficacy in patients with acute cerebral infarction. Pract J Card Cereb Pneum Vasc Dis. 2010;18:1433–4.Google Scholar
  72. Ma J, Yu NW, Ren ZW, Chen M, Wu HH. Effect of breviscapine on serum NSE,Ang-2 and IL-6 levels and its efficacy in patients with acute cerebral infarction. Chinese J Biochem Pharm. 2010;35:110–2.Google Scholar
  73. Ma J, Yu NW, Wu HH, Chen M, Ren ZW, Zhao DD. Effect of Danhong injection on nerve function and hemorheology for patients with acute ischemic stroke. Chinese J Exp Tradit Med Formulae. 2015;21:204–7.Google Scholar
  74. Chen H. Clinical study on 67 cases acute cerebral infarction treated by Shuxuetong injection. Asia-Pacific Tradit Med. 2015;11:137–8.Google Scholar
  75. Luan T. The clinical effects of Xuesaitong injection in the treatment of acute cerebral infarction. Guide China Med. 2014;12:42–3.Google Scholar
  76. Huang ML. Clinical study on 150 cases acute cerebral infarction treated by Xueshuangtong injection. Mod Diagn Treat. 2012;23:2254–5.Google Scholar
  77. Li X, Zheng WW, Gao YB. Effect of carthamin yellow injection on NT-proBNP and TXB_2 for patients with acute ischemic stroke. Chinese J Integr Med Cardio/Cerebrovascular Dis. 2015;13:1900–2.Google Scholar
  78. Ma ZL, Wu BX, Cheng DM, Zhang XL, Hu Y. Clinic observation of the curative effect of safflor yellow in the treatment of acute cerebral infarction. Chinese J Pract Nerv Dis. 2011;14:30–1.Google Scholar
  79. Zhang Y, Hou J, Hu Y, Mu ZB, HY M. Study on Danshen Chuanxiongqin injection combined with edaravone in treatment of acute cerebral infarction. Chinese J Integr Med Cardio/Cerebrovascular Dis. 2012;10:168–9.Google Scholar
  80. Liu M. Study on Danshen Chuanxiongqin injection combined with edaravone in treatment of acute cerebral infarction. Mod J Integr Tradit Chinese Western Med. 2014;23:2105–7.Google Scholar
  81. Chen YC. Clinic observation of the curative effect of Ginkgo damole injection in the treatment of acute cerebral infarction. Chinese Foreign Med Res. 2011;9:45–6.Google Scholar
  82. Yang RF. Clinical research of edaravone combined with Shuxuetong in treating acute cerebral infarction. China J Chinese Med. 2013;28:1228–9.Google Scholar
  83. Lin YF, Wang ML, Huang ZQ, Yan P, Su Y. Clinical research of combined Ginkgo damole injection with aspirin in treating acute cerebral infarction. Proc Clin Med. 2008;17:761–2.Google Scholar
  84. Peng T, Pang YL. Clinic observation of the curative effect of Shuxuetong injection in the treatment of acute cerebral infarction. Pract J Card Cereb Pneum Vasc Dis. 2006;14:388.Google Scholar
  85. Li XH. Clinic observation of the curative effect of Shuxuening injection in the treatment of acute cerebral infarction. Asia-Pacific Tradit Med. 2011;7:129–30.Google Scholar
  86. Liu L, Yang XS, Chen W, Liu ZT. Clinic observation of the curative effect of Danhong injection in the treatment of acute cerebral infarction. Clin J Tradit Chin Med. 2014;26:166–7.Google Scholar
  87. Zhang YH, Liu WJ, Ding S. The clinical research of Danhong combinded with low molecular heparin calcium to treat the acute cerebral infarction. Pract J Card Cereb Pneum Vasc Dis. 2010;18:3–5.Google Scholar
  88. Fan J. Clinic observation of the curative effect of Ginkgo damole injection in the treatment of acute cerebral infarction. China Pharm. 2006;15:54.Google Scholar
  89. Liu HY, Liu YM. Clinical study on 64 cases acute cerebral infarction treated by Xuesaitong injection. Jilin Med J. 2014;2014:4963–4.Google Scholar
  90. Li FQ. Clinical study on 64 cases acute cerebral infarction treated by Ginkgo damole injection. Chinese J Ethnomed Ethnopharmacy. 2010;19:106.Google Scholar
  91. Lian CL. Clinical observation on 46 cases of acute cerebral infarction treated with combination of traditional Chinese and western medicine. J Pract Tradit Chin Med. 2013;29:456.Google Scholar
  92. Chen S, Jiang KW, Lu HZ. Clinic observation of the curative effect of Xuesaitong injection in the treatment of acute cerebral infarction. J Pract Med. 2006;22:1405–6.Google Scholar
  93. Cao L. Clinic observation of the curative effect of Xueshuangtong injection in the treatment of acute cerebral infarction. Chinese J Ethnomed Ethnopharmacy. 2012;21:71.Google Scholar
  94. Liu Y. Effective observation on acute cerebral infarction treated by Shuxuetong injection. Chinese J Med Guide. 2009;11:1157–8.Google Scholar
  95. Luo XD, Wang P, Zeng XR. Xuesaitong injection plus routine therapy for acute cerebral infarction and the influence on plasma C-reactive protein. Pract J Clin Med. 2011;8:96–8.Google Scholar
  96. Liao MJ, Chen ZB. Clinical study on 30 cases acute cerebral infarction treated by safflower yellow injection. Med Inf. 2014;27:109–10.Google Scholar
  97. Shi JL, Cheng JL. The clinical research of Ginkgo-damole combinded with atorvastatin calcium to treat the acute cerebral infarction. Chinese J Pract Nerv Dis. 2010;13:52–3.Google Scholar
  98. Ni H. Clinical study on 59 cases of Shuxuening combined with sodium ozagrel to treat the acute cerebral infarction. Jilin Med J. 2010;30:3078–9.Google Scholar
  99. Li CP. Clinical study on 80 cases acute cerebral infarction treated by Shuxuening injection. J Shanxi Coll Tradit Chin Med. 2007;8:37–8.Google Scholar
  100. Zhou ZP, Yang GS, Wang AY. Effect of erigeron injection on MMP- 9 in patient with acute cerebral infarction. Mod Prev Med. 2011;38:2660–1.Google Scholar
  101. Chen C. Efficacy and safety of aspirin plus clopidogrel and Shuxuetong in treatment of patients with acute cerebral infarction. Eval Anal Drug-Use Hosp China. 2015;15:808–10.Google Scholar
  102. Chen JY, Wang DC, Luo SW. Clinical study on 54 cases of Shuxuetong plus aspirin and clopidogrel to treat the acute cerebral infarction. China Pharmaceuticals. 2012;21:53–4.Google Scholar
  103. Luo QY. Clinic observation of the curative effect of Ginkgo bilboa injection in the treatment of acute cerebral infarction. Youjiang Med J. 2007;35:133–4.Google Scholar
  104. Chen J, Li SJ. Clinical observation of Ginkgo-dipyidamolum injection in treatment of acute cerebral infarction. Neural Inj Funct Reconstr. 2007;7:291–3.Google Scholar
  105. Zhang XL, Zhang LL, Heng XL, Ma Y, Pang W. Effect of Mailuoning injection on blood rheology for patients with acute ischemic stroke. Nerv Dis Mental Health. 2015;5:216–7.Google Scholar
  106. Ni HQ, Wu L, Li JF, Chen J. Meta-analysis of comparative study on Ginkgo dipyridolum injection in the treatment of acute cerebral infarction. China Pharm. 2008;19:1655–8.Google Scholar
  107. Xi BC, Zhang C, Sun LL. Meta-analysis of comparative study on Shuxuening injection in the treatment of acute cerebral infarction. Pharm Care Res. 2012;12:354–7.View ArticleGoogle Scholar
  108. Zheng WK, Zhang L, Shang HC. Systematic review on Shuxuening injection in treating acute cerebral infarction. Chinese Licensed Pharmacist. 2012;9:33–41.Google Scholar
  109. Rodríguez M, Ringstad L, Schäfer P, Just S, Hofer HW, Malmsten M, et al. Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients. Atherosclerosis. 2007;192:438–44.PubMedView ArticleGoogle Scholar
  110. Luo Y. Alzheimer's disease, the nematode Caenorhabditis elegans, and Ginkgo biloba leaf extract. Life Sci. 2006;78:2066–72.PubMedView ArticleGoogle Scholar
  111. Park Y-M, Won J-H, Yun K-J, Ryu J-H, Han Y-N, Choi S-K, et al. Preventive effect of Ginkgo biloba extract (GBB) on the lipopolysaccharide-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 via suppression of nuclear factor-κB in RAW 264.7 cells. Biol Pharm Bull. 2006;29:985–90.PubMedView ArticleGoogle Scholar
  112. Biddlestone L, Corbett AD, Dolan S. Oral administration of Ginkgo biloba extract, EGb-761 inhibits thermal hyperalgesia in rodent models of inflammatory and post-surgical pain. Br J Pharmacol. 2007;151:285–91.PubMedPubMed CentralView ArticleGoogle Scholar
  113. Nada SE, Tulsulkar J, Shah ZA. Heme oxygenase 1-mediated neurogenesis is enhanced by Ginkgo biloba (EGb 761®) after permanent ischemic stroke in mice. Mol Neurobiol. 2014;49:945–56.PubMedView ArticleGoogle Scholar
  114. Tulsulkar J, Shah ZA. Ginkgo biloba prevents transient global ischemia-induced delayed hippocampal neuronal death through antioxidant and anti-inflammatory mechanism. Neurochem Int. 2013;62:189–97.PubMedView ArticleGoogle Scholar
  115. Chen J-S, Huang P-H, Wang C-H, Lin F-Y, Tsai H-Y, Wu T-C, et al. Nrf-2 mediated heme oxygenase-1 expression, an antioxidant-independent mechanism, contributes to anti-atherogenesis and vascular protective effects of Ginkgo biloba extract. Atherosclerosis. 2011;214:301–9.PubMedView ArticleGoogle Scholar
  116. Shah ZA, Nada SE, Doré S. Heme oxygenase 1, beneficial role in permanent ischemic stroke and in Ginkgo biloba (EGb 761) neuroprotection. Neuroscience. 2011;180:248–55.PubMedPubMed CentralView ArticleGoogle Scholar

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