Promoting blood circulation for removing blood stasis therapy for acute intracerebral hemorrhage: a systematic review and meta-analysis

Acta Pharmacologica Sinica, May 2015

Aim: To conduct a systematic review and meta-analysis to assess the current evidence available regarding the promoting blood circulation and removing blood stasis (PBCRBS) therapy for Chinese patients with acute intracerebral hemorrhage (ICH). Methods: Six databases were searched from their inception to November 2013. The studies assessed in ≥4 domains with 'yes' were selected for detailed assessment and meta-analysis. The herbal compositions for PBCRBS therapy for acute ICH patients were also assessed. Results: From the 6 databases, 292 studies claimed randomized-controlled clinical trials (RCTs). Nine studies with 798 individuals were assessed in ≥4 domains with 'yes' by using the Cochrane RoB tool. Meta-analysis showed that PBCRBS monotherapy and adjuvant therapy for acute ICH could improve the neurological function deficit, reduce the volume of hematoma and perihematomal edema, and lower the mortality rate and dependency. Moreover, there were fewer adverse effects when compared with Western conventional medication controls. Xueshuantong Injection and Fufang Danshen Injection, Buyang Huanwu Decoction and Liangxue Tongyu formula, and three herbs (danshen root, sanqi and leech) were the most commonly used Chinese herbal patent injections, herbal prescriptions and single herbs, respectively. Conclusion: Despite the apparently positive findings, it is premature to conclude that there is sufficient efficacy and safety of PBCRBS for ICH because of the high clinical heterogeneity of the included studies and small number of trials in the meta-analysis. Further large sample-sizes and rigorously designed RCTs are needed.

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Promoting blood circulation for removing blood stasis therapy for acute intracerebral hemorrhage: a systematic review and meta-analysis

Abstract Aim: To conduct a systematic review and meta-analysis to assess the current evidence available regarding the promoting blood circulation and removing blood stasis (PBCRBS) therapy for Chinese patients with acute intracerebral hemorrhage (ICH). Methods: Six databases were searched from their inception to November 2013. The studies assessed in ≥4 domains with 'yes' were selected for detailed assessment and meta-analysis. The herbal compositions for PBCRBS therapy for acute ICH patients were also assessed. Results: From the 6 databases, 292 studies claimed randomized-controlled clinical trials (RCTs). Nine studies with 798 individuals were assessed in ≥4 domains with 'yes' by using the Cochrane RoB tool. Meta-analysis showed that PBCRBS monotherapy and adjuvant therapy for acute ICH could improve the neurological function deficit, reduce the volume of hematoma and perihematomal edema, and lower the mortality rate and dependency. Moreover, there were fewer adverse effects when compared with Western conventional medication controls. Xueshuantong Injection and Fufang Danshen Injection, Buyang Huanwu Decoction and Liangxue Tongyu formula, and three herbs (danshen root, sanqi and leech) were the most commonly used Chinese herbal patent injections, herbal prescriptions and single herbs, respectively. Conclusion: Despite the apparently positive findings, it is premature to conclude that there is sufficient efficacy and safety of PBCRBS for ICH because of the high clinical heterogeneity of the included studies and small number of trials in the meta-analysis. Further large sample-sizes and rigorously designed RCTs are needed. Introduction Spontaneous intracerebral hemorrhage (ICH) is one of the most detrimental subtypes of stroke. It accounts for 10%–15% of all strokes and is an important public health problem that leads to significant morbidity and mortality1. The epidemiological perspective on ICH remains bleak. ICH affects 24.6 per 100 000 person-years; the median case fatality within 1 month was 40.4%, and the functional dependency after ICH was approximately 75%2. In China, a nation of 1.4 billion, which accounts for almost one-fifth of the world's total population, stroke is already the leading cause of death3. In addition, a recent systematic review showed that the Chinese have higher overall stroke incidence. ICH accounts for a higher proportion of stroke in Chinese than the white population4. Currently, no specific therapies or treatments improve the outcome after ICH. The updated evidence-based guidelines for the management of ICH from the American Heart Association/American Stroke Association remain multifaceted; most recommendations are symptomatic and supportive5. In the trial in surgery, the results of spontaneous supratentorial lobar intracerebral hematomas (STICH II) confirmed that early surgery did not increase the rate of death or disability at 6 months. This suggested that there is a small survival advantage for patients with ICH who did not have intraventricular hemorrhage6. Acute hemostatic management is not usually recommended to control bleeding in ICH guidelines; the exception is rare cases, such as those including oral anticoagulants, coagulation factor deficiencies, and platelet abnormalities, in which underlying hemostatic abnormalities may contribute to ICH7. Although hemostatic therapy with rFVIIa can limit the extent of hematoma expansion in noncoagulopathic ICH patients, there is an increase in thromboembolic risk with rFVIIa, and the survival or functional outcome after ICH is not increased8. Faced with the limitations of the present available treatments, complementary and/or alternative medicine (CAM) is thus increasingly sought to treat stroke worldwide. In China, traditional Chinese medicine (TCM), including various forms of herbal medicine, acupuncture, massage (Tuina), exercise (qigong), and dietary therapy, has been used to treat stroke patients for over 2000 years9. In fact, TCM was the major available method of healthcare in the western pacific region of the world before modern Western medicine was introduced. However, stroke was divided into ischemic and hemorrhagic until the end of the Qing Dynasty (1616–1911). A brief history of TCM application in acute ICH has been summarized by Zheng et al10as follows: (1) before the 1950s–1960s, the pathogenesis of acute ICH emphasized up-stirring of the liver and adverse-rising of both blood and qi; (2) from the 1970s, the central pathogenesis of acute ICH has been considered as a blocked passage of the middle Jiao, a disorder of qi in ascending and descending and abnormal flow of qi and blood; (3) from the 1980s, it was claimed that the vital pathogenesis of acute ICH was blood stasis; (4) in recent years, theories of endogenous toxins and deficient vital qi have been developed. However, blood stasis syndrome can be found throughout the pathological process of ICH under the TCM theory of 'abnormal flow of the blood is blood stasis' in Xuezheng Lun (On Blood Syndromes), written by Tang Rong-chuan during the Qing Dynasty. Thus, the key point of the treatment method for ICH was promoting blood circulation for removing blood stasis (PBCRBS). Blood stasis, known as 'Oketsu' in Japanese, 'Xueyu' in Chinese and 'Eohyul' in Korean, refers to whenever the circulation of blood is not smooth or the blood flow is stagnant and forms stasis11. Although the consensus among the interviewed experts was that the definition of blood stasis is rather complicated and that there is no gold standard marker for detecting blood stasis12, blood stasis refers to a group of distinct syndromes. Over the following three decades, there have been a number of clinical trials to evaluate the efficacy and safety of the PBCRBS method for acute ICH. Therefore, the objective of the present systematic review is to assess the current evidence available regarding the PBCRBS method for patients suffering from acute ICH. Methods Standard protocol registration This systematic review was registered in PROSPERO, and the registration identifier of the protocol is CRD4201400900313. Study criteriaTypes of studies Only randomized controlled clinical trials (RCTs), which evaluate the efficacy and safety of the PBCRBS prescription for acute ICH, were included in the qualitative analyses, regardless of blinding, publication status or language. We included the RCTs assessed in ≥4 domains with 'yes' for the analyses using the Cochrane RoB tool14,15. Quasi-RCTs, taking those using the admission sequence for treatment allocation as example, were not considered. Types of participants: patients of any gender, age, or race/ethnicity with ICH within 14 d from the onset were included. The ICH was diagnosed according to the Chinese national criteria in Diagnostic Essentials of Various Cerebrovascular Diseases revised at the Fourth National Conference of the China Society of Medicine on Cerebrovascular Diseases in 199516. The diagnosis of ICH was confirmed by CT scan or MRI. Types of interventions The patients of the control groups were given Western conventional medication (WCM), WCM plus stereotactic microsurgery (SM), or placebo alone. The patients at the treatment groups were given PBCRBS intervention as add-on therapy, which included PBCRBS prescriptions, Chinese patent herbal oral preparations, and Chinese patent herbal injections. PBCRBS therapy was defined as the use of common blood-invigorating and stasis-removing herbal prescriptions, based on the Eight Principles plus differentiation between qi and blood11, and any Chinese patent herbal preparation that comes from commonly used blood-invigorating and stasis-removing herbs based on both TCM theory and Western medicine. Studies comparing different forms of TCM were excluded. The clinical trials were included regardless of the dosage or duration of treatment. The mode of delivery was the oral route or injection route. Types of outcome measurements The primary outcome measures were mortality and dependency at the end of the treatment course or at the end of follow-up. Dependency was defined as needing assistance in the activity of daily living scale (ADL), using the Barthel Index (BI) and modified Rankin Standard (mRS). The secondary outcome measures were the clinical effective rate, the neurological deficit improvement, volume of hematoma, volume of perihematomal edema and adverse events. The neurological deficit improvement was assessed using the Chinese Clinical Neurological Deficit Scale (CCNDS) and National Institutes of Health Stroke Scale (NIHSS) score after treatment. Literature search A comprehensive literature search was conducted in CENTRAL (The Cochrane Library), PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), VIP Journals Database and the Wanfang database from inception to December 2013. The search terms used were '(Promoting Blood Circulation OR Removing Blood Stasis) AND (intracerebral hemorrhage OR hemorrhagic stroke)' in English and (Huoxue OR Huayu) AND (Naochuxue OR Chuxuezhongfeng) in Chinese pinyin in the Chinese databases. The search was restricted to clinical trials or reviews. No limitation was placed on publication date, country or language. The reference lists of all relevant articles were also searched for appropriate studies. Study selection and data collection process All articles were screened by 2 independent reviewers, who extracted data from the articles according to a standardized data extraction form, including study design, patients' characteristics (age, gender, and onset of ICH), PBCRBS treatment protocol, control intervention, and outcome parameters. The reasons for inclusion and exclusion of studies were recorded at all stages. For eligible studies, 2 authors of this work extracted the data independently. The missing data were obtained by contacting the authors of the original studies. Disagreements were settled through discussion or consultation with corresponding authors. Risk of bias and grading the quality of evidence The risk of bias was assessed using the 7 criteria recommended by the Cochrane Handbook17. We included the RCTs assessed in ≥4 domains with 'yes' for the analyses; ie, we excluded those cases assessed in ≥3 domains with 'unclear' or 'no' which were classified as having a high risk of bias14,15. The level of evidence was assessed by the updated GRADE system18. We classified evidence into 4 grades: high quality, moderate quality, low quality and very low quality. The low and very low quality of evidence showed a serious limitation in the study design, study quality, consistency, directness of the evidence and precision of the results. Description of the herbal medicine and herbal prescription The selection criteria of high-frequency herbs and herbal prescriptions in the treatment of ICH were those with cumulative frequencies of over 50%. Data analysis All data analyses were performed using Review Manager 5.1.0, compiled by the Cochrane Collaboration. The risk ratio (RR), with a 95% confidence interval (CI), was calculated for dichotomous outcomes, whereas weighted mean differences (WMD) or standardized mean differences (SMD) were used for continuous outcomes. Heterogeneity was examined by the chi-square test at a significance level of 0.05. An I2 statistic was also calculated to estimate variation among studies as follows: I2 values of 25%, 50%, and 75% correspond to low, moderate, and high level of heterogeneity, respectively. However, on account of the clinical heterogeneity, all meta-analyses were performed using a random-effect model. Publication bias was detected by funnel plot analyses. Two-tailed P values less than 0.05 were considered statistically significant. Results Description of the selection process We identified 3426 potentially relevant articles from 6 databases. After removal of duplicates, 1330 records remained. After going through the titles and abstracts, we excluded 594 studies for at least one of following reasons: (1) the study was a case report or review, (2) not a clinical trial, or (3) did not include Chinese herbs and formulas for promoting blood circulation and removing blood stasis. By reading the full texts of the remaining 736 articles, we excluded 444 studies for at least one of following reasons: (1) there were no RCTs or no real RCTs, (2) the study did not include the acute phase of intracerebral hemorrhage, or (3) the study compared TCM or acupuncture. The remaining 292 studies examining the efficacy of Chinese herbs and formulas were included for qualitative analysis. Of the 292 studies, 9 studies assessed ≥4 domains with 'yes'; these were selected for detailed assessment and meta-analysis. The flow diagram is shown in Figure 1. Figure 1 PRISMA 2009 flow diagram. Full size image Download PowerPoint slide Description of the studies The sample sizes of the 9 studies ranged from 21 to 213, with a total of 830 subjects (Table 1). All studies were carried out in China and published in Chinese language journals from 2000 to 2013. The criteria used in these 9 studies for diagnosis of ICH were the Chinese Cerebrovascular Disease Diagnosis Standard 1995 (CCDDS 1995). Of the 9 studies, 5 studies compared PBCRBS plus WCM with WCM alone, 2 studies19,20 compared PBCRBS plus WCM plus SM with WCM plus SM, one21 compared PBCRBS plus WCM plus SM with WCM alone, and only one22 used a placebo control. The subjects' durations of ICH reported in the 9 studies were all within 3 d. The course of PBCRBS treatment lasted 10 d to 8 weeks in the 9 studies. Seven of the 9 studies reported follow-up; follow-up was from 30 d to one year after finishing treatment. Table 1: The characteristics of included studies. Full size table Assessment by the Cochrane's risks of bias Eight of the 9 studies had at least one domain rated as high risk of bias19,20,21,23,24,25,26,27 (Table 2). In the double-blind study, none of the domains were rated as having high risks of bias. In the 2 single-blind studies, the blinding procedure was not described, and there was a high risk of bias in concealment of allocation. In the 6 open-label studies, there were high risks of bias both in concealment of allocation and blinding: neither the subjects nor the evaluators were blinded. Table 2: Assessment of study quality and risk of bias. Full size table Description of the PBCRBS herbs and prescriptions A total of 41 standardized Chinese herbal formulas were examined in 229 (78.4%) of the 292 studies, while the other 63 studies used an individualized approach. The top 8 herbal formulas were used in 142 (48.6%) of the 292 reviewed studies (Table 3). These included Xueshuantong Injection (11.3%), an extract from Sanqi (Radix Notoginseng); Fufang Danshen Injection/Xiangdan Injection (10.3%), composition of Danshen (Radix Salviae miltiorrhizae) and Jiangxiang (Lignum Dalbergiae Odoriferae); Danshen Injection (7.9%), an extract from Danshen root; Shuxuetong Injection (5.5%), composition of Shuizhi (Hirudo) and Dilong (Lumbricus); Shuxuening injection/Yinxingye Preparations (4.1%), an extract from Yinxingye (Folium Ginkgo); Dengzhan Xixin Injection/Dengzhan Huashu Injection (3.8%), an extract from Dengzhan Xixin (Herba Erigerontis); Buyang Huanwu decoction (3.1%), and Liangxue Tongyu Injection/Liangxue Tongyu oral liquid (2.7%). These commonly used prescriptions corresponded to syndromes, including the syndrome of blood stasis (due to bleeding), syndrome of stagnation of qi and blood stasis, syndrome of blood stasis due to blood deficiency, syndrome of intermingled phlegm and blood stasis, syndrome of blood stasis, syndrome of blood stasis due to coagulated cold, syndrome of blood stasis due to qi deficiency, and syndrome of blood stasis due to heat toxicity, respectively (Table 3). Seven out of the 8 prescriptions are Chinese herbal patent preparations, which are quality controlled for manufacturing methods. In addition, 6 Chinese herbal patent preparations all have injection preparations, which are more convenient during a stroke emergency. The remaining preparation is a famous Chinese herbal prescription, Buyang Huanwu decoction, which is specifically used to treat stroke, according to the theory of qi deficiency and blood stasis recorded in Yilin Gaicuo (Correction of Errors in Medical Classics), written by Wang Qingren in 1830. Table 3: The most commonly used prescription corresponding to syndrome and pharmacological study for acute intracerebral hemorrhage. Full size table The numbers of Chinese herbs in the formulas varied from 1 to 9. The top 15 single herbs are shown in Table 4. Danshen (Radix Salviae miltiorrhizae) was the most frequently used single herb; it was used in 109 (37.3%) of the 292 studies. This was followed by Sanqi (Radix Panax notoginseng) (36.3%), Shuizhi (Hirudo) (30.1%), Chuanxiong (Rhizoma Ligustici Chuanxiong) (27.4%), Taoren (Semen Persicae) (23.3%), Chishao (Radix Paeoniae rubra) (20.2%), Honghua (Flos Cartham) (19.9%), Dilong (Lumbricus) (18.8%), Danggui (Radix Angelicae sinensis) (16.8%), Chuanniuxi (Radix Cyathulae) (13.0%), Jiangxiang (Lignum Dalbergiae Odoriferae) (12.0%), Huangqi (Radix Astragali seu Hedysari) (6.8%), Yujin (turmeric root tuber, Curcuma longa) (5.5%), Shexiang (musk) (5.1%), and Quanxie (scorpion) (4.5%). Table 4: The most commonly used herbs for acute intracerebral hemorrhage. Full size table Efficacy assessmentMortality The mortality was reported in 7 of the 9 studies. Meta-analysis showed that PBCRBS treatment significantly reduced the mortality rate in the trial group compared with the control group. The risk ratio in the 7 studies varied from 0.24 to 0.86, with an overall risk ratio of 0.50 (95% CI: 0.35 to 0.71, P<0.05, I2=0%, Figure 2). In the double-blind placebo control study22, the risk ratio was 0.41, which was lower than the overall risk ratio. Figure 2 The forest plot: mortality rate. Full size image Download PowerPoint slide ADL score The Barthel Index was used in 2 studies22,27 and evaluated at 90 d after PBCRBS treatment. There were significant differences between the PBCRBS group and the control group (1.86, 95% CI: 1.39 to 2.49, P<0.05, I2= 0%, Figure 3). In addition, the mRS was used in Chen's study22. At the last time point investigated, there were 60 patients (55.5%) who achieved a good outcome (mRS 0, 1, 2) in the PBCRBS group and 30 patients (28.5%) in the control group; there were significant differences among these studies, according to the Cochran-Mantel-Hansel (CMH) test (P=0.048). For the subjects who began treatment within 24 h after an attack, there were 5 patients (4.6%) who had severe disability (mRS 4, 5, 6) in the PBCRBS group and 9 patients (8.6%) in the control group; there were no significant differences between these groups, according to the CMH test (P=0.741). For the subjects who began treatment between 24 and 48 h after the attack, there were 5 patients (5.1%) who had severe disability (mRS 4, 5, 6) in the PBCRBS group and 15 patients (16.7%) in the control group; there was a significant difference between these two groups, according to the CMH test (P=0.048). For the subjects who began treatment between 48 and 72 h after an attack, there were 7 patients (7.5%) who had severe disability (mRS 4, 5, 6) in the PBCRBS group and 19 patients (21.2%) in the control group; there were significant differences between these groups, according to the CMH test (P=0.031). Figure 3 The forest plot: the barthel index. Full size image Download PowerPoint slide Clinical effective rate The clinical efficacy was reported in 3 of the 9 studies. The definition of effective rate was not standardized. It was defined according to CCNDS 1995 in 2 studies20,26 and according to the clinical guidelines for new drugs for TCM28 in the remaining 1 study24. The risk ratio of clinical efficacy in the 3 studies varied from 1.35 to 1.59, with an overall risk ratio of 1.44 (95% CI: 1.16 to 1.78, P<0.05, I2=0%, Figure 4); for the SM group20, the risk ratio was 1.35; for the non-SM groups24,26, the risk ratios were 1.47 and 1.59, respectively. Figure 4 The forest plot: Clinical effective rate. Full size image Download PowerPoint slide Volume of hematoma The volume of hematoma was used as an outcome measure in 3 of the 9 studies; the volume was evaluated at 14 and 28 d after PBCRBS treatment. Meta-analysis showed that PBCRBS treatment significantly reduced the volume of hematoma in the trial group when compared with the control group (−2.72, 95% CI: −4.12 to −1.32, P<0.05, I2=77%). The volume of hematoma in the trial group was more significantly reduced than that in the control group at 28 d (−2.05, 95% CI: −2.89 to −1.22, P<0.05, I2=0%) after PBCRBS treatment, but not at 14 d (−3.21, 95% CI: −6.34 to −0.09, P=0.04, I2=91%, Figure 5). Figure 5 The forest plot: volume of hematoma. Full size image Download PowerPoint slide Volume of perihematomal edema The volume of perihematomal edema was used as an outcome measure in 3 of the 9 studies and evaluated at 7, 14, and 21 d after PBCRBS treatment. Meta-analysis showed that PBCRBS treatment significantly reduced the volume of perihematomal edema in the trial group compared with the control group (−5.84, 95% CI: −8.62 to −3.06, P<0.05, I2=95%). After PBCRBS treatment, significant differences between the trial group and control group were detected at 21 d (−7.27, 95% CI: −7.91 to −6.64, P<0.05, I2=0%), but not at 7 d (−3.08, 95% CI: −7.23 to 1.07, P=0.15, I2=54%) or 14 d (−7.39, 95% CI: −15.06 to 0.28, P=0.06, I2=88%, Figure 6). Figure 6 The forest plot: volume of perihematomal edema. Full size image Download PowerPoint slide NIHSS score Two19,26 of the 9 studies used NIHSS scores to determine the effect of PBCRBS on the neurological function of the patients. The NIHSS score was assessed at 14 and 28 d after PBCRBS treatment. The overall results indicate that the PBCRBS group had a measurably better recovery of neurological functions than the control group (−5.34, 95% CI: −7.14 to −3.53, P<0.05, I2=92%). Furthermore, the NIHSS score in the PBCRBS group was significantly lower when compared with the control group at 14 d (−4.75, 95% CI: −5.57 to −3.93, P<0.05, I2=0%) and 28 d (−5.68, 95% CI: −8.87 to −2.49, P<0.05, I2=94%, Figure 7). Figure 7 The forest plot: national institute of health stroke scale (NIHSS) score. Full size image Download PowerPoint slide CCNDS score The CCNDS score was used in 2 studies25,27 and assessed at 14, 30 and 90 d following PBCRBS treatment. Meta-analysis showed that PBCRBS treatment significantly reduced the CCNDS score in the trial group compared with the control group (−4.50, 95% CI: −6.44 to −2.57, P<0.05, I2=83%). After PBCRBS treatment, significant differences between the trial group and control group were detected at 30 d (−5.38, 95% CI: −7.73 to −3.03, P<0.05, I2=52%) and 90 d (−2.96, 95% CI: −3.99 to −1.92, P<0.05, I2=83%), but not at 14 d (−4.74, 95% CI: −10.49 to 1.01, P=0.11, I2=90%, Figure 8). Figure 8 The forest plot: Chinese clinical neurological deficit scale (CCNDS) score. Full size image Download PowerPoint slide Adverse event reporting Adverse events were reported in 2 of the 9 studies and not mentioned in the remaining 7 studies. Chen et al22 reported that there were 24 cases of adverse events related to drugs and 2 cases of serious adverse events in the trial group, but there were 41 cases of adverse events and 6 cases of serious adverse events in the control group. The frequency of adverse events in this study was 26/108 in the trial group and 47/105 in the control group. Fan et al24 reported 7 types of adverse events, including 2 cases of mild diarrhea, 3 cases of mild epigastric discomfort, 3 cases of transient renal damage, 5 cases of electrolyte imbalances, and 1 case of melena in the trial group; there were 8 cases of transient renal damage, 17 cases of electrolyte imbalances, 3 cases of transient liver damage, 6 cases of melena and 1 case of hematemesis in the control group. GRADE profile evidence Quality assessment of the evidence is shown in Table 5. The quality of evidence in the outcomes of the clinical effectiveness rate, Barthel Index (90 d), volume of perihematomal edema (21 d), volume of hematoma (28 d), and neurological deficit scores (NIHSS score and CCNDS score) were high; the quality of evidence in the outcomes of mortality rate, volume of perihematomal edema (7 d and 14 d), and volume of hematoma (14 d) were moderate. Table 5: The updated GRADE profile. Full size table Discussion Summary of evidence This study is an updated systematic review and meta-analysis of the efficacy and safety of PBCRBS for ICH. Two hundred and 29 studies claimed RCTs. Nine better quality studies with 798 individuals assessed in ≥4 domains with 'yes' were identified based on the Cochrane RoB tool. The main findings were that PBCRBS monotherapy and adjuvant therapy for acute ICH could improve neurological function deficits, reduce the volume of hematoma and perihematomal edema, and lower the mortality rate and dependency; there were fewer adverse effects in comparison with WCM controls. The quality of the evidence was mostly moderate to high, according to the quality assessment, using the GRADE methodology and profiler. Despite the apparently positive findings, it is premature to conclude that there is increased efficacy and safety of PBCRBS for ICH because of the high clinical heterogeneity of the included studies and small number of trials in the meta-analysis. Limitations There are several limitations to this review. First, none of included studies in this review had been formally registered. Thus, protocols were not available to confirm free of selective reporting29. Second, although the strength of this systematic review and meta-analysis was that all the RCTs included were of better quality and assessed in ≥4 domains with 'yes', we did acknowledge some methodological weaknesses in the primary studies, such as allocation concealment and blindedness. Research outcomes could possibly be influenced by either the selection bias or the observer bias. Third, among the 9 included studies, only one22 used a formal placebo control. Because of the lack of placebo controls, the interpretation of the positive findings of treatment with Chinese herbal medicine (CHM) should be made with caution. Fourth, most of the included studies were of relatively small sample size and did not include a formal sample size estimation. Trials with inadequate sample sizes often run the risk of overestimating intervention benefits30. Fifth, the clinical heterogeneity compromised the validity of the included studies. There were large variations in the formulation, dosage, administration, and duration of treatments of the CHM in the included studies. Implications for practice Based on a brief overview of TCM application history of acute ICH10, the main methods for ICH were the following: (1) subduing the liver yang, calming down the internal wind and clearing heat; (2) purging the Fu organ and the harmony of qi and blood; (3) PBCRBS; and (4) anti-toxin or benefiting vital qi. However, PBCRBS is the essence of the TCM treatment method for ICH because blood stasis syndrome can be found throughout the pathological process of ICH. On a practical level, this systematic review provides premature evidence for the efficacy and safety of PBCRBS therapy after acute ICH; the evidence remains limited because of the high clinical heterogeneity and small number of trials included. However, it should be remembered that a lack of scientific evidence does not necessarily mean that the treatment is ineffective31. Modern pharmacological studies further supported the potential use of PBCRBS therapy for acute ICH as follows (1) Sanqi (Radix Notoginseng) could ameliorate brain edema by inhibiting the expression of AQP-432 and decreasing thrombin generation33, protect neurons and abate neuronal apoptosis by decreasing the expression of Bax and increasing Bcl-234, and protect neurons by regulating excitatory amino acid receptors35; (2) Danshen (Radix Salviae miltiorrhizae) could ameliorate brain edema by decreasing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) activity36, and protect neurons and abate neuronal apoptosis by deceasing caspase-337; (3) Shuizhi (Hirudo) could ameliorate brain edema as a thrombin inhibitor38, improve the development of hyperplasia of the capillaries, glial cells and their respective activities39; (4) an extract from Yinxingye (Folium Ginkgo biloba) could abate neuronal apoptosis by decreasing the expression of Bax and caspase-3 and increasing Bcl-240, protect the brain against inflammatory injury by the inhibition of interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1 mediated neutrophil infiltration41; (5) an extract from Dengzhan Xixin (Herba Erigerontis) could protect neurons by decreasing inflammatory factors, including TNF-α and IL-8 in the brain areas around the hemorrhagic focus42, alleviate secondary nerve damage by repressing the expression of ICAM-143; (6) Buyang Huanwu decoction could improve the neurological function deficits and alleviate brain edema through inhibition of AQP-4 expression44, prohibit neuronal apoptosis and promote absorption of the hematoma through decreasing the expression of activated caspase-345, enhance angiogenesis by promoting the expression of VEGF46; and (7) Liangxue Tongyu preparations could ameliorate brain edema and facilitate hematoma removal through up-regulation of t-PA and tissue inhibitor of metalloproteinase-1, and down-regulation of matrix metalloproteinase-947,48. These herbal preparations may clinically contribute to further combating ICH. It is worth noting that PBCRBS for acute ICH may raise a concern regarding the enlargement of the hematoma because doctors are afraid of potentially increasing bleeding. In actuality, hematoma size and hematoma expansion is an independent predictor of mortality and functional outcomes49. It has been well established that initial hemorrhage volume in approximately one-third of spontaneous ICH patients is not static but frequently progresses, usually within the early 6 h after the ictus50. Thus, the selection of patients at high risk for hematoma enlargement is crucial for PBCRBS treatment. Although most studies reporting PBCRBS therapy did not increase or reduce hemorrhage volume and mortality rate, an issue of hematoma expansion may still warrant consideration. In addition, Nie et al51 reported that Panax Notoginseng saponins were used in treating ICH patients with large amounts of hematoma at super-early stages, which may worsen brain edema and increase the nerve defect score, although it could promote the absorptance of the hematoma. Thus, we suggest several aspects for safety considerations as follows: (1) the contrast extravasation on CT angiography (CTA) is a well-established imaging predictor for subsequent hematoma expansion that may be used as a useful imaging marker to guide therapies; (2) a number of risk factors have been associated with hematoma progression, such as an irregularly shaped hematoma, coagulation abnormalities, hyperglycemia, hypertension, and anticoagulation. These risk factors should be controlled when the levels are compatible; (3) PBCRBS therapy is best to use 24 h, or at least 6 h, after ICH onset; (4) the most common herbs and prescriptions, especially their method of treatment, that are identified in the present study may be used prior to the clinic visit; (5) intensive monitoring of adverse reactions related to PBCRBS use in ICH patients should be performed. Implications for further research This work identifies some key areas for further research. Firstly, PBCRBS is widely used in the treatment of ICH. The most common herbal preparation is a promising candidate for further mechanism study and clinical trial of ICH. For example, thrombin plays dual roles both in brain injury and in brain protection after ICH; its deleterious effects come either from resident neural cells or from prothrombin in the blood52. Hirudin, a thrombin inhibitor, is a naturally occurring peptide in the salivary glands of medicinal leeches (such as Hirudo medicinalis) that has a blood anticoagulant property. An upcoming random double-blind controlled clinical trial will investigate the safety and efficacy of acute ICH treated with Hirudo and Tabanus PBCRBS therapy. The question whether the traditional methods can influence brain hematoma enlargement must be verified. This study is currently recruiting participants53. Secondly, disease-syndrome combination mainly refers to the idea and theory of disease differentiation in Western medicine as well as syndrome differentiation in TCM. The syndrome is not only the core of TCM basic theory and syndrome differentiation but also the bridge to associate disease and prescription, ie, prescription corresponding to syndrome54. Based on each individual syndrome, a precisely tailored Chinese herbal prescription for individuals can help to improve the efficacy of the selected TCM herbal prescription (Fufang) intervention55. One high-quality study published in JAMA56indicated that using individualized CHM for the treatment of irritable bowel syndrome is more effective than prescribing a common hypnotic prescription. The research on blood stasis syndrome and corresponding PBCRBS therapy is one of the most active areas regarding syndrome identification in China57. In recent years, the essence of blood stasis syndrome was mostly investigated in the form of disease-syndrome combination. Interesting, all patients suffering from ICH may be considered as having a blood stasis syndrome according to the TCM theory of 'the blood flow outside the vessels is the blood stasis'; this also takes advantage of the utility of a CT scan or MRI in the diagnosis of ICH. Thus, all ICH patients can be treated with PBCRBS therapy. However, the syndrome summarizes the nature, location, and syndrome of diseases, which is traditionally identified from a comprehensive analysis of clinical information from four main diagnostic TCM methods: observation, listening, questioning, and pulse analyses58. Whether modern blood stasis is different from traditional blood stasis and whether their correlation with prescriptions corresponds to the syndrome requires further clarification; this may contribute to not only the essence of the blood stasis syndrome but also evidence-based syndrome identification in ICH. Thirdly, although the PBCRBS evaluated in this review was well tolerated by ICH patients, the safety of PBCRBS could not be confirmed because only 2 studies reported the safety of interventions or investigated adverse events. Investigators of these studies might have underestimated possible adverse events. In addition, the safety of herbal patent injection itself has become a major concern to both national health authorities and the general public59. A standard reporting format for adverse drug reactions (ADR) has been developed60, and we suggest that improvement of the reporting of adverse events and ADRs of PBCRBS should be closely followed. Fourthly, improvement in the methodological quality of primary RCTs is still crucial for future clinical studies. We recommend that specific guidelines, such as the CONSORT 2010 statement61, guidelines for RCTs investigating CHM62 and CONSORT for TCM63, should be used as a combined guideline when designing and reporting RCTs for CHM. Conclusion Despite the apparently positive findings, it is premature to conclude that there is increased efficacy and safety of PBCRBS for ICH because of the high clinical heterogeneity in the included studies and small number of trials in the meta-analysis. 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PubMedArticleGoogle Scholar Download references Acknowledgements This project was supported by the National Natural Science Foundation of China (81173395/H2902); the young and middle-aged university discipline leaders of Zhejiang province, China (2013277); the Project of Wenzhou Municipal Science and Technology Bureau in Zhejiang province (Y20110031); and the Administration of Traditional Chinese Medicine of Zhejiang Province (2011ZB094). Author information Author notesHui-qin Li & Jing-jing Wei The first two authors contributed equally to this work. AffiliationsDepartment of Neurology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, ChinaHui-qin Li, Jing-jing Wei, Wan Xia, Ji-huang Li, Ai-ju Liu, Su-bing Yin, Chen Wang, Liang Song & Guo-qing ZhengDepartment of Cardiology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, ChinaYan WangChina Academy of Chinese Medical Sciences, Beijing 100700, ChinaJi-ping Fan AuthorsSearch for Hui-qin Li in:Nature Research journals • PubMed • Google ScholarSearch for Jing-jing Wei in:Nature Research journals • PubMed • Google ScholarSearch for Wan Xia in:Nature Research journals • PubMed • Google ScholarSearch for Ji-huang Li in:Nature Research journals • PubMed • Google ScholarSearch for Ai-ju Liu in:Nature Research journals • PubMed • Google ScholarSearch for Su-bing Yin in:Nature Research journals • PubMed • Google ScholarSearch for Chen Wang in:Nature Research journals • PubMed • Google ScholarSearch for Liang Song in:Nature Research journals • PubMed • Google ScholarSearch for Yan Wang in:Nature Research journals • PubMed • Google ScholarSearch for Guo-qing Zheng in:Nature Research journals • PubMed • Google ScholarSearch for Ji-ping Fan in:Nature Research journals • PubMed • Google Scholar Corresponding authors Correspondence to Guo-qing Zheng or Ji-ping Fan. Rights and permissions To obtain permission to re-use content from this article visit RightsLink. About this article Publication history Received 23 August 2014 Accepted 17 November 2014 Published 11 May 2015 DOI https://doi.org/10.1038/aps.2014.139


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Hui-qin Li, Jing-jing Wei, Wan Xia, Ji-huang Li, Ai-ju Liu, Su-bing Yin, Chen Wang, Liang Song, Yan Wang, Guo-qing Zheng, Ji-ping Fan. Promoting blood circulation for removing blood stasis therapy for acute intracerebral hemorrhage: a systematic review and meta-analysis, Acta Pharmacologica Sinica, 2015, 659-675, DOI: 10.1038/aps.2014.139