Abstract
Background
Evidence regarding the effect of Panax notoginseng saponins (PNS) on treating elderly stroke patients is scare and inconsistent. This study investigated the efficacy and safety of PNS by means of meta-analysis so as to provide an evidence-based reference for the treatment of elderly patients with stroke.
Methods
We searched the PubMed, Embase, Cochrane Library, Web of Science, CNKI, VIP, Wanfang, and China Biomedical Database to identify the eligible randomized controlled trials (RCTs) concerning using PNS to treat elderly people with stroke from their inception to first, May 2022. Meta-analysis was used for pool analysis of the included studies, whose quality was assessed via Cochrane Collaboration's RCT risk of bias tool.
Results
Altogether 206 studies published between 1999 and 2022 with a low risk of bias were included, covering 21,759 participants. The results showed that the improved neurological status shown in the intervention group with PNS alone was statistically significant (SMD = −0.826, 95% CI: −0.946 to −0.707) in contrast to the control group. The total clinical efficacy (Relative risk (RR) = 1.197, 95% Confidence interval (CI): 1.165 to 1.229) and daily living activities (SMD = 1.675, 95% C: 1.218 to 2.133) of elderly stroke patients were significantly improved as well. In addition, the invention group using PNS combined with WM/TAU displayed significant improvement in neurological status (SMD = −1.142, 95% CI: −1.295 to −0.990) and the total clinical efficacy (RR = 1.191, 95% CI: 1.165 to 1.217) compared with the control group.
Conclusion
Single PNS intervention or PNS combined with WM/TAU significantly improves the neurological status, the overall clinical efficacy and daily living activities of elderly stroke patients. However, more multicenter RCT research with high quality is required in the future to verify the results in this study. The trial registration number: Inplasy protocol 202330042. doi:10.37766/inplasy2023.3.0042.
1. Introduction
Stroke, a major cause of disability and death, is a common disease among elderly people. As the second cause of death among people aged over 60 around the world, its mortality is on the rise every year. China has the highest incidence of stroke, where 1,763 out of 100,000 people suffer from ischemic stroke per year [1]. Meanwhile, disability rate of stroke is as high as 75% in China [2]. According to a report from Global Burden of Disease, 1.7 million people died from stroke in 2010 [3]. In recent years, stroke has become the first cause of death in China [4]. According to statistics, from 2015 to 2018, around 2% of people over 40 years old had a stroke, up to 50% of whom were no more than 64, which suggest that the average age of stroke onset is going down. With a high rate of prevalence, disability and mortality, stroke has thus become a global public health concern.
Internationally, the main treatment adopted now for stroke is still vascular recanalization (thrombolysis and endovascular interventional therapy), whose effect [5, 6], however, is enjoyed by only a few patients due to factors such as short time window, high cost, and limited medical level. Panax notoginseng saponins (PNS), with the functions of dispersing blood stasis and hemostasis, reducing swelling and relieving pain, is widely used for treating stroke in China. Modern pharmacological studies believe that PNS can reduce the infarct size of ischemic stroke, inhibit edema [7], protect the blood-brain barrier, reduce nerve damage, and inhibit relevant inflammation [8, 9]. Commonly used PNS products mainly include oral-type products, such as Xueshuantong capsule (XC), Xuesaitong soft capsule (XSC), Sanqi Tongshu capsule (STC), and compound Xueshuantong capsule (CXC), and injection type products, such as Xueshuantong capsule, Xuesaitong soft capsule, Sanqi Tongshu capsule, and compound Xueshuantong capsule.
With the increase of age, the elderly are more susceptible to stroke hemiplegia because of gradually declining body function and continually weakening cardiovascular system. For these patients, Western medicine (WM) often adopts recovery treatment that helps improve movement function to a certain extent, but rehabilitation cannot be achieved [10]. Although PNS has been extensively used for treating stroke and many clinical trials have confirmed its clinical efficacy and safety [11, 12], whether it is effective and safe for the elderly population remains to be investigated. However, related evidence-based studies for this age group were rarely reported and the majority of previous studies measured only a single stroke outcome (eg., clinical efficacy). Furthermore, there were many problems with the methodological quality of previous studies. For instance, the studies included had low quality and serious bias, which may adversely affect the credibility of evidence and confuse subsequent clinical practice and health decision-making. As a result, this study, targeting at the elderly population, comprehensively analyzed the efficacy and safety of PNS in multiple outcomes by meta-analysis in order to provide more systematic clinical evidence for clinical medication and health decision-making concerning elderly stroke patients.
2. Methods
This study was reported in strict accordance with the Priority Reporting Item for Systematic Reviews and Meta-Analysis (PRISMA) [13]. All the analyses were based on previously published studies, and therefore, no ethical approval and participants' consent were required.
2.1. Search Strategies and Study Selection
Based on the standard of the Cochrane Collaboration, a comprehensive literature search, without restrictions on publication time, literature type, or region, was conducted to identify randomized controlled trials (RCTs) related to treating elderly stroke patients with PNS from their inception to first, May 2022, in PubMed, Embase, Cochrane library, Web of Science, CNKI, VIP, Wanfang, and China Biomedical Database. References in the included studies, related conference abstracts, published research papers and gray literature in the form of government reports, etc., are all consulted in case of leaving out any potentially useful data. The literature search was performed based on the combination of subject words and free words. The Chinese search terms included stroke, cerebral infarction, cerebral embolism, cerebral apoplexy, ischemic stroke, ischemic stroke, Panax notoginseng saponins, blood embolism Tong, Xueshuantong, Sanqi Tongshu Capsules, and randomized controlled trials. The English search terms were Xueshuantong capsule, Sanqi Tongshu capsule, Xuesaitong soft capsule, brain infarction, compound Xueshuantong, cerebral infarction, stroke, brain embolism, ischemic stroke, cerebrovascular disorders, and RCT. The specific search strategies of each database were attached in Appendix.
After the initial search, the collected studies were screened to remove duplicates. Ineligible articles were filtered out according to their titles and abstracts. For the remaining potentially relevant results, their full texts were reviewed and assessed according to our screening criteria, during which ineligible articles were excluded, numbered, and then registered with the reasons why they were ruled out. For texts with incomplete information or problems, we evaluated their eligibility after contacting the author.
2.2. Inclusion and Exclusion Criteria
In this study, the screening criteria conformed with the PICOS (population, intervention, comparators, outcomes, and study design) principles of the Cochrane Collaboration to assess the quality of studies. Detailed information is listed below.
2.3. Population
The symptoms of the population were in line with the relevant diagnostic criteria for stroke both at home and abroad and were confirmed as ischemic stroke by medical imaging tests such as MRI or CT. International criteria formulated by the World Health Organization, the National Center for Neurological Disorders and Stroke Research, and the Japanese Ministry of Health and Welfare were considered. Domestic criteria include ischemic stroke in arteriosclerosis thrombosis cerebral infarction, cerebral embolism, and lacunar cerebral infarction diagnosis standard set by National Cerebrovascular Disease Conference, Stroke Therapeutic Effect Evaluation Standard of Traditional Chinese Medicine (TCM) Diagnosis set by the Chinese Institute of TCM, Tentative Evaluation Standard for Stroke Diagnosis and Therapeutic Effect set by the State Administration of TCM Encephalopathy Emergency research consortium in 1995, Diagnostic Basis, Syndrome Classification and Therapeutic Effect Evaluation of Stroke in The Traditional Chinese Medicine Industry Standard of People's Republic of China—Standard of Diagnosis and Curative effect Evaluation of TCM Disease, and the classification standard in Chinese Classification of Cerebrovascular Diseases 2015 [14]. The subject groups were older adults with an average age of over 60, regardless of gender or race [15].
2.4. Intervention
Intervention involves single use of PNS such as Xuesaitong injection, Xueshuantong injection, Lulutong injection, Sanqitongshu capsule, Xuesaitong soft capsule, Xuesaitong Tablets, Xueshuantong Capsules, and Xuesaitong Dropping Pills, combined use of PNS and WM or PNS and treatment as usual (TAU).
2.5. Comparator
All the patients in the controlled group underwent conventional routine treatment to improve their cerebral blood supply and drug treatment, such as taking medication to nourish their brain tissues. Conventional therapy in WM, which followed Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2015 [5], includes intravenous thrombolysis, endovascular therapy, antiplatelet, anticoagulation, decrease of fibrinogen, increase of blood volume, improvement of cerebral circulation, nutrition of nerves, lipid regulation, blood pressure reduction, hypoglycemia, and rehabilitation. The regular treatments for the controlled groups and the treated groups must be the same, and the course of treatment is not limited.
2.6. Outcomes
Measurement for the outcomes should be clearly defined and includes at least one of the following items: neurological deficit score, the clinical response rate, and assessment of activities of daily living (ADLs).
2.7. Study Design
All the included studies were RCTs or clinical controlled trials. The study design adopted RCT. In other words, “random grouping” should be mentioned in the article or its grouping method was “tossing a coin,” “drawing lots,” “rolling dice,” “random number table,” “computer coding,” “block randomization,” or “stratified randomization.”
2.8. Exclusion Criteria
Exclusion criteria were as follows: (1) research with duplicate publications or duplicate data; (2) research with incomplete data or serious errors; (3) research without the full text; (4) research involving unconventional treatments in Western medicine such as Chinese herbs or acupuncture; (5) observational research, fundamental research based on cell or animal specimens, experience summaries, review papers, and case study reports.
2.9. Outcome Measures and Data Extraction
The primary outcome measure was the post-treatment neurological deficit score graded by the National Institutes of Health Stroke Scale (NIHSS). Secondary outcome measures included (1) overall clinical response rate [16] and (2) posttreatment ADL score.
The included studies were numbered for the convenience of reviewing. Basic information and data in these studies consisted of title, authors, publication year, specific treatments, number of cases, sample ages, male to female ratio, experimental design methodologies (including randomized method, blind method and the like), key factors for evaluating risk of bias, the outcome measures and the results, the course of treatment, etc.
2.10. Quality Assessment of the Included Studies
The risk of bias in the included studies was assessed via the Cochrane Collaboration's RCT risk of bias tool [17]. There were 7 assessed items random sequence generation, allocation concealment, blinding of participants and intervention providers, blinding of outcome assessors, outcome completeness, selective reporting of outcomes, and other sources of bias, which were rated as low, and unclear or high bias level. The assessment of included RCTs was separately conducted by two researchers, who then exchanged the results and checked. Disagreement would first be discussed by the two researchers, who would refer to the supervision researcher if they could not reach a consensus. Finally, the risk of bias map was drawn with RevManand Office software.
2.11. Statistical Analyses
Categorical data (such as the overall clinical response rate) were to be combined and measured by relative risk (RR) and numerical data (such as neurological deficit score, and the activity of daily living score) by standard mean difference (SMD), whose 95% of confidence interval (CI) was calculated. The heterogeneity of the included studies was measured by the chi-square test (with a significant level of 0.1) and judged by the value of I2 at the same time. During the meta-analysis, when statistically significant heterogeneity (P < 0.10 or I2 > 50%) was shown, the random effect model would be chosen; otherwise, (P ≥ 0.10 or I2 ≤ 50%) the fixed effect model would be applied [18]. For significant heterogeneity, subgroup, or sensitivity analysis or only descriptive analysis was conducted to deal with the data. If more than ten studies were concerned with one certain variable, the publication bias would be assessed by a funnel plot and Egger's test [19]. The above data analyses were done with the help of Software STATA (Version 14.0, Stata, Corp, College Station, TX).
3. Results
3.1. Literature Screening
The initial database search yielded 5,542 articles and 5,351 remained after removing duplicates by Endnote. Then, 545 articles were removed by checking titles and abstracts, and 120 articles were excluded from the rest after the full text review. Finally, 206 eligible papers were included for quantitative analysis. The detailed information on literature screening is presented in Figure 1 [13, 20].
Figure 1.
The detailed information on literature screening.
3.2. Characteristics of the Included Studies
This study collected 206 RCTs for analysis, with 21,759 participants involved, among whom 11,118 were randomly distributed in the intervention group and 10,641 in the controlled group. All included articles were published between 1999 and 2022, 204 of which are Chinese. The average age of participants was 63.20 years old with 12,502 male participants, accounting for 57.46%. The course of treatment varied from 3 days to 6 months. 108 studies reported acute stroke period, 4 studies reported the recovery period, and 94 did not report the information of stroke periods. See Table 1 for all basic information on the included studies.
Table 1.
Basic information on the included studies.
| Number | Author | Date | Title |
|---|---|---|---|
| 1 | Ning Ao | 2005 | The effect of Xuesetong and Danshen on acute cerebral infarction |
| 2 | Yan Cao | 2016 | Effect of Xuesetong injection on neurological function and blood rheology in elderly ischemic stroke |
| 3 | Airong Zeng | 2019 | Clinical value of Xuesetong with alprostadil for cerebral infarction |
| 4 | Qingli Zeng | 2015 | Intervention effect of Xuesetong combined with edaravone on thrombosis in acute cerebral infarction |
| 5 | Dongmei Chang | 2009 | Xueshuantong combine with naloxone for the treatment of acute cerebral infarction |
| 6 | Guiying Che | 2014 | Study on the clinical efficacy of rehabilitation training with Xueshuantong in stroke patients |
| 7 | Zhenxian Shen | 2015 | The clinical effect of Xueshuantong combined with edaravone in treatment of acute cerebral infarction and its impact on neurological deficits and activities of daily living |
| 8 | Caihua Chen | 2019 | Efficacy of edaravone and Xuesetong in cerebral infarction |
| 9 | Hongfen Chen | 2012 | Evaluation of the treatment effect of acute cerebral infarction in Xueshuantong |
| 10 | Jie Chen | 2022 | Improvement effect of Xuesaitong injection on degree of neurological deficit in patients with cerebral infarction effect of panax notoginseng injection in the treatment of intracerebral hemorrhage |
| 11 | Lin Chen | 2002 | Clinical efficacy of naloxone and Xuesetong in elderly patients with acute cerebral infarction and its effect on neurological and motor function |
| 12 | Mai Chen | 2018 | Effect of Xuesaitong combined with nimodipine on cognitive function in patients with acute cerebral infarction |
| 13 | Minghui Chen | 2019 | Efficacy of sodium ozagrel and Xueshuantong in acute cerebral infarction |
| 14 | Mingxian Chen | 2013 | Clinical effect of Xueshuantong injection in acute cerebral infarction |
| 15 | Rui Chen | 2005 | Using Xuesetong for 22 patients with the acute phase of cerebral hemorrhage to improve circulatory treatment |
| 16 | Songlin Chen | 2006 | Clinical efficacy of Xuesetong and prostadil in the treatment of cerebral infarction |
| 17 | Sufen Chen | 2018 | Clinical effect of Xueshuantong freeze-dried powder injection in the treatment of acute cerebral infarction |
| 18 | Xishan Chen | 2015 | Clinical effect of Xuesetong injection in the treatment of 34 cases of acute cerebral infarction |
| 19 | Xiaoyan Chen | 2009 | Clinical effect of Xuesetong injection in the treatment of ischemic stroke |
| 20 | Xiaomei Chen | 2015 | Xueshuantong clinical observation on the treatment of the acute phase of ischemic stroke |
| 21 | Yuxun Chen | 2013 | Analysis of the efficacy of Xuesetong injection in patients with cerebral infarction |
| 22 | Huabi Chen | 2014 | Analysis of the efficacy of Xuesetong injection in patients with cerebral infarction observation of the result through treating patients with thrombotic cerebral infaration by Xie-Sai-Tong |
| 23 | Tiejun Dai | 2005 | Clinical observation on acute cerebral infarction treated with clopidogrel hydrochloride and Xueshuantong |
| 24 | Desheng Dan | 2018 | The effect of Xueshuantong and plasmin in acute cerebral infarction |
| 25 | Yu Deng | 2013 | Analysis of the curative effect of Xueshuantong freeze dried powder needle to cerebral infarction |
| 26 | Shuikang Ding | 2008 | Analysis of the curative effect of Xuesetong freeze dried powder needle to cerebral infarction |
| 27 | Shuikang Ding | 2009 | Clinical effect of benphthalein combined with Xuesetong in acute cerebral infarction |
| 28 | Haiyan Du | 2018 | Clinical observation on the curative effect of acute ischemic stroke treated with Xueshuantong injection and argatroban |
| 29 | Aiqin Fan | 2018 | Effect of Xuesaitong on peripheral blood WBC count and serum content of S-100B protein in patients with acute cerebral infarction |
| 30 | Rong Fan | 2010 | Clinical study on Xueshuantong for treating acute cerebral infarction |
| 31 | Dongmei Fang | 2014 | Clinical study on Xuesaitong injection for treating cerebral infarction |
| 32 | Fang Fang | 2014 | Clinical study on astragale injection combined with Sanqi Panax Notoginseng for Injection for treating ischemic stroke |
| 33 | Conglian Feng | 2011 | Efficacy of Xueshuantong combined with limb rehabilitation in the treatment of patients with cerebral arterial thrombosis |
| 34 | Xiangyon gFeng | 2015 | Clinical study of Xueshuantong combined with aspirin in the treatment of elderly patients with acute cerebral infarction |
| 35 | Xuecai Feng | 2020 | Clinical effect of Xueshuantong combined with sodium ozagrel in the treatment of acute cerebral infarction and the effect on nerve function |
| 36 | Zhe Feng | 2020 | Clinical effect of Xueshuantong combined with sodium ozagrel in the treatment of acute cerebral infarction and the effect on nerve function |
| 37 | Biao Fu | 2017 | Effect of Xueshuantong combined with butylphthalide soft capsules on the ECG and nerve function in patients with acute cerebral infarction effect of atorvastatin calcium dispersible tablet combined with Xuesaitong injection on blood lipid, |
| 38 | WeiFu | 2018 | Hemorheology and neurological function in patients with acute cerebral infarction clinical study on Xuesaitong in the treatment of 47 cases of acute cerebral infarction |
| 39 | Hanbiao Gan | 2009 | Hemorheology and neurological function in patients with acute cerebral infarction clinical study on Xuesaitong in the treatment of 47 cases of acute cerebral infarction |
| 40 | Chaoqun Gao | 2019 | Effect of Xuesaitong injection combined with fibrinogenase injection in elderly patients with ischemic stroke |
| 41 | Chu Gao | 2019 | Effects of Xueshuantong capsule combined with Xuesaitong for injection in elderly patients with cerebral infarction |
| 42 | Dongyang Gao | 2022 | Effect of Xueshuantong capsule on cerebral infarction and hemorheology |
| 43 | Guili Gao | 2007 | Xuesaitong injection in the treatment of cerebral infarction controlled observation |
| 44 | Yan Sun | 2012 | Study on Xuesaitong soft capsule in the treatment of 45 cases of ischemic stroke in recovery period |
| 45 | Hua Lan | 2012 | Study on Xueshuantong capsule and acupuncture and massage combined with Western medicine for treating of limb functions of cerebral infarction |
| 46 | Wei Gao | 2022 | Clinical study on Xueshuantong injection in the treatment of 48 cases of acute cerebral infarction |
| 47 | Yi Gao | 2011 | Effects of total Panax notoginseng saponins on neurological function and complement 3 in patients with acute intracerebral hemorrhage |
| 48 | Ying Gao | 2011 | Clinical study on edaravone injection combined with Xuesaitong for treating cerebral infarction |
| 49 | Zhiqing Gao | 2019 | Clinical study on Xueshuantong in the treatment of acute cerebral infarction |
| 50 | Haiping Gu | 2016 | Clinical study on Xuesaitong injection combined with ozagrel sodium for treating acute cerebral infarction |
| 51 | Zhiyan Gu | 2014 | Effect of Xueshuantong injection combined with urokinase intravenous thrombolysis on neurological deficit, vWF, and hs-CRP |
| 52 | Yafen Guan | 2019 | Study on clinical effect of edaravone injection combined with Xuesaitong for treating cerebral infarction |
| 53 | Binqing Guo | 2019 | Clinical study on Xuesaitong soft capsule in the treatment of 40 cases of cerebral infarction |
| 54 | Yanping Guo | 2005 | Study on the effect of Xueshuantong injection combined with Folium Ginkgo tablet in the treatment of acute cerebral infarction |
| 55 | Leisen Han | 2003 | Clinical study on edaravone combined with Xueshuantong in the treatment of acute cerebral infarction |
| 56 | Lijuan Han | 2018 | Influence of Xuesaitong on serum C-reactive protein level in the treatment of acute cerebral infarction and its clinical value |
| 57 | Yan Han | 2014 | Study on the effect of Naloxone combined with Xuesaitong in the treatment of elderly patients with acute cerebral infarction |
| 58 | Guoxiang Hu | 2013 | Effects of Xuesaitong capsules combined with butylphthalide soft capsules on cerebral blood folw and prognosis in patients with cerebral infarction in recovery period |
| 59 | Haitao Hu | 2021 | prognosis in patients with cerebral infarction in recovery period |
| 60 | Yaozhong | 2017 | Clinical curative effect of Xuesaitong injection combined with edaravone in treatment of elderly patients with acute cerebral infarction and influence on hemorheology of patients with plasma C reactive protein clinical effect of Ureklin combined with Xueshuantong on patients with the clinical effect of Ureklin combined |
| 61 | Debo Huang | 2019 | With Xueshuantong on acute ischemic stroke and changes of neurological deficit score and ability of daily living were analyzed |
| 62 | Huibin Huang | 2009 | Therapeutic effect of Xueshuantong for acute cerebral infarction and its influence on hemodynamics Clinical study on 150 cases with acute cerebral infarction treated by Xueshuantong |
| 63 | Meilin Huang | 2012 | Study on the effect of compound Xueshuantong capsules in the treatment of ischemic stroke |
| 64 | Wubiao Huang | 2018 | Influence of notoginseng triterpeneson applied at early stage on plasma MMP-9 level and neurological function recovery in patients with cerebral hemorrhage |
| 65 | Lijun Jia | 2009 | Curative effect observation of Xuesaitong injection for cerebral infarction |
| 66 | Mingxia Jiang | 2004 | Clinical observation of 40 cases of cerebral thrombosis treated with Xueshuantong |
| 67 | Rongfeng Jiang | 2012 | Influence of Xueshuantong injection on serum hypersensitivity C-reactive protein and interleukin-6 levels in patients with acute cerebral infarction |
| 68 | Yan Jiao | 2016 | Study on the effect of Xueshuantong injection in the treatment of cerebral infarction |
| 69 | Bo Jin | 2015 | Observation of clinical effect for Xuesaitong injection in treatment 70 cases with cerebral infarction patient |
| 70 | Yunjing Jin | 2002 | Effect and the changes of neurological function of aspirin combined with saponins of Panax notoginseng in the treatment of cerebral infarction |
| 71 | Xulin Ke | 2016 | In accordance with the adr and blood plug joint for the treatment of cerebral infarction clinical curative effect analysis |
| 72 | Yinchun Leng | 2016 | Clinical study on Sanqi Tongshu combined with edaravone in the treatment of acute cerebral infarction |
| 73 | Chunhong Li | 2012 | Effect of edaravone combined with Xueshuantong injection on acute cerebral infarction |
| 74 | Cunming Li | 2014 | Observation on curative effects of treatment with Panax notoginsenoside injection combined with batroxobin for acutely cerebral infarction in 31 patients |
| 75 | Fei Li | 1999 | Study on the effect of Xueshuantong injection in the treatment of acute cerebral infarction |
| 76 | Hui Li | 2004 | Clinical effect observation of Xueshuantong combined with ligustrazine treating acute ischemic stroke of type obstruction of collaterals by blood stasis |
| 77 | Huijun Li | 2015 | Clinical study on the effect of Xueshuantong injection in adjuvant treatment of ischemic stroke |
| 78 | Qin Li | 2014 | Study on Shuxuening injection combined with Xuesaitong injection in the treatment of cerebral infarction in 90 cases Clinical study on Xueshuantong combined with Aspirin in the treatment of elderly patients with acute cerebral |
| 79 | Ruiqi Li | 2012 | Clinical study on Xueshuantong combined with aspirin in the treatment of elderly patients with acute cerebral infarction |
| 80 | Song Li | 2016 | Discussion on the clinical value of Naloxone combined with Xuesaitong in the treatment of elderly patients with cerebral infarction |
| 81 | Wei Li | 2017 | Clinical observation of Xuesaitong combined Lumbrokinase in treating acute cerebral infarction |
| 82 | Wenlong Li | 2010 | Clinical study on Sanqi Panax notoginseng for injection combined with sodium ozagrel in the treatment of acute cerebral infarction |
| 83 | Yongzhon gLi | 2013 | Clinical efficacy of neurological recovery of butylphthalide soft capsules and Xueshuantong in patients with acute cerebral infarction |
| 84 | Yuqing Li | 2016 | Study on the effect of Sanqi Tongshu capsules combined with Huoxuetongmai tablet in the treatment of ischemic stroke |
| 85 | Yuanjun Li | 2018 | Clinical study on Xuesaitong combined with Levamlodipine in the treatment of cerebral hemorrhage and hypertension |
| 86 | Yuanlin Li | 2015 | Influence of Xueshuantong injection combined with alteplase on neurological function and vascular endothelial function in patients with acute cerebral infarction |
| 87 | Zhongyin Li | 2021 | Clinical study on Xuesaitong injection combined with edaravone in the treatment of acute cerebral hemorrhage |
| 88 | Bixian Liang | 2011 | The injection Xueshuantong the treatment of acute cerebral infarction with clinical efficacy and safety observed |
| 89 | Haiqiu Liang | 2012 | Effect of alteplase intravenous thrombolysis combined with Xueshuantong soft capsule on nerve function and quality of life in patients with acute cerebral infarction |
| 90 | Huili Liang | 2018 | Clinical study on Xuesaitong in treating syndrome of static blood blocking collaterals in recovery period of cerebral hemorrhage |
| 91 | Junjun Liang | 2018 | Clinical study on edaravone combined with Xueshuantong in the treatment of acute cerebral infarction |
| 92 | Kui Lin | 2012 | Analysis of clinical effect of applying Xueshuantong in acute lacunar cerebral infarction |
| 93 | Fangyin Lin | 2018 | Curative effect of Xuesaitong combined with edaravone on patients with cerebral infarction |
| 94 | Baogui Liu | 2019 | Clinical study on 40 cases with cerebral infarction treated by Xueshuantong |
| 95 | Bin Liu | 2010 | Study on 64 cases with acute cerebral infarction treated by Sanqi Panax Notoginseng for injection |
| 96 | Hongyan Liu | 2014 | Xueshuantong combined with Aspirin in treatment of senile acute cerebral infarction for 45 cases |
| 97 | Huiying Liu | 2016 | Study on 120 cases with cerebral infarction treated by Xuesaitong combined with edaravone injection |
| 98 | Lili Liu | 2017 | Clinical study on 160 cases with cerebral infarction treated by Xuesaitong injection |
| 99 | Qingping Liu | 2012 | Observation on the Therapeutic effect of fibrinogenase injection combined with Xueshuantong in elderly |
| 100 | Xiaojun Liu | 2017 | Patients with ischemic stroke study on the effect of Xuesaitong injection combined with phentolamine mesylate for injeacute cerebral infarction in treating |
| 101 | Yanli Liu | 2011 | Effect of compound Xueshuantong capsule on clopidogrel resistance of acute cerebral infarction and nerve function |
| 102 | Yang Liu | 2020 | Function of the clinical effect of Xuesaitong soft capsule to treat lacunar infarction |
| 103 | Shulin Lu | 2010 | Study on the effect of Xueshuantong in elderly patients with acute cerebral infarction and its influence on serum D-dimer level |
| 104 | Jinqiang Lu | 2020 | Serum D-dimer level clinical study on Xuesaitong injection in the treatment of acute cerebral infarction in 56 cases |
| 105 | Qin Ma | 2015 | Xue Sai Tong injection plus routine therapy for acute cerebral infarction and the influence on plasma C-reactive protein |
| 106 | Xiangdo Ng Luo | 2011 | Clinical study on Xueshuantong injection in the treatment of acute cerebral infarction in 60 cases |
| 107 | Junhua Ma | 2010 | Curative effect discussion of Xue Shuan Tong injection combined with edaravone in the treatment of acute cerebral infarction in 64 cases |
| 108 | Yong Ma | 2015 | Cerebral infarction in 64 cases |
| 109 | Hua Mei | 2011 | Clinical evaluation of combining Xuesaitong with vinpocetine on acute cerebral infarction Clinical observation on effect of ginkgo leaf extract and dipyridamole injection combined with Sanqi Panax |
| 110 | Xiaoneng Mo | 2008 | Notoginseng injection on acute cerebral infarction patients study on Xueshuantong injection in the treatment of cerebral hemorrhage in recovery period in 184 cases |
| 111 | Qiaolin Ou | 2006 | Clinical study on Xuesaitong combined with cytidine disodium triphosphate in the treatment of acute cerebral infarction in 43 cases |
| 112 | Dongzhen Piao | 2016 | Clinical efficacy of naloxone combined with Xueshuantong injection in the treatment of cerebral infarction and its effect on neurological function and motor function |
| 113 | Yan Pan | 2019 | Study on the effect of Xueshuantong combined with edaravone in the treatment of elderly patients with acute cerebral infarction and its influence on blood rheology and nerve function |
| 114 | Qiubo Qiao | 2021 | Discussion on clinical value of naloxone combined with Xuesaitong in the treatment of elderly patients with cerebral infarction |
| 115 | Liyuan Qin | 2016 | Effect of Panax notoginseng saponins in the treatment of acute cerebral infarct Xueshuantong injection in the treatment of acute cerebral infarction |
| 116 | Liqiang Qu | 2014 | Xueshuantong injection in the treatment of acute cerebral infarction |
| 117 | Qibo Ran | 2011 | Effect of Xueshuantong combined with edaravone on patients with acute cerebral infarction |
| 118 | Lihong Rong | 2021 | Clinical study on Xueshuantong injection in the treatment of acute cerebral infarction in 93 cases |
| 119 | Zhi Shang | 2011 | Study on the effect of Xueshuantong injection in the treatment of patients with ischemic stroke |
| 120 | Xinyou Shu | 2017 | Clinical study on vinpocetine combined with Xueshuantong in the treatment of acute cerebral infarction |
| 121 | Shuyi Song | 2008 | Effect observation on Xueshuantong injection in the treatment of transient ischemic attack |
| 122 | Ke Su | 2012 | Observation on the efficacy of combined therapy of thrombus and aspirin in the treatment of elderly patients |
| 123 | Dan Sun | 2015 | With acute cerebral infarction |
| 124 | Haijiao Sun | 2021 | Xueshuantong combined with aspirin in the treatment of acute cerebral infarction and its influence on S-100β |
| 125 | Weihui Qin | 2021 | Clinical study on Xueshuantong injection in the treatment of cerebral infarction in 30 cases clinical study on Xueshuantong in the treatment of acute cerebral infarction |
| 126 | Yujun Qin | 2001 | Clinical study on Xueshuantong in the treatment of acute cerebral infarction |
| 127 | Feifei Tan | 2021 | Effect of Xueshuantong injection on the serum levels of inflammatory factors in patients with acute cerebral infarction |
| 128 | Wenlan Tan | 2018 | Clinical study on Xuesaitong injection in the treatment of cerebral infarction in 100 cases |
| 129 | Yuming Tan | 2003 | The Clinical effect of naloxone combined with Xuesaaitong in treating se-nile cerebral infarction |
| 130 | Bo Tang | 2018 | Clinical study on Xueshuantong injection in the treatment of primary intracerebral hemorrhage |
| 131 | Lanzhi Tong | 2012 | Study on clinical effect of Xueshuantong combined with piracetam in the treatment of acute cerebral infarction and its influence on serum TC, SOD, and hs-CRP levels |
| 132 | Xiaolin Tong | 2021 | Efficacy observation of Xueshuantongin the treatment of acute cerebral infarction |
| 133 | Yongshe Ng Wang | 2011 | Effects of Xueshuantong on serum inflammatory factor levels and intracranial hematoma in patients with acute cerebral hemorrhage |
| 134 | Chaofeng Wang | 2019 | Clinical study on Naloxone combined with Xueshuantong in the treatment of acute cerebral infarction |
| 135 | Feifei Wang | 2013 | Effect of Xueshuantong injection combined with clopidogrel sulfate on neural function and oxidative stress indexes in patients with progressive ischemic stroke |
| 136 | Hailin Wang | 2021 | Study on the clinical effect of Xuesaitong combined with alprostadil in treating cerebral infarction and its influence on activities of daily living |
| 137 | Mengjue Wang | 2018 | Effect and safety of Xueshuantong injection in the treatment of acute cerebral infarction |
| 138 | Shan Wang | 2021 | Evaluation of 3-butylphthalide combined with Xueshuantong in treating ischemic stroke |
| 139 | Tianpeng Wang | 2018 | Clinical study on edaravone combined with Xuesaitong in the treatment of cerebral infarction |
| 140 | Xia Wang | 2015 | Effect of Xueshitong combined with butylphthalide on serum fibulin-5, Bdnf, and S100B in aged patients with acute cerebral infarction |
| 141 | Xiaoyu Wang | 2018 | Study on the effect of minimally invasive operation combined with Qingkailing and Xuesaitong in the treatment of acute cerebral hemorrhage clinical observation of 65 cases with acute cerebral infarction treated by Xuesaitong injection |
| 142 | Xinmin Wang | 2007 | Clinical observation of 65 cases with acute cerebral infarction treated by Xuesaitong injection |
| 143 | Xunwen Wang | 2010 | Clinical effect and safety of sodium ozagrel combined with Xueshuantong in the treatment of acute cerebral |
| 144 | Yanfen Wang | 2019 | Study on the clinical effect and safety of Xueshuantong combined with aspirin in treating elderly patients with acute cerebral infarction C |
| 145 | Yang Wang | 2017 | Clinical effect of Fufang Xueshuantong capsules on elderly acute cerebral infarction and its impact on vascular endothelial cell function |
| 146 | Zhiqing Wang | 2015 | Influence of notoginseng triterpenes on serum C-reactive protein level in patients with acute cerebral infarction |
| 147 | Xianping Wei | 2007 | Clinical effect of sodium ozagrel combined with Xueshuantong in the treatment of acute cerebral infarction |
| 148 | Xiaohong Wei | 2016 | The clinical effect of Xuesaitong combined with alprostadil in the treatment of cerebral infarction |
| 149 | Yan Wen | 2016 | Study on the effect of Xueshuantong injection combined with acupuncture in recovery period of ischemia cerebral vessels disease |
| 150 | Chunfang Wu | 2021 | Clinical observation of 68 cases with acute cerebral infarction treated by Sanqitongshu capsules |
| 151 | Fangting Wu | 2012 | Study on the effect of Xuesaitong injection combined with compound Danshen injection in the treatment of acute cerebral infarction |
| 152 | Fen Wu | 2014 | Evaluation of clinical value of edaravone combined with Xueshuantong in the treatment of acute progressive cerebral infarction |
| 153 | Fenghua Wu | 2019 | Study on the effect of Xueshuantong injection in the treatment of cerebral infarction |
| 154 | Lijun Wu | 2015 | Clinical study on Xuesaitong soft capsule in treating syndrome of static blood blocking collaterals in recovery period of cerebral infarction |
| 155 | Qiongfen Wu | 2011 | Primary study on safety and clinical effect of Xuesaitong in the treatment of cerebral infarction |
| 156 | Shuhua Wu | 2016 | Observation of 30 cases with acute cerebral infarction treated by Naloxone combined with Xueshuantong |
| 157 | Xiaoqiu Wu | 2001 | Study on Xueshuantong injection combined with batroxobin in the treatment of acute cerebral infarction |
| 158 | Yu Wu | 2013 | Clinical study on Xuesaitong injection combined with cattle encephalon glycoside and ignotin injection in treatment of elderly patients with acute cerebral infarction |
| 159 | Zhigang Wu | 2018 | Clinical study on Xuesaitong combined with alprostadil in the treatment of cerebral infarction effect of Xuesaitong combined with butylphthalide injection on PARK7, GFAP, CXCL12, and sV |
| 160 | Dejun Xia | 2018 | Effect of Xuesaitong combined with butylphthalide injection on PARK7, GFAP, CXCL12, and sV-CAM-1 in patients with acute cerebral infarction |
| 161 | Jundong Xia | 2019 | Clinical study on clopidogrel sulfate combined with Xueshuantong in the treatment of acute cerebral infarction |
| 162 | Xiamixi Nuer | 2020 | Clinical effect of Xuesaitong combined with sodium ozagrel in the treatment of acute cerebral infarction |
| 163 | Yanfei Xiang | 2015 | Clinical effect and mechanism of Xuesaitong applied to cerebral infarction |
| 164 | Huiling Xie | 2013 | Clinical study of Xuesaitong combined with sodium ozagrel in the treatment of cerebral infarction |
| 165 | Shanyu Xiong | 2013 | The effects of xue-sai-tong injection combined with intravenous thrombolysis on hemodynamics, nerve function, serum Hcy, NSE, and S-100β in patients with ischemic stroke |
| 166 | Dengfu Yan | 2020 | Clinical effect of Xueshuantong combined with sodium ozagrel in the treatment of cerebral infarction |
| 167 | Hongjun Yang | 2020 | Clinical observation of 38 cases with acute cerebral infarction treated by Xuesaitong injection |
| 168 | Hua Yang | 2005 | Random parallel comparison research of Xuesaitong combined with Bayer aspirin randomized parallel controlled study |
| 169 | Junhua Yang | 2017 | Influence of Xueshuantong combined with butylphthalide soft capsule on neurological deficit score and quality of life in patients with cerebral infarction in recovery period |
| 170 | Shizhan Yang | 2019 | Clinical observation of Xueshuantong for 52 cases with acute cerebral infarction |
| 171 | Tao Yang | 2010 | Clinical research for 76 cases on acute cerebral infarction treated with Xueshuantong injection |
| 172 | Wenming Yang | 2004 | Curative effect of Xuesaitong injection on acute cerebral infarction of 50 patients study on the effect of naloxone combined with Xuesaitong in the treatment of elderly patients with cerebral |
| 173 | Deliang Yao | 2007 | Study on the effect of naloxone combined with Xuesaitong in the treatment of elderly patients with cerebral infarction |
| 174 | Li Yao | 2021 | Study on 76 cases with cerebral infarction treated by Xuesaitong |
| 175 | Xiaoli Yao | 2013 | Study on Xueshuantong injection in the treatment of progressive cerebral infarction Study on clinical effect of Xueshuantong combined with sodium ozagrel in the treatment of cerebral infarction |
| 176 | Xiaobin Ye | 2008 | Study on clinical effect of Xueshuantong combined with sodium ozagrel in the treatment of cerebral infarction in 80 cases and its influence on hemorheology effect of Xueshuanton |
| 177 | Jianjun Yin | 2010 | Effect of Xueshuantong combined with aspirin in the treatment of elderly patients with acute cerebral infarction |
| 178 | Hao Yu | 2020 | Clinical study on the effect of naloxone combined with Xuesaitong in the treatment of elderly patients with cerebral infarction |
| 179 | Qiang Yu | 2016 | Influence of fluoxetine hydrochloride combined with Sanqi Tongshu capsule on NIHSS score and serum CGRP and IGF-1 level in elderly patients with ischemic stroke |
| 180 | Weiping Zang | 2021 | Observation of the effect of Xueshuantong injection combined with ginkgo leaf extract in the treatment of cerebral infarction |
| 181 | Fenguo Zhang | 2012 | Study on Xuesaitong injection combined with edaravone in treating acute cerebral hemorrhage |
| 182 | Guosheng Zhang | 2014 | Clinical study on Xuesaitong combined with edaravone in treating cerebral infarction |
| 183 | Haijie Zhang | 2013 | Evaluation on the effect of Xuesaitong in the treatment of cerebral infarction |
| 184 | Hui Zhang | 2017 | Influence of Xueshuantong combined with piracetam on TCM syndrome score neurological function and serum NPY and Hcy in patients with cerebral ischemic stroke |
| 185 | Xiping Zhang | 2021 | Observation on 45 cases of progressive cerebral infarction treated by Batroxobin combined with Xueshuantong |
| 186 | Xiaoshi Zhang | 2011 | Observation on 45 cases of progressive cerebral infarction treated by batroxobin combined with Xueshuantong |
| 187 | Xiaoshi Zhang | 2012 | Clinical effect of Xueshuantong injection combined with early rehabilitation on patients with acute cerebral infarction |
| 188 | Yang Zhang | 2014 | Clinical study of sodium ozagrel combined with Xuesaitong in the treatment of acute cerebral infarction |
| 189 | Yinguang Zhang | 2015 | Study on clinical effect of Xuesaitong combined with edaravone in treating elderly patients with acute cerebral infarction and its influence on hemodynamics |
| 190 | Yingwei Zhang | 2020 | Observation on the effect of low molecular weight heparin combined with Xuesaitong in the treatment of acute cerebral infarction |
| 191 | Yongcheg Zhang | 2006 | Study on the effect of Xueshuantong combined with edaravone in treating elderly patients with acute cerebral infarction and its influence on cytokines, cerebral hemodynamics, and vascular endothelial function |
| 192 | Yuming Zhang | 2018 | Clinical observation of cerebral infarction treated by acupuncture combined with intravenous infusion of Xuesaitong |
| 193 | Yuqin Zhang | 2010 | Effect of Panax notoginseng saponins on serum NSE levels and functional recovery in patients with acute cerebral infarction |
| 194 | Chan Zhao | 2016 | Clinical observation on Xueshuantong injection in treatment of acute cerebral infarction patients with clopidogrel resistance |
| 195 | Jing Zhao | 2015 | Observation on the effect of Xuesaitong injection combined with early rehabilitation in the treatment of acute cerebral thrombosis |
| 196 | Kun Zhao | 2019 | Influence of early rehabilitation combined with Xuesaitong injection on quality of life in patients with cerebral infarction |
| 197 | Xian Zhao | 2014 | Observation of Xueshuantong injection in the treatment of cerebral thrombosis |
| 198 | Yanli Zhao | 2012 | Application of Xueshuantong injection in the treatment of cerebral infarction |
| 199 | Jianyong Zheng | 2016 | Study on clinical value of Xueshuantong injection in the treatment of ischemic stroke |
| 200 | Li Zheng | 2015 | Clinical value of protoparaxotril saporlirs combined with aspirin in the secondary prevention of cerebral infarction |
| 201 | Borong Zhou | 2008 | Clinical research of total saponin of Panax notoginseng in the treatment of early cerebral hemorrhage |
| 202 | Chunlin Zhou | 2016 | Study on the effect and safety of Xueshuantong injection in the treatment of acute cerebral infarction |
| 203 | Yudong Zhou | 2015 | Study on the effect of Xuesaitong in the treatment of cerebral infarction |
| 204 | Saihua Zhu | 2012 | Clinical observation of rehabilitation therapy combined with Xuesaitong in treating sequelae of cerebral infarction |
| 205 | Xiaomin Zhu | 2018 | Clinical observation of cerebral protective effect of Xuesaitong on patients with cerebral infarction |
| 206 | Rong Zou | 2018 |
3.3. Quality Assessment
All of the 206 articles were RCTs, which were considered low risk of bias in the generation of random sequences. Without clarifying allocation concealment, 143 articles were rated unclear risk of bias. 15 articles reported blinding of participants and 41 used blinding for assessors. All included studies were at low risk of bias in terms of outcome completeness. 7 articles were rated as low risk for selective reporting bias. For other bias, 38 and 168 studies were at unclear and low risk of bias, separately. Detailed information on the quality assessment of the included studies were introduced in Table 2 and Figure 2. Moreover, certainty assessment of the included studies was shown in Table 3.
Table 2.
ROB individual (risk of bias of the included studies).
| Publications | ROB items | ||||||
|---|---|---|---|---|---|---|---|
| Random sequence generation (Selection bias) | Allocation concealment (Selection bias) | Blinding of participants & personnel (Performance bias) | Blinding of outcome assessors (Detection bias) | Incomplete outcome data (Attrition bias) | Selective reporting (reporting bias) | Other bias | |
| Fei Li, 1999 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Yunjing Jin, 2002 | Low | Unclear | Unclear | Unclear | Low | Low | Low |
| Mingxia Jiang, 2004 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Hua Yang, 2005 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Shuyi Song, 2008 | Low | Low | Low | Unclear | Low | Low | Low |
| Borong Zhou, 2008 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Dongmei Chang, 2009 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Lijun Jia, 2008 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Ying Gao, 2011 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Xiangdong Luo, 2011 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Zhi Shang, 2011 | Low | Low | Unclear | Unclear | Low | Low | Low |
| Hongfen Chen, 2012 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Haiqiu Liang, 2012 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Kui Lin, 2012 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Qiongfen Wu, 2012 | Low | Unclear | Low | Low | Low | Unclear | Low |
| Guoxiang Hu, 2013 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Yan Han, 2014 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Guosheng Zhang, 2012 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Xiangyong Feng, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yuanlin Li, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Zhiqing Wang, 2015 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Jing Zhao, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yan Cao, 2016 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Xulin Ke, 2016 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Song Li, 2016 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Yuqing Li, 2016 | Low | Low | Unclear | Unclear | Low | High | Low |
| Huiying Liu, 2016 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yan Wen, 2016 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Qiang Yu, 2016 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Chunlin Zhou, 2016 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Yaozhong Hu, 2017 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Wei Li, 2017 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Xiaojun Liu, 2017 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Yang Wang, 2017 | Low | Unclear | Unclear | Low | Low | Unclear | Unclear |
| Junhua Yang, 2017 | Low | Low | Unclear | Unclear | Low | Low | Low |
| Mai Chen, 2018 | Low | Low | Unclear | Low | Low | Unclear | Unclear |
| Zhiqing Gao, 2018 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Fangying Ling, 2018 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Bo Tang, 2018 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Xiaoyu Wang, 2018 | Low | Low | Unclear | Unclear | Low | High | Low |
| Zhigang Wu, 2018 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Dejun Xia, 2018 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Yuming Zhang, 2018 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Xiaomin Zhu, 2018 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Chu Gao, 2019 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yafen Guan, 2019 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Xianzhong Qi, 2018 | Low | Low | Unclear | Low | Low | Unclear | Unclear |
| Jundong Xia, 2019 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Kun Zhao, 2019 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Xuecai Feng, 2020 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Yang Liu, 2020 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Jinqiang Lu, 2020 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Hao Yu, 2020 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Yingwei Zhang, 2020 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Haiyan Du, 2021 | Low | Unclear | Low | Unclear | Low | Unclear | Unclear |
| Li Yao, 2021 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Weiping Zang, 2021 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Xiping Zhang, 2021 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Dongyang Gao, 2022 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Xiaoqiu Wu, 2001 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Lin Chen, 2002 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Leisen Han, 2003 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yuming Tan, 2003 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Hui Li, 2004 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Wenming Yang, 2004 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Ning Ao, 2005 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Rui Chen, 2005 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Tiejun Dai, 2005 | Low | Unclear | Unclear | Low | Low | Unclear | Unclear |
| Yanping Guo, 2005 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Songlin Chen, 2006 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Qiaolin Ou, 2006 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Yongcheng Zhang, 2006 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Guili Gao, 2007 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Xinmin Wang, 2007 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Xianping Wei, 2007 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Deliang Yao, 2007 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Shuikang Ding, 2008 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Xiaoneng Mo, 2008 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Xiaobin Ye, 2008 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Xiaoyan Chen, 2009 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Shuikang Ding, 2009 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Hanbiao Gan, 2009 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Huibing Huang, 2009 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Rong Fan, 2010 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yunxie Guo, 2010 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Wenlong Li, 2010 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Bin Liu, 2010 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Shulin Lu, 2010 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Junhua Ma, 2010 | Low | Unclear | Unclear | Unclear | Low | High | Unclear |
| Xunwen Wang, 2010 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Tao Yang, 2010 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Jianjun Yin, 2010 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yuqin Zhang, 2010 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Conglian Feng, 2011 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Yi Gao, 2011 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Bixian Liang, 2011 | Low | Unclear | Unclear | Unclear | Low | Low | Unclear |
| Yanli Liu, 2011 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Hua Mei, 2011 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Qibo Ran, 2011 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Yongsheng Wang, 2011 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Xiaoshi Zhang, 2011 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Guofeng Gao, 2012 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Linrong Gao, 2012 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Meilin Huang, 2012 | Low | Unclear | Low | Low | Low | Unclear | Low |
| Rongfeng Jiang, 2012 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Chunhong Li, 2012 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Ruiqi Li, 2012 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Qingping Liu, 2012 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Ke Su, 2012 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Lanzhi Tong, 2012 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Fangting Wu, 2012 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Fenguo Zhang, 2012 | Low | Unclear | Low | Unclear | Low | High | Unclear |
| Xiaoshi Zhang, 2012 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Yanli Zhao, 2012 | Low | Unclear | Unclear | Unclear | Low | High | Unclear |
| Saihua Zhu, 2012 | Low | Unclear | Unclear | Unclear | Low | High | Unclear |
| Mingxian Chen, 2013 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yuxun Chen, 2013 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yu Deng, 2013 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Yongzhong Li, 2013 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Feifei Wang, 2013 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yu Wu, 2013 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Huilin Xie, 2013 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Shanyu Xiong, 2013 | Low | Low | Unclear | Unclear | Low | High | Unclear |
| Xiaoli Yao, 2013 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Haijie Zhang, 2013 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Guiying Che, 2014 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Zhengquan Chen, 2014 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Dongmei Fang, 2014 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Fang Fang, 2014 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Zhiyan Gu, 2014 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Cunming Li, 2014 | Low | Low | Unclear | Unclear | Low | Low | Low |
| Qin Li, 2014 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Hongyan Liu, 2014 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| LiQiang Qu, 2014 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Fen Wu, 2014 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yang Zhang, 2014 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Xian Zhao, 2014 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Qingli Zeng, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Xishan Chen, 2015 | Low | Low | Unclear | Unclear | Low | High | Low |
| Xiaomei Chen, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Bo Jin, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Huijun Li, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Jianwei Lv, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yong Ma, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Zhenxian Shen, 2015 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Dan Sun, 2015 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Xia Wang, 2015 | Low | Unclear | Unclear | Unclear | Low | High | Unclear |
| Lijun Wu, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Yanfei Xiang, 2015 | Low | Unclear | Unclear | Unclear | Low | High | Unclear |
| Yinguang Zhang, 2015 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Li Zheng, 2015 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Yudong Zhou, 2015 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Haiping Gu, 2016 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Yan Jiao, 2016 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Yinchun Leng, 2016 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Dongzhen Piao, 2016 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Liyuan Qin, 2016 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Xiaohong Wei, 2016 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Shuhua Wu, 2016 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Can Zhao, 2016 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Jianyong Zheng, 2016 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Zhe Feng, 2017 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Biao Fu, 2017 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Lili Liu, 2017 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Xinyou Shu, 2017 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Hui Zhang, 2017 | Low | Unclear | Unclear | Low | Low | Unclear | Unclear |
| Sufen Chen, 2018 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Desheng Dan, 2018 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Aiqin Fan, 2018 | Low | Low | Unclear | Unclear | Low | High | Low |
| Wei Fu, 2018 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Lijuan Han, 2018 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Wubiao Huang, 2018 | Low | Unclear | Unclear | Unclear | Low | Low | Low |
| Yuanjun Li, 2018 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Mengjue Wang, 2018 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Tianpeng Wang, 2018 | Low | Low | Unclear | Low | Low | Unclear | Unclear |
| Airong Zeng, 2019 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Chaoqun Gao, 2019 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Shizhan Yang, 2019 | Low | Unclear | Low | Unclear | Low | Unclear | Low |
| Huili Liang, 2018 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Junjun Liang, 2018 | Low | Low | Unclear | Unclear | Low | Unclear | Unclear |
| Wenlan Tan, 2018 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Rong Zou, 2018 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Caihua Chen, 2019 | Low | Unclear | Unclear | Low | Low | Unclear | Unclear |
| Minghui Chen, 2019 | Low | Low | Unclear | Low | Low | Unclear | Unclear |
| Binqing Guo, 2019 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Debo Huang, 2019 | Low | Unclear | Unclear | Unclear | Low | High | Low |
| Baogui Liu, 2019 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Chaofeng Wang, 2019 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Fenghua Wu, 2019 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Xiamixinuer·Aihemaiti, 2020 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Dengfu Yan, 2020 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Hongjun Yang, 2020 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Haitao Hu, 2021 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Zhongyin Li, 2021 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Qiubo Qiao, 2021 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Lihong Rong, 2021 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Haijiao Sun, 2021 | Low | Low | Unclear | Low | Low | Unclear | Low |
| Weihui Qin, 2021 | Low | Unclear | Unclear | Unclear | Low | Unclear | Unclear |
| Feifei Tan, 2021 | Low | Unclear | Unclear | Unclear | Low | High | Unclear |
| Xiaolin Tong, 2021 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Hailin Wang, 2021 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
| Shan Wang, 2021 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Yanfen Wang, 2021 | Low | Unclear | Unclear | Low | Low | Unclear | Low |
| Chunfang Wu, 2021 | Low | Low | Unclear | Unclear | Low | Unclear | Low |
| Jie Chen, 2022 | Low | Low | Unclear | Unclear | Low | High | Low |
| Wei Gao, 2022 | Low | Unclear | Unclear | Unclear | Low | Unclear | Low |
Figure 2.
ROB summary (risk of bias of the included studies).
Table 3.
Certainty assessment of included studies in the meta-analysis.
| Interventions | Certainty assessment | No. of patients | Effect size | Certainty | Importance | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Intervention group | Control group | Absolute (95% CI) | |||
| PNS alone | Neurological status (NIHSS) | |||||||||||
| 77 | RCT | Seriousa | Seriousb | Not serious | Not serious | None | 4,495 | 4,094 | RR: 1.197 (1.229 lower to 1.165 higher) | Low | CRITICAL | |
| Total clinical efficacy | ||||||||||||
| 59 | RCT | Seriousa | Seriousb | Not serious | Not serious | None | 3,079 | 2,996 | SMD: −0.826 (−0.707 lower to −0.946 higher) | Low | CRITICAL | |
| Daily living activities | ||||||||||||
| 11 | RCT | Seriousa | Seriousb | Not serious | Seriousc | None | 419 | 420 | RR: 1.675 (2.133 lower to 1.218 higher) | Low | CRITICAL | |
|
| ||||||||||||
| PNS combined with WM/TAU | Neurological status (NIHSS) | |||||||||||
| 100 | RCT | Seriousa | Seriousb | Not serious | Not serious | None | 5,144 | 5,105 | RR: 1.191 (1.217 lower to 1.165 higher) | Low | CRITICAL | |
| Total clinical efficacy | ||||||||||||
| 100 | RCT | Seriousa | Seriousb | Not serious | Not serious | None | 5,191 | 5,156 | SMD: −1.142 (−0.990 lower to −1.295 higher) | Low | CRITICAL | |
| Daily living activities | ||||||||||||
| 44 | RCT | Seriousa | Seriousb | Not serious | Not serious | None | 2,271 | 2,237 | RR: 1.034 (1.168 lower to 0.900 higher) | Low | CRITICAL | |
aAll studies had a high risk of bias based on the ROB assessment; bmoderate to high heterogeneity was detected (I2: 42.8% to 92.1%); cthe total number of sample size is less than 1,000 as recommended.
3.4. Primary Outcome: Neurological Deficit Score
Centered on applying single PNS to treatment, 59 articles involving 6,045 participants reported information on neurological deficit. The intervention group significantly improved the neurological conditions of elderly stroke patients (SMD = −0.826, 95% CI:−0.946 to −0.707; I2 = 78.9%, Pheterogeneity < 0.001) (Table 4 and Figure 3) [16]. The funnel plot and Egger's test results indicated no publication bias (P = 0.066) (Figure 4).
Table 4.
Main analysis and stratified analysis of the effect of panax notoginseng saponins for stroke among older population.
| Interventions | Outcomes and subgroups | Number of studies | Number of patients | Pool effect size (95% CI) | P Z | Heterogeneity | Effects model | ||
|---|---|---|---|---|---|---|---|---|---|
| EG | CG | I 2 (%) | P H | ||||||
| PNS alone | Outcomes | ||||||||
| NIHSS∗ | 59 | 3,079 | 2,966 | −0.826 (−0.946 to −0.707) | <0.001 | 78.9 | <0.001 | Random | |
| Total clinical efficacy∗∗ | 77 | 4,495 | 4,094 | 1.197 (1.165 to 1.229) | <0.001 | 52.9 | <0.001 | Random | |
| ADL∗ | 11 | 419 | 420 | 1.675 (1.218 to 2.133) | <0.001 | 87.7 | <0.001 | Random | |
| Subgroups analyses based on the total clinical efficacy | |||||||||
| Region | |||||||||
| Overall | 77 | 4,495 | 4,094 | 1.197 (1.165 to 1.229) | <0.001 | 52.9 | <0.001 | Random | |
| Develop regions | 42 | 2,121 | 2,026 | 1.195 (1.155 to 1.237) | <0.001 | 37.9 | 0.008 | Random | |
| Developing or undevelop regions | 34 | 2,374 | 2,068 | 1.196 (1.150 to 1.245) | <0.001 | 60.6 | <0.001 | Random | |
| Publication year | |||||||||
| Overall | 77 | 4,495 | 4,094 | 1.197 (1.165 to 1.229) | <0.001 | 52.9 | <0.001 | Random | |
| Above and equal 2015 | 26 | 1,272 | 1,268 | 1.193 (1.151 to 1.236) | <0.001 | 11.9 | 0.0291 | Random | |
| Below 2015 | 51 | 3,223 | 2,826 | 1.193 (1.153 to 1.234) | <0.001 | 59.9 | <0.001 | Random | |
| Total sample size | |||||||||
| Overall | 77 | 4,495 | 4,094 | 1.197 (1.165 to 1.229) | <0.001 | 52.9 | <0.001 | Random | |
| Above or equal 100 | 35 | 2,914 | 2,566 | 1.195 (1.155 to 1.237) | <0.001 | 37.9 | 0.008 | Random | |
| Below 100 | 42 | 1,581 | 1,528 | 1.196 (1.150 to 1.245) | <0.001 | 60.6 | <0.001 | Random | |
| Male to female ratio | |||||||||
| Overall | 68 | 4,067 | 3,696 | 1.198 (1.165 to 1.232) | <0.001 | 54.1 | <0.001 | Random | |
| Above or equal 1 | 62 | 3,444 | 3,316 | 1.203 (1.168 to 1.239) | <0.001 | 54.6 | 0.047 | Random | |
| Below 1 | 6 | 623 | 380 | 1.155 (1.045 to 1.276) | <0.001 | 55.6 | <0.001 | Random | |
|
| |||||||||
| PNS combined with WM/TAU | Outcomes | ||||||||
| NIHSS∗ | 100 | 5,191 | 5,156 | −1.142 (−1.295 to −0.990) | <0.001 | 92.1 | <0.001 | Random | |
| Total clinical efficacy∗∗ | 100 | 5,144 | 5,105 | 1.191 (1.165 to 1.217) | <0.001 | 42.8 | <0.001 | Random | |
| ADL∗ | 44 | 2,271 | 2,237 | 1.034 (0.900 to 1.168) | <0.001 | 77.8 | <0.001 | Random | |
| Subgroups analyses based on the total clinical efficacy | |||||||||
| Region | |||||||||
| Overall | 100 | 5,144 | 5,105 | 1.191 (1.165 to 1.217) | <0.001 | 42.8 | <0.001 | Random | |
| Develop regions | 40 | 1,939 | 1,952 | 1.199 (1.144 to 1.256) | <0.001 | 65.3 | <0.001 | Random | |
| Developing or undevelop regions | 60 | 3,205 | 3,153 | 1.181 (1.158 to 1.205) | <0.001 | 0.0 | 0.553 | Random | |
| Publication year | |||||||||
| Overall | 100 | 5,144 | 5,105 | 1.191 (1.165 to 1.217) | 0.0049 | 42.8 | <0.001 | Random | |
| Above and equal 2015 | 64 | 3,355 | 3,373 | 1.188 (1.138 to 1.240) | <0.001 | 35.7 | 0.003 | Random | |
| Below 2015 | 36 | 1,789 | 1,732 | 1.192 (1.163 to 1.222) | <0.001 | 53.2 | <0.001 | Random | |
| Total sample size | |||||||||
| Overall | 100 | 5,144 | 5,105 | 1.191 (1.165 to 1.217) | <0.001 | 42.8 | <0.001 | Random | |
| Above or equal 100 | 50 | 3,281 | 3,225 | 1.182 (1.144 to 1.221) | 0.0078 | 60.8 | <0.001 | Random | |
| Below 100 | 50 | 1,863 | 1,880 | 1.195 (1.164 to 1.227) | <0.001 | 0.0 | 0.708 | Random | |
| Male to female ratio | |||||||||
| Overall | 92 | 4,723 | 4,684 | 1.190 (1.162 to 1.218) | <0.001 | 44.8 | <0.001 | Random | |
| Above or equal 1 | 87 | 4,439 | 4,400 | 1.188 (1.159 to 1.216) | <0.001 | 46.2 | <0.001 | Random | |
| Below 1 | 5 | 284 | 284 | 1.220 (1.132 to 1.314) | <0.001 | 0.0 | 0.5 | Random | |
∗ Pool effect sizes were presented as standard mean differences (SMDs); ∗∗Pool effect sizes were presented as risk ratio (RR).
ADL, activities of daily living; CG, control group; EG, experimental group; NIHSS, National Institutes of Health Stroke Scale; PNS, Panax notoginseng saponins; TAU, treatment as usual; TCE, total clinical efficacy; WM, Western medicine.
Figure 3.
PNS alone NIHSS forest plot.
Figure 4.
NIHSS-SMD-Ran-funnel plot.
By contrast, 100 articles involving 10,347 participants reported information on neurological deficit after the treatment of combining PNS with WM/TAU. Similarly, the intervention group showed a significant improvement in the neurological conditions (SMD = −1.142, 95% CI:−1.295 to −0.990; I2 = 92.1%, Pheterogeneity < 0.001) (Table 4 and Figure 5) of elderly stroke patients. There was no hint of publication bias in the funnel plot and Egger's test results (P < 0.001) (Figure 6).
Figure 5.
PNS combination NIHSS forest plot.pdf.
Figure 6.
NIHSS-SMD-Ran-funnel plot.pdf.
3.5. Secondary Outcomes: Total Clinical Efficacy
There were 77 articles reporting the outcomes of overall clinical efficacy for using PNS alone, involving 8,589 participants. Our results indicated that, compared to the controlled group, the overall clinical efficacy of the PNS alone group showed statistically significant difference (RR = 1.191, 95% CI: 1.165 to 1.217; I2 = 52.9%, Pheterogeneity<0.001) (Table 4 and Figure 7). The funnel plot and Egger's test results revealed hint of publication bias (P < 0.001) (Figure 8).
Figure 7.
PNS alone total clinical effect forest plot.
Figure 8.
Total clinical effect-RR-Ran-funnel plot.pdf.
For the intervention group using PNS combined with WM/TAU, 100 articles reported the outcome of overall clinical efficacy, with 10,249 participants involved. Compared with the controlled group, there was statistical significance in the overall clinical efficacy of PNS combined with WM/TAU in treating elderly stoke (RR = 1.191, 95% CI: 1.165 to 1.217; I2 = 42.8%, Pheterogeneity<0.001), as shown in Table 4 and Figure 9. Hint of publication bias was observed in the funnel plot and Egger's test results (P < 0.001) (Figure 10).
Figure 9.
PNS combination total clinical effect forest plot.
Figure 10.
Total clinical effect-RR-Ran-funnel plot.pdf.
3.6. Activities of Daily Living Score
There were 11 articles reporting ADLs of 839 elderly stroke patients who were treated with PNS alone. As shown in Table 4, elderly stroke patients in the intervention group who were treated with PNS displayed significant improvement in their ADLs (RR = 1.675, 95% CI: 1.218 to 2.133; I2 = 87.7%, Pheterogeneity<0.001) (Table 4 and Figure 11). The funnel plot and Egger's test results hinted the existence of publication bias (P = 0.012) (Figure 12).
Figure 11.
PNS alone ADL forest plot.pdf.
Figure 12.
ADL-SMD-Ran-funnel plot [1].pdf.
As for the effect of PNS combined with WM/TAU on ADLs in elderly stroke patients (SMD = 1.034, 95% CI: 0.900 to 1.168; I2 = 77.8%, Pheterogeneity<0.001) (Table 4 and Figure 13), 44 articles with 4,508 participants showed that compared to the controlled group, elderly stroke patients in the intervention group did not improve significantly. The funnel plot and Egger's test results indicated hint of publication bias (P = 0.003) (Figure 14).
Figure 13.
PNS combination ADL forest plot.pdf.
Figure 14.
ADL-SMD-Ran-Funnel plot.pdf.
3.7. Subgroup Analysis
Due to the significant heterogeneity of total clinical efficacy, subgroup analysis was conducted based on the following variables: area (developed vs. developing areas), publication year (before vs. and after 2015), sample size (less vs. no less than 100), and male to female ratio (below vs. not below one). The analysis results showed that, for the single PNS intervention, heterogeneity mainly came from articles published before 2015 (Table 4). For the intervention group using PNS combined with WM/TAU, the primary source of heterogeneity was articles with a sample size of less than 100 or with a male to female ratio of less than 1. Results of the analyses revealed that the source of heterogeneity potentially correlated with publication year, treatment duration, and total sample size as well as region development condition. The subgroup analysis results are shown in Table 4.
4. Discussion
In this study, 206 articles involving 21,759 participants were collected for meta-analysis. The results showed that compared with the controlled group, single PNS or PNS combined with WM/TAU significantly improved the neurological status, overall clinical efficacy, and ADLs of elderly stroke patients.
In clinical treatment for ischemic stroke, antiplatelet, statin, and antihypertension were the three “cornerstones” [21]. However, the application of WM hit a bottleneck due to issues such as drug resistance, impairment of liver and kidney function, and interactions caused by the co-use of multiple drugs and the like. On the strength of traditional Chinese medicine theory and experience, Chinese medical workers have achieved favorable results in preventing and treating cerebrovascular diseases with natural medicines. After extensively reviewing and analyzing 206 PNS-related clinical trials, this study confirmed the effectiveness of PNS in the treatment of stroke in the elderly population and provided a theoretical basis for treating them in the field of traditional Chinese medicine.
As a traditional Chinese medicine with a history of over 600 years, PNS has the functions of promoting blood circulation, removing blood stasis, reducing swelling, relieving pain, etc. PNS products, such as Sanqitongshu capsule, are mainly composed of panaxtriol saponins (PTS), a component in Sanqi capable of promoting blood circulation and removing blood stasis [22, 23]. By now, the mechanism of PNS is still unclear. It is likely that PTS reduces endothelin levels in the peripheral blood, increases cerebral blood supply to ischemic areas, regulates blood hypercoagulability, and improves the microcirculation in ischemic brain tissue [24]. The major active component in PTS, Rg1 (accounting for 60%), and R1 and Re (accounting for 20%), can improve cerebral ischemic dysfunction, restore ischemic cerebral metabolic abnormalities, resist platelet aggregation, and reduce blood viscosity in the treatment of cerebral arterial thrombosis. In addition, Rg1 enhances the activity of the fibrinolytic system, promotes the release of nitric oxide from the vascular endothelium, and thus, has an antithrombotic effect [25]. For ischemic reperfusion injury, PNS can reduce calcium overload, cerebral edema, and structural damage and promote nerve repair during reperfusion [26] and help reduce mortality during ischemic-reperfusion. What is more, relevant studies show that PNS enhances the ischemic tolerance of the brain and reduces the recurrence of fatal ischemic brain injury, which is beneficial to the secondary prevention of ischemic stroke [27].
PNS has a wide range of pharmacological effects, including scavenging free radicals and antioxidative stress, inhibiting inflammatory factors, blocking calcium ion channels, improving microcirculation and energy metabolism, etc. These effects account for the favorable results of PNS in the treatment of ischemic cerebrovascular disease. PNS can dilate cerebral blood vessels so that cerebrovascular resistance reduces and cerebral blood flow increases. For animals, experimental results indicated that mean blood pressure (BMP) and cerebrovascular resistance (CVR) of anaesthetized rabbits and rats are reduced after the intervention of PNS, depending on the dosage used, but their cerebral blood flow did not increase [28]. PNS for injection, made of Sanqi, has high bioavailability, rapid action, and definite curative effect, which, however, is likely to cause adverse reactions, because it is complicatedly composed, the content of its active components and impurities is difficult to control, and it acts on multiple aspects of the brain. Therefore, it is essential to specify the ingredients and their doses in the injectable PNS so that the quality of the injection as well as the safety of patients can be ensured [28]. Related preparation research explained that compound Xueshuantong capsules effectively reduce blood viscosity, inhibit platelet activation and aggregation, enhance vasodilation regulation function, and increase fibrinase activity, thereby mitigating the cerebrovascular injury caused by oxidative stress response due to ischemic oxygen feeding. Additionally, compound Xueshuantong capsules reduce blood viscosity, regulate blood lipids, and block calcium ion channels, which is conducive to the recovery of cranial nerve function [29–32]. Oral PNS can be used for treating acute stroke by way of multi-target and multi-path. It can improve cerebral blood supply, repair nerve function, narrow the infarct size, and improve the clinical prognosis displaying the clinical advantages of traditional Chinese medicines.
Subgroup analysis discovered that PNS intervention or PNS combined with WM/TAU improved the overall clinical efficacy, neurological status, and ADLs of elderly stroke patients. Sources of heterogeneity probably came from articles with smaller sample sizes or older publications. Conclusions drawn from these articles were less reliable and the evidence was not fully updated, consequently giving rise to heterogeneity in our meta-analysis results.
To our knowledge, this is the first meta-analysis of the clinical efficacy and safety of PNS in the treatment of elderly stroke patients. Based on extensive experimental data, this study made a scientific and objective evaluation of the efficacy and safety of PNS in the treatment of acute elderly stroke. Additionally, clinical application of the study provided an objective and reliable evidence-based reference for the follow-up research, nursing staff, clinical workers, and health policy decision makers. However, there were some limitations. For one thing, some of the articles involved were of relatively low quality, with unclear randomization methods, allocation concealment, and uncalculated sample size, which affected the reliability of the conclusion in this study. For another, the fact that all the included studies are Chinese led to linguistic bias in the results. Therefore, follow-up studies should carefully be designed, implemented, and reported following the standard of RCTs [33]. Moreover, we found a moderate to high heterogeneity across our study, which might directly affect the reliability of our evidence. Although by implementing subgroup analyses based on the primary results, we identified the sources of heterogeneity caused by different treatment duration and regional development condition in different literature, there were still other hidden elements affecting the measured effect of PNS in this study. Consequently, it is crucial to carry out multi-center and larger-sample RCTs on treating elderly stroke patients with PNS so as to provide guidance for clinical treatment and follow-up research.
5. Conclusion
Our study found that PNS intervention or PNS combined with WM/TAU significantly improved the neurological function, DLAs, and the overall clinical efficacy in elderly stroke patients. Considering the quality of the included studies, the results of this study should be interpreted with caution. And it is necessary to conduct more multi-center RCTs with high quality to explore the efficacy and safety of PNS for elderly stroke patients in the future, thus contributing more reliable primary data to evidence-based decision-making.
Acknowledgments
The work was supported by the Science and Technology Development Fund of Macao (FDCT: 0055/2019/AMJ).
Abbreviations
- PNS:
Panax notoginseng saponins
- RCT:
Randomized controlled trials
- RR:
Relative risk
- CI:
Confidence interval
- SMD:
Standard mean difference
- WM:
Western medicine
- TAU:
Treatment as usual
- XC:
Xueshuantong capsule
- XSC:
Xuesaitong soft capsule
- STC:
Sanqi Tongshu capsule
- CXC:
Compound Xueshuantong capsule
- TCM:
Traditional Chinese Medicine
- NIHSS:
National Institutes of Health Stroke Scale
- PTS:
Panaxtriol saponins
- BMP:
Mean blood pressure
- CVR:
Cerebrovascular resistance.
Appendix
A. PubMed
#1 “Stroke” [Mesh]
#2 (((((((((((((((((((((((((((Strokes[Title/Abstract]) OR (Cerebrovascular Accident[Title/Abstract])) OR (Cerebrovascular Accidents[Title/Abstract])) OR (CVA (Cerebrovascular Accident[Title/Abstract]))) OR (CVAs (Cerebrovascular Accident[Title/Abstract]))) OR (Cerebrovascular Apoplexy[Title/Abstract])) OR (Apoplexy, Cerebrovascular[Title/Abstract])) OR (Vascular Accident, Brain[Title/Abstract])) OR (Brain Vascular Accident[Title/Abstract])) OR (Brain Vascular Accidents[Title/Abstract])) OR (Vascular Accidents, Brain[Title/Abstract])) OR (Cerebrovascular Stroke[Title/Abstract])) OR (Cerebrovascular Strokes[Title/Abstract])) OR (Stroke, Cerebrovascular[Title/Abstract])) OR (Strokes, Cerebrovascular[Title/Abstract])) OR (Apoplexy[Title/Abstract])) OR (Cerebral Stroke[Title/Abstract])) OR (Cerebral Strokes[Title/Abstract])) OR (Stroke, Cerebral[Title/Abstract])) OR (Strokes, Cerebral[Title/Abstract])) OR (Stroke, Acute[Title/Abstract])) OR (Acute Stroke[Title/Abstract])) OR (Acute Strokes[Title/Abstract])) OR (Strokes, Acute[Title/Abstract])) OR (Cerebrovascular Accident, Acute[Title/Abstract])) OR (Acute Cerebrovascular Accident[Title/Abstract])) OR (Acute Cerebrovascular Accidents[Title/Abstract])) OR (Cerebrovascular Accidents, Acute[Title/Abstract])
#3 (“Stroke” [Mesh]) OR ((((((((((((((((((((((((((((Strokes[Title/Abstract]) OR (Cerebrovascular Accident[Title/Abstract])) OR (Cerebrovascular Accidents[Title/Abstract])) OR (CVA (Cerebrovascular Accident[Title/Abstract]))) OR (CVAs (Cerebrovascular Accident[Title/Abstract]))) OR (Cerebrovascular Apoplexy[Title/Abstract])) OR (Apoplexy, Cerebrovascular[Title/Abstract])) OR (Vascular Accident, Brain[Title/Abstract])) OR (Brain Vascular Accident[Title/Abstract])) OR (Brain Vascular Accidents[Title/Abstract])) OR (Vascular Accidents, Brain[Title/Abstract])) OR (Cerebrovascular Stroke[Title/Abstract])) OR (Cerebrovascular Strokes[Title/Abstract])) OR (Stroke, Cerebrovascular[Title/Abstract])) OR (Strokes, Cerebrovascular[Title/Abstract])) OR (Apoplexy[Title/Abstract])) OR (Cerebral Stroke[Title/Abstract])) OR (Cerebral Strokes[Title/Abstract])) OR (Stroke, Cerebral[Title/Abstract])) OR (Strokes, Cerebral[Title/Abstract])) OR (Stroke, Acute[Title/Abstract])) OR (Acute Stroke[Title/Abstract])) OR (Acute Strokes[Title/Abstract])) OR (Strokes, Acute[Title/Abstract])) OR (Cerebrovascular Accident, Acute[Title/Abstract])) OR (Acute Cerebrovascular Accident[Title/Abstract])) OR (Acute Cerebrovascular Accidents[Title/Abstract])) OR (Cerebrovascular Accidents, Acute[Title/Abstract]))
#4 “Ischemic Stroke” [Mesh]
#5 (((((((((((((((((((((((Ischemic Strokes[Title/Abstract]) OR (Stroke, Ischemic[Title/Abstract])) OR (Ischemic Stroke[Title/Abstract])) OR (Ischemic Strokes[Title/Abstract])) OR (Stroke, Ischemic[Title/Abstract])) OR (Cryptogenic Ischemic Stroke[Title/Abstract])) OR (Cryptogenic Ischemic Strokes[Title/Abstract])) OR (Ischemic Stroke, Cryptogenic[Title/Abstract])) OR (Stroke, Cryptogenic Ischemic[Title/Abstract])) OR (Cryptogenic Stroke[Title/Abstract])) OR (Cryptogenic Strokes[Title/Abstract])) OR (Stroke, Cryptogenic[Title/Abstract])) OR (Cryptogenic Embolism Stroke[Title/Abstract])) OR (Cryptogenic Embolism Strokes[Title/Abstract])) OR (Embolism Stroke, Cryptogenic[Title/Abstract])) OR (Stroke, Cryptogenic Embolism[Title/Abstract])) OR (Wake-up Stroke[Title/Abstract])) OR (Stroke, Wake-up[Title/Abstract])) OR (Wake up Stroke[Title/Abstract])) OR (Wake-up Strokes[Title/Abstract])) OR (Acute Ischemic Stroke[Title/Abstract])) OR (Acute Ischemic Strokes[Title/Abstract])) OR (Ischemic Stroke, Acute[Title/Abstract])) OR (Stroke, Acute Ischemic[Title/Abstract])
#6 (“Ischemic Stroke”[Mesh]) OR ((((((((((((((((((((((((Ischemic Strokes[Title/Abstract]) OR (Stroke, Ischemic[Title/Abstract])) OR (Ischemic Stroke[Title/Abstract])) OR (Ischemic Strokes[Title/Abstract])) OR (Stroke, Ischemic[Title/Abstract])) OR (Cryptogenic Ischemic Stroke[Title/Abstract])) OR (Cryptogenic Ischemic Strokes[Title/Abstract])) OR (Ischemic Stroke, Cryptogenic[Title/Abstract])) OR (Stroke, Cryptogenic Ischemic[Title/Abstract])) OR (Cryptogenic Stroke[Title/Abstract])) OR (Cryptogenic Strokes[Title/Abstract])) OR (Stroke, Cryptogenic[Title/Abstract])) OR (Cryptogenic Embolism Stroke[Title/Abstract])) OR (Cryptogenic Embolism Strokes[Title/Abstract])) OR (Embolism Stroke, Cryptogenic[Title/Abstract])) OR (Stroke, Cryptogenic Embolism[Title/Abstract])) OR (Wake-up Stroke[Title/Abstract])) OR (Stroke, Wake-up[Title/Abstract])) OR (Wake up Stroke[Title/Abstract])) OR (Wake-up Strokes[Title/Abstract])) OR (Acute Ischemic Stroke[Title/Abstract])) OR (Acute Ischemic Strokes[Title/Abstract])) OR (Ischemic Stroke, Acute[Title/Abstract])) OR (Stroke, Acute Ischemic[Title/Abstract]))
#7 ((“Stroke”[Mesh]) OR ((((((((((((((((((((((((((((Strokes[Title/Abstract]) OR (Cerebrovascular Accident[Title/Abstract])) OR (Cerebrovascular Accidents[Title/Abstract])) OR (CVA (Cerebrovascular Accident[Title/Abstract]))) OR (CVAs (Cerebrovascular Accident[Title/Abstract]))) OR (Cerebrovascular Apoplexy[Title/Abstract])) OR (Apoplexy, Cerebrovascular[Title/Abstract])) OR (Vascular Accident, Brain[Title/Abstract])) OR (Brain Vascular Accident[Title/Abstract])) OR (Brain Vascular Accidents[Title/Abstract])) OR (Vascular Accidents, Brain[Title/Abstract])) OR (Cerebrovascular Stroke[Title/Abstract])) OR (Cerebrovascular Strokes[Title/Abstract])) OR (Stroke, Cerebrovascular[Title/Abstract])) OR (Strokes, Cerebrovascular[Title/Abstract])) OR (Apoplexy[Title/Abstract])) OR (Cerebral Stroke[Title/Abstract])) OR (Cerebral Strokes[Title/Abstract])) OR (Stroke, Cerebral[Title/Abstract])) OR (Strokes, Cerebral[Title/Abstract])) OR (Stroke, Acute[Title/Abstract])) OR (Acute Stroke[Title/Abstract])) OR (Acute Strokes[Title/Abstract])) OR (Strokes, Acute[Title/Abstract])) OR (Cerebrovascular Accident, Acute[Title/Abstract])) OR (Acute Cerebrovascular Accident[Title/Abstract])) OR (Acute Cerebrovascular Accidents[Title/Abstract])) OR (Cerebrovascular Accidents, Acute[Title/Abstract]))) OR ((“Ischemic Stroke”[Mesh]) OR ((((((((((((((((((((((((Ischemic Strokes[Title/Abstract]) OR (Stroke, Ischemic[Title/Abstract])) OR (Ischemic Stroke[Title/Abstract])) OR (Ischemic Strokes[Title/Abstract])) OR (Stroke, Ischemic[Title/Abstract])) OR (Cryptogenic Ischemic Stroke[Title/Abstract])) OR (Cryptogenic Ischemic Strokes[Title/Abstract])) OR (Ischemic Stroke, Cryptogenic[Title/Abstract])) OR (Stroke, Cryptogenic Ischemic[Title/Abstract])) OR (Cryptogenic Stroke[Title/Abstract])) OR (Cryptogenic Strokes[Title/Abstract])) OR (Stroke, Cryptogenic[Title/Abstract])) OR (Cryptogenic Embolism Stroke[Title/Abstract])) OR (Cryptogenic Embolism Strokes[Title/Abstract])) OR (Embolism Stroke, Cryptogenic[Title/Abstract])) OR (Stroke, Cryptogenic Embolism[Title/Abstract])) OR (Wake-up Stroke[Title/Abstract])) OR (Stroke, Wake-up[Title/Abstract])) OR (Wake up Stroke[Title/Abstract])) OR (Wake-up Strokes[Title/Abstract])) OR (Acute Ischemic Stroke[Title/Abstract])) OR (Acute Ischemic Strokes[Title/Abstract])) OR (Ischemic Stroke, Acute[Title/Abstract])) OR (Stroke, Acute Ischemic[Title/Abstract])))
#8 “Panax notoginseng”[Mesh]
#9 ((((((((((((((((((((((((((((((((((((Panax notoginsengs[Title/Abstract]) OR (notoginsengs, Panax[Title/Abstract])) OR (fufang xueshuantong[Title/Abstract])) OR (Xueshuantong[Title/Abstract])) OR (Xue shuan tong[Title/Abstract])) OR (xueshuangtong capsule[Title/Abstract])) OR (compound xueshuantong capsule[Title/Abstract])) OR (xuesaitong soft capsule[Title/Abstract])) OR (sanqi tongshu capsule[Title/Abstract])) OR (xueshuantong injection[Title/Abstract])) OR (notoginseng saponin[Title/Abstract])) OR (total notoginsenoside[Title/Abstract])) OR (panax notoginseng saponins[Title/Abstract])) OR (radix notoginseng[Title/Abstract])) OR (radix panax notoginseng[Title/Abstract])) OR (sanqi[Title/Abstract])) OR (san qi[Title/Abstract])) OR (san-qi[Title/Abstract])) OR (panax pseudoginseng[Title/Abstract])) OR (pseudoginseng[Title/Abstract])) OR (notoginseng[Title/Abstract])) OR (pseudo ginseng[Title/Abstract])) OR (pseudo-ginseng[Title/Abstract])) OR (tianqi[Title/Abstract])) OR (tian qi[Title/Abstract])) OR (xuesetong[Title/Abstract])) OR (xue se tong[Title/Abstract])) OR (xuesaitong[Title/Abstract])) OR (xue sai tong[Title/Abstract])) OR (lulutong[Title/Abstract])) OR (lu lu tong[Title/Abstract])) OR (zheng kang nao ming[Title/Abstract])) OR (nao ming[Title/Abstract])) OR (luo tai[Title/Abstract])) OR (xin nao tai[Title/Abstract])) OR (san qi tong shu[Title/Abstract]))
#10 (“Panax notoginseng”[Mesh]) OR (((((((((((((((((((((((((((((((((((((Panax notoginsengs[Title/Abstract]) OR (notoginsengs, Panax[Title/Abstract])) OR (fufang xueshuantong[Title/Abstract])) OR (Xueshuantong[Title/Abstract])) OR (Xue shuan tong[Title/Abstract])) OR (xueshuangtong capsule[Title/Abstract])) OR (compound xueshuantong capsule[Title/Abstract])) OR (xuesaitong soft capsule[Title/Abstract])) OR (sanqi tongshu capsule[Title/Abstract])) OR (xueshuantong injection[Title/Abstract])) OR (notoginseng saponin[Title/Abstract])) OR (total notoginsenoside[Title/Abstract])) OR (panax notoginseng saponins[Title/Abstract])) OR (radix notoginseng[Title/Abstract])) OR (radix panax notoginseng[Title/Abstract])) OR (sanqi[Title/Abstract])) OR (san qi[Title/Abstract])) OR (san-qi[Title/Abstract])) OR (panax pseudoginseng[Title/Abstract])) OR (pseudoginseng[Title/Abstract])) OR (notoginseng[Title/Abstract])) OR (pseudo ginseng[Title/Abstract])) OR ( pseudo-ginseng[Title/Abstract])) OR (tianqi[Title/Abstract])) OR (tian qi[Title/Abstract])) OR (xuesetong[Title/Abstract])) OR (xue se tong[Title/Abstract])) OR (xuesaitong[Title/Abstract])) OR (xue sai tong[Title/Abstract])) OR (lulutong[Title/Abstract])) OR (lu lu tong[Title/Abstract])) OR (zheng kang nao ming[Title/Abstract])) OR (nao ming[Title/Abstract])) OR (luo tai[Title/Abstract])) OR (xin nao tai[Title/Abstract])) OR (san qi tong shu[Title/Abstract])))
#11 (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])
#12 (((“Stroke”[Mesh]) OR ((((((((((((((((((((((((((((Strokes[Title/Abstract]) OR (Cerebrovascular Accident[Title/Abstract])) OR (Cerebrovascular Accidents[Title/Abstract])) OR (CVA (Cerebrovascular Accident[Title/Abstract]))) OR (CVAs (Cerebrovascular Accident[Title/Abstract]))) OR (Cerebrovascular Apoplexy[Title/Abstract])) OR (Apoplexy, Cerebrovascular[Title/Abstract])) OR (Vascular Accident, Brain[Title/Abstract])) OR (Brain Vascular Accident[Title/Abstract])) OR (Brain Vascular Accidents[Title/Abstract])) OR (Vascular Accidents, Brain[Title/Abstract])) OR (Cerebrovascular Stroke[Title/Abstract])) OR (Cerebrovascular Strokes[Title/Abstract])) OR (Stroke, Cerebrovascular[Title/Abstract])) OR (Strokes, Cerebrovascular[Title/Abstract])) OR (Apoplexy[Title/Abstract])) OR (Cerebral Stroke[Title/Abstract])) OR (Cerebral Strokes[Title/Abstract])) OR (Stroke, Cerebral[Title/Abstract])) OR (Strokes, Cerebral[Title/Abstract])) OR (Stroke, Acute[Title/Abstract])) OR (Acute Stroke[Title/Abstract])) OR (Acute Strokes[Title/Abstract])) OR (Strokes, Acute[Title/Abstract])) OR (Cerebrovascular Accident, Acute[Title/Abstract])) OR (Acute Cerebrovascular Accident[Title/Abstract])) OR (Acute Cerebrovascular Accidents[Title/Abstract])) OR (Cerebrovascular Accidents, Acute[Title/Abstract]))) OR ((“Ischemic Stroke”[Mesh]) OR ((((((((((((((((((((((((Ischemic Strokes[Title/Abstract]) OR (Stroke, Ischemic[Title/Abstract])) OR (Ischemic Stroke[Title/Abstract])) OR (Ischemic Strokes[Title/Abstract])) OR (Stroke, Ischemic[Title/Abstract])) OR (Cryptogenic Ischemic Stroke[Title/Abstract])) OR (Cryptogenic Ischemic Strokes[Title/Abstract])) OR (Ischemic Stroke, Cryptogenic[Title/Abstract])) OR (Stroke, Cryptogenic Ischemic[Title/Abstract])) OR (Cryptogenic Stroke[Title/Abstract])) OR (Cryptogenic Strokes[Title/Abstract])) OR (Stroke, Cryptogenic[Title/Abstract])) OR (Cryptogenic Embolism Stroke[Title/Abstract])) OR (Cryptogenic Embolism Strokes[Title/Abstract])) OR (Embolism Stroke, Cryptogenic[Title/Abstract])) OR (Stroke, Cryptogenic Embolism[Title/Abstract])) OR (Wake-up Stroke[Title/Abstract])) OR (Stroke, Wake-up[Title/Abstract])) OR (Wake up Stroke[Title/Abstract])) OR (Wake-up Strokes[Title/Abstract])) OR (Acute Ischemic Stroke[Title/Abstract])) OR (Acute Ischemic Strokes[Title/Abstract])) OR (Ischemic Stroke, Acute[Title/Abstract])) OR (Stroke, Acute Ischemic[Title/Abstract])))) AND ((“Panax notoginseng”[Mesh]) OR (((((((((((((((((((((((((((((((((((((Panax notoginsengs[Title/Abstract]) OR (notoginsengs, Panax[Title/Abstract])) OR (fufang xueshuantong[Title/Abstract])) OR (Xueshuantong[Title/Abstract])) OR (Xue shuan tong[Title/Abstract])) OR (xueshuangtong capsule[Title/Abstract])) OR (compound xueshuantong capsule[Title/Abstract])) OR (xuesaitong soft capsule[Title/Abstract])) OR (sanqi tongshu capsule[Title/Abstract])) OR (xueshuantong injection[Title/Abstract])) OR (notoginseng saponin[Title/Abstract])) OR (total notoginsenoside[Title/Abstract])) OR (panax notoginseng saponins[Title/Abstract])) OR (radix notoginseng[Title/Abstract])) OR (radix panax notoginseng[Title/Abstract])) OR (sanqi[Title/Abstract])) OR (san qi[Title/Abstract])) OR (san-qi[Title/Abstract])) OR (panax pseudoginseng[Title/Abstract])) OR (pseudoginseng[Title/Abstract])) OR (notoginseng[Title/Abstract])) OR (pseudo ginseng[Title/Abstract])) OR ( pseudo-ginseng[Title/Abstract])) OR (tianqi[Title/Abstract])) OR (tian qi[Title/Abstract])) OR (xuesetong[Title/Abstract])) OR (xue se tong[Title/Abstract])) OR (xuesaitong[Title/Abstract])) OR (xue sai tong[Title/Abstract])) OR (lulutong[Title/Abstract])) OR (lu lu tong[Title/Abstract])) OR (zheng kang nao ming[Title/Abstract])) OR (nao ming[Title/Abstract])) OR (luo tai[Title/Abstract])) OR (xin nao tai[Title/Abstract])) OR (san qi tong shu[Title/Abstract]))))
B. Embase
#1 “cerebrovascular accident”/exp
#2 “strokes”: ab, ti OR “cerebrovascular accident”: ab, ti OR “cerebrovascular accidents”: ab, ti OR “cva (cerebrovascular accident)”: ab, ti OR “cvas (cerebrovascular accident)”: ab, ti OR “cerebrovascular apoplexy”: ab, ti OR “apoplexy, cerebrovascular”: ab, ti OR “vascular accident, brain”: ab, ti OR “brain vascular accident”: ab, ti OR “brain vascular accidents”: ab, ti OR “vascular accidents, brain”: ab, ti OR “stroke, cerebrovascular”: ab, ti OR “cerebrovascular strokes”: ab, ti OR “apoplexy”: ab, ti OR “strokes, cerebrovascular”: ab, ti OR “cerebral strokes”: ab, ti OR “cerebral stroke”: ab, ti OR “stroke, cerebral”: ab, ti OR “strokes, cerebral”: ab, ti OR “stroke, acute”: ab, ti OR “acute stroke”: ab, ti OR “acute strokes”: ab, ti OR “strokes, acute”: ab, ti OR “cerebrovascular accident, acute”: ab, ti OR “acute cerebrovascular accident”: ab, ti OR “acute cerebrovascular accidents”: ab, ti OR “cerebrovascular accidents, acute”: ab, ti
#3 “cerebrovascular accident”/exp
#4 “ischemic strokes”: ti, ab OR “stroke, ischemic”: ab, ti OR “ischemic stroke”: ab, ti OR “ischemic strokes”: ab, ti OR “stroke, ischemic”: ab, ti OR “cryptogenic ischemic stroke”: ab, ti OR “cryptogenic ischemic strokes”: ab, ti OR “ischemic stroke, cryptogenic”: ab, ti OR “stroke, cryptogenic ischemic”: ab, ti OR “scryptogenic stroke”: ab, ti OR “cryptogenic strokes”: ab, ti OR “stroke, cryptogenic”: ab, ti OR “cryptogenic embolism stroke”: ab, ti OR “cryptogenic embolism strokes”: ab, ti OR “embolism stroke, cryptogenic”: ab, ti OR “stroke, cryptogenic embolism”: ab, ti OR “wake-up stroke”: ab, ti OR “stroke, wake-up: ab, ti OR “wake up stroke”: ab, ti OR “wake-up strokes”: ab, ti OR “acute ischemic stroke”: ab, ti OR “acute ischemic strokes”: ab, ti OR “ischemic stroke, acute”: ab, ti OR “stroke, acute ischemic”: ab, ti OR
#5 “panax notoginseng”/exp OR “panax notoginseng extract”/exp
#6 “panax notoginsengs”: ab, ti OR notoginsengs, panax”: ab, ti OR “fufang xueshuantong”: ab, ti OR “xueshuantong”: ab, ti OR “xue shuan tong”: ab, ti OR “xueshuangtong capsule”: ab, ti OR “ompound xueshuantong capsule”: ab, ti OR “xuesaitong soft capsule”: ab, ti OR “tsanqi tongshu capsule”: ab, ti OR “xueshuantong injection”: ab, ti OR “notoginseng saponin”: ab, ti OR “total notoginsenoside”: ab, ti OR “panax notoginseng saponins”: ab, ti OR “radix notoginseng”: ab, ti OR “radix panax notoginseng”: ab, ti OR “sanqi”: ab, ti OR “san qi”: ab, ti OR “san-qi”: ab, ti OR “panax pseudoginseng”: ab, ti OR “pseudoginseng”: ab, ti OR “notoginseng”: ab, ti OR “pseudo ginseng”: ab, ti OR “pseudo-ginseng”: ab, ti OR “tianqi”: ab, ti OR “tian qi”: ab, ti OR “xuesetong”: ab, ti OR “xue se tong”: ab, ti OR “xuesaitong”: ab, ti OR “xue sai tong”: ab, ti OR “lulutong”: ab, ti OR “lu lu tong”: ab, ti OR “zheng kang nao ming”: ab, ti OR “nao ming”: ab, ti OR “luo tai”: ab, ti OR “luotai”: ab, ti OR “xin nao tai”: ab, ti OR “xinnaotai”: ab, ti OR “naoming”: ab, ti OR “san qi tong shu”: ab, ti OR “sanqitongshu”: ab, ti OR
#7 “crossover procedure”: de OR “double-blind procedure”: de OR “randomized controlled trial”: de OR “single-blind procedure”: de OR random∗: de, ab, ti OR factorial∗: de, ab, ti OR crossover∗: de, ab, ti OR ((cross NEXT/1over∗): de, ab, ti) OR placebo∗: de, ab, ti OR ((doubl∗NEAR/1 blind∗): de, ab, ti) OR ((singl∗ NEAR/1 blind∗): de, ab, ti) OR assign∗: de, ab, ti OR allocat∗: de, ab, ti OR volunteer∗: de, ab, ti
#8 #1 OR #2 OR #3 OR #4
#9 #5 OR #6
#10 #8 AND #9 AND #10
C. Cochrane Library
#1 MeSH descriptor: [Stroke] explode all trees
#2 (Strokes): ti, ab, kw OR (Cerebrovascular Accident): ti, ab, kw OR (Cerebrovascular Accidents): ti, ab, kw OR (CVA (cerebrovascular accident)): ti, ab, kw OR (CVAs (cerebrovascular accident)): ti, ab, kw OR (cerebrovascular apoplexy): ti, ab, kw OR (apoplexy, cerebrovascular): ti, ab, kw OR (vascular accident, brain): ti, ab, kw OR (brain vascular accident): ti, ab, kw OR (brain vascular accidents): ti, ab, kw OR (vascular accidents, brain): ti, ab, kw OR (cerebrovascular stroke): ti, ab, kw OR (cerebrovascular strokes): ti, ab, kw OR (stroke, cerebrovascular): ti, ab, kw OR (strokes, cerebrovascular): ti, ab, kw OR (apoplexy): ti, ab, kw OR (cerebral stroke): ti, ab, kw OR (cerebral strokes): ti, ab, kw OR (stroke, cerebral): ti, ab, kw OR (strokes, cerebral): ti, ab, kw OR (stroke, acute): ti, ab, kw OR (acute stroke): ti, ab, kw OR (acute strokes): ti, ab, kw OR (strokes, acute): ti, ab, kw OR (cerebrovascular accident, acute): ti, ab, kw OR (acute cerebrovascular accident): ti, ab, kw OR (acute cerebrovascular accidents): ti, ab, kw OR (cerebrovascular accidents, acute): ti, ab, kw OR (ischemic stroke): ti, ab, kw OR (ischemic strokes): ti, ab, kw OR (stroke, ischemic): ti, ab, kw OR (ischemic stroke): ti, ab, kw OR (ischemic strokes): ti, ab, kw OR (stroke, ischemic): ti, ab, kw OR (cryptogenic ischemic stroke): ti, ab, kw OR (cryptogenic ischemic strokes): ti, ab, kw OR (ischemic stroke, cryptogenic): ti, ab, kw OR (stroke, cryptogenic ischemic): ti, ab, kw OR (cryptogenic stroke): ti, ab, kw OR (cryptogenic strokes): ti, ab, kw OR (stroke, cryptogenic): ti, ab, kw OR (cryptogenic embolism stroke): ti, ab, kw OR (cryptogenic embolism strokes): ti, ab, kw OR (embolism stroke, cryptogenic): ti, ab, kw OR (stroke, cryptogenic embolism): ti, ab, kw OR (wake-up stroke): ti, ab, kw OR (stroke, wake-up): ti, ab, kw OR (wake up stroke): ti, ab, kw OR (wake-up strokes): ti, ab, kw OR (acute ischemic stroke): ti, ab, kw OR (acute ischemic strokes): ti, ab, kw OR (ischemic stroke, acute): ti, ab, kw OR (stroke, acute ischemic): ti, ab, kw
#3 MeSH descriptor: [Ischemic Stroke] explode all trees
#4 (notoginsengs, panax): ti, ab, kw OR (panax notoginsengs): ti, ab, kw OR (panax notoginseng extract): ti, ab, kw OR (xueshuantong): ti, ab, kw OR (fufang xueshuantong): ti, ab, kw OR (xue shuan tong): ti, ab, kw OR (xueshuangtong capsule): ti, ab, kw OR (compound xueshuantong capsule): ti, ab, kw OR (xuesaitong soft capsule): ti, ab, kw OR (sanqi tongshu capsule): ti, ab, kw OR (xueshuantong injection): ti, ab, kw OR (notoginseng saponin): ti, ab, kw OR (total notoginsenoside): ti, ab, kw OR (panax notoginseng saponins): ti, ab, kw OR (radix notoginseng): ti, ab, kw OR (radix panax notoginseng): ti, ab, kw OR (sanqi): ti, ab, kw OR (san qi): ti, ab, kw OR (san-qi): ti, ab, kw OR (panax pseudoginseng): ti, ab, kw OR (pseudoginseng): ti, ab, kw OR (notoginseng): ti, ab, kw OR (pseudo ginseng): ti, ab, kw OR (pseudo-ginseng): ti, ab, kw OR (tianqi): ti, ab, kw OR (tian qi): ti, ab, kw OR (xuesetong): ti, ab, kw OR (xue se tong): ti, ab, kw OR (xuesaitong): ti, ab, kw OR (xue sai tong): ti, ab, kw OR (lulutong): ti, ab, kw OR (lu lu tong): ti, ab, kw OR (zheng kang nao ming): ti, ab, kw OR (nao ming): ti, ab, kw OR (luo tai): ti, ab, kw OR (xin nao tai): ti, ab, kw OR (san qi tong shu): ti, ab, kw
#5 #1 OR #2 OR #3
#6 #4 AND #5
D. Web of Science
#1 TS = (stroke OR stroke∗ OR cerebrovascular accident OR cerebrovascular accident∗ OR CVA (cerebrovascular accident) OR CVAs (cerebrovascular accident) OR cerebrovascular apoplexy OR apoplexy, cerebrovascular OR vascular accident, brain OR brain vascular accident OR brain vascular accidents OR vascular accidents, brain OR cerebrovascular stroke OR cerebrovascular strokes OR stroke, cerebrovascular OR strokes, cerebrovascular OR apoplexy OR cerebral stroke OR cerebral strokes OR stroke, cerebral OR strokes, cerebral OR stroke, acute OR acute stroke OR acute strokes OR strokes, acute OR cerebrovascular accident, acute OR acute cerebrovascular accident OR acute cerebrovascular accidents OR cerebrovascular accidents, acute OR ischemic stroke OR ischemic strokes OR stroke, ischemic OR ischemic stroke OR ischemic strokes OR stroke, ischemic OR cryptogenic ischemic stroke OR cryptogenic ischemic strokes OR ischemic stroke, cryptogenic OR stroke, cryptogenic ischemic OR cryptogenic stroke OR cryptogenic strokes OR stroke, cryptogenic OR cryptogenic embolism stroke OR cryptogenic embolism strokes OR embolism stroke, cryptogenic OR stroke, cryptogenic embolism OR wake-up stroke OR stroke, wake-up OR wake up stroke OR wake-up strokes OR acute ischemic stroke OR acute ischemic strokes OR ischemic stroke, acute OR stroke, acute ischemic)
#2 TS = (panax notoginseng OR panax notoginsengs OR panax notoginseng extract OR notoginsengs, panax OR fufang xueshuantong OR xueshuantong OR xue shuan tong OR xueshuangtong capsule OR compound xueshuantong capsule OR xuesaitong soft capsule OR sanqi tongshu capsule OR xueshuantong injection OR notoginseng saponin OR total notoginsenoside OR panax notoginseng saponins OR radix notoginseng OR radix panax notoginseng OR sanqi OR san qi OR san-qi OR panax pseudoginseng OR pseudoginseng OR notoginseng OR pseudo ginseng OR pseudo-ginseng OR tianqi OR tian qi OR xuesetong OR xue se tong OR xuesaitong OR xue sai tong OR lulutong OR lu lu tong OR zheng kang nao ming OR nao ming OR luo tai OR xin nao tai OR san qi tong shu)
#3 TS = clinical trial∗ OR TS = research design OR TS = comparative stud∗ OR TS = evaluation stud∗ OR TS = controlled trial∗ OR TS = follow-up stud∗ OR TS = prospective stud∗ OR TS = random∗ OR TS = placebo∗ OR TS = (single blind∗) OR TS = (double blind∗)
#4 #1 AND #2 AND #3
Data Availability
Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in references.
Disclosure
The authors affirm that the work submitted for publication is original and has not been published other than as an abstract or preprint in any language or format and has not been submitted elsewhere for print or electronic publication consideration. The authors affirm that each person listed as authors participated in the work in a substantive manner, in accordance with ICMJE authorship guidelines, and is prepared to take public responsibility for it. All authors consent to the investigation of any improprieties that may be alleged regarding the work. Each author further releases and holds harmless the Endocrine Society from any claim or liability that may arise there from.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
Peiyu Guan, principal author with full access to all the data in the study, takes responsibility for the accuracy of the data analysis, and the integrity of the data. Peiyu Guan, Youhua Xu, and Dingkun Gui contributed to the conception and design. Peiyu Guan contributed to data acquisition and interpretation. Peiyu Guan contributed to draft of the manuscript. Youhua Xu and Dingkun Gui contributed to revision of the article and final approval.
Supplementary Materials
Supplementary PRISMA-2020 checklist [20].
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary PRISMA-2020 checklist [20].
Data Availability Statement
Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in references.