Efficacy and safety of traditional Chinese medicine combined with western medicine for early-phase treatment of acute ischemic stroke based on the primary syndrome elements: protocol for a randomized controlled trial
Fu-Sheng Liu1, Xiao-Lei Fang1, Zhi-Rui Cheng2, Jin Liu3, Zhi Liu1, Chen-Chen Sun1, Lei Sun1, Hui Jin2
1 Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
2 Beijing University of Chinese Medicine, Beijing, China
3 Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
|Date of Submission||08-Dec-2018|
|Date of Acceptance||01-Feb-2019|
|Date of Web Publication||27-May-2019|
Dongfang Hospital of Beijing University of Chinese Medicine, Beijing
Source of Support: None, Conflict of Interest: None
Background and objective: Acute ischemic stroke is a major cause of disability among adults. Although traditional Chinese medicine and western medicine have been widely used for the treatment of acute ischemic stroke, their efficacy when used in combination for the treatment of acute ischemic stroke during the early phase is poorly understood. According to traditional Chinese medicine theory, the primary syndrome elements of acute ischemic stroke during the early stage include three pathogens, “wind,” “fire,” and “phlegm,” and treatments that target these primary syndrome elements contribute to recovery from the condition. We have designed a randomized controlled trial to investigate the efficacy and safety of traditional Chinese medicine combined with western medicine in the treatment of acute ischemic stroke during the early phase based on the primary syndrome elements.
Subjects and methods: This prospective, single-center, assessor-blinded, randomized controlled trial will enroll 120 eligible patients with acute ischemic stroke who will receive treatment in the Department of Emergency, Dongfang Hospital of Beijing University of Chinese Medicine, China. Participants will be randomly assigned to a combined treatment group or a control group. Both groups will undergo treatment with conventional western medicine, and patients in the combined treatment group will also receive traditional Chinese medicine (i.e., oral stroke initial state decoction, intravenous Gastrodin injection, and Tanreqing injection; Xingnaojing injection will be added for patients who are unconscious). Immediately after admission, patients will undergo 3-day treatment for early-phase ischemic stroke and subsequently undergo a 2-week follow up. This study was approved by Hospital Ethics Committee, Dongfang Hospital, Beijing University of Traditional Medicine, China (approval No. JDF-IRB-2016033602) on November 2, 2016. Written informed consent will be obtained from conscious patients or the legal guardians of unconscious patients.
Outcome measures: The primary outcome measures of this study are the National Institute of Health Stroke Scale score and traditional Chinese medicine stroke scale score on days 1, 3, 7, and 14 after treatment. Secondary outcome measures include National Institute of Health Stroke Scale score, Barthel index, Modified Rankin scale score, Glasgow coma scale score on days 1, 3, 7, and 14 after treatment, serum matrix metalloproteinase-9 and vascular endothelial growth factor levels on days 1 and 3 after treatment. Safety outcomes on days 1 and 3 after treatment and adverse events on days 3, 7, and 14 after treatment are also evaluated.
Discussion: The results of this study will provide evidence to support the rationale for using traditional Chinese medicine combined with western medicine for the treatment of acute ischemic stroke during the early phase, and may indicate the underlying mechanism in this treatment strategy.
Trial registration: This study was registered with the Chinese Clinical Trial Registration (registration number: ChiCTR-INR-16010075) on December 4, 2016. Study protocol refers to 1.0. Patient recruitment began in December 2016 and will be ended in November 2019.
Keywords: traditional Chinese medicine; acute ischemic stroke; Barthel index; vascular endothelial growth factor; stroke initial state decoction; Gastrodin injection and Tanreqing injection; Xingnaojing injection; randomized controlled trial
|How to cite this article:|
Liu FS, Fang XL, Cheng ZR, Liu J, Liu Z, Sun CC, Sun L, Jin H. Efficacy and safety of traditional Chinese medicine combined with western medicine for early-phase treatment of acute ischemic stroke based on the primary syndrome elements: protocol for a randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2019;4:44-50
|How to cite this URL:|
Liu FS, Fang XL, Cheng ZR, Liu J, Liu Z, Sun CC, Sun L, Jin H. Efficacy and safety of traditional Chinese medicine combined with western medicine for early-phase treatment of acute ischemic stroke based on the primary syndrome elements: protocol for a randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2019 [cited 2020 Jun 7];4:44-50. Available from: http://www.actnjournal.com/text.asp?2019/4/2/44/257971
| Introduction|| |
Acute ischemic stroke (AIS) is a major cause of adult disability (Catanese et al., 2017; Rabinstein, 2017; Sun et al., 2017). Early diagnosis and intervention is considered an important measure in preventing long-term disability after AIS (Ly and Maquet, 2018; Yin and Wang, 2018). Current standard methods for early treatment of AIS include fibrinolytic therapy (Phan et al., 2016) and antiplatelet therapy (Yin and Wang, 2018). However, few patients with AIS receive fibrinolytic therapy within 3–4.5 hours after disease onset (Cheng and Kim, 2015; Yan et al., 2015), and there is evidence that antiplatelet therapy does not lower the risk for recurrent stroke, but can instead increase the risk for hemorrhage (Bakheet et al., 2015).
Traditional Chinese medicine is the most widely used method to treat AIS in Chinese and Central Asian Chinese communities (Venketasubramanian et al., 2009, 2013; Young et al., 2010; Chen et al., 2013; Wan et al., 2015; Du et al., 2016; Zhang et al., 2016). Given the limitations of standard therapies, researchers are increasingly interested in the use of traditional Chinese medicine to treat this condition (Chang et al., 2016). According to traditional Chinese medicine theory, the syndrome is the overall reaction of the body’s pathophysiological state. AIS has been shown to be caused by three pathogens, “wind,” “fire,” and “phlegm” (Song et al., 2009), and the elimination of these pathogenic factors may alleviate the symptoms of stroke.
Although traditional Chinese medicine and western medicine have been widely used for treatment of AIS in clinical settings (Chen et al., 2013; Wan et al., 2015; Du et al., 2016) [Table 1], the objective efficacy of traditional Chinese medicine combined with western medicine requires further investigation.
|Table 1: Clinical trial results of traditional Chinese medicine for treatment of acute ischemic stroke|
Click here to view
This randomized controlled trial will investigate the efficacy and safety of traditional Chinese medicine combined with western medicine in the treatment of AIS during the early phase.
| Subjects And Methods|| |
A prospective, single-center, assessor-blinded randomized controlled trial.
Dongfang Hospital, Beijing University of Chinese Medicine, China.
Dongfang Hospital, Beijing University of Chinese Medicine is a grade 3 class-A traditional Chinese medicine hospital, and has previously participated in a number of key traditional Chinese medicine projects funded by the National Population and Family Planning Commission and Ministry of Health of China. Each investigator within the study team is educated to master’s degree level or higher, has a professional title of associate chief physician or higher, and has more than 5 years of clinical experience in neurology.
Patients with AIS will receive treatment at the emergency department because of their unstable disease condition. Therefore, the study population will be screened for eligibility and recruited from the Department of Emergency, Dongfang Hospital, Beijing University of Traditional Chinese Medicine. Demographic data for each patient, including sex, age, body mass, body weight, and medical history, will be collected on a case report form upon admission.
Patients who are scheduled to receive treatment will be considered for inclusion if they meet the following criteria: a) fulfillment of the diagnostic criteria for AIS as per the 2014 Chinese Guidelines on the Diagnosis and Treatment of Acute Ischemic Stroke (Chinese Society of Neurology and Chinese Society of Neurology Cerebrovascular Disease Section, 2015); b) National Institute of Health Stroke Scale (NIHSS) score of 5–20; c) stroke onset time ≤ 72 hours; d) men and women > 40 years of age; e) provision of written informed consent from participants, or from the legal guardians of patients who are unconscious.
Patients presenting with one or more of the following criteria will be excluded from the study: a) mental disorders; b) severe liver dysfunction (total bilirubin > 2 mg, transaminase levels > 10 times the upper reference limit), kidney dysfunction (creatinine clearance < 30 mL/min), cardiac dysfunction (New York Heart Association (NYHA) class III or higher (Raphael et al., 2007)) or severe systemic diseases; c) allergy to gastrodin injection, Tanreqing injection, Xingnaojing injection, or Chinese decoction; d) women who are lactating or pregnant; e) participation in other clinical trials within 3 months prior to enrolment
Patients presenting with one or more of the following criteria will be withdrawn from the study: a) Allergy to the study drug; b) concomitant use of other treatments or drugs that may enhance the efficacy of the investigational products; c) worsening condition, serious complications, or serious adverse events. The detailed reasons for withdrawal will be recorded in the case report forms.
Patients that experience serious adverse events or die following an adverse drug reaction will be financially compensated by an insurance company. Serious adverse events refer to adverse drug reactions that occur during the duration of the clinical trial and result in hospitalization, prolonged hospital stay, disability, or decreased work capacity; are life-threatening; or result in death.
Patients will be randomly divided into one of two groups: a traditional Chinese medicine + western medicine group (com-bined treatment group) and a control group. Immediately after admission, all patients will receive 3-day early treatment for AIS.
Both groups of patients will receive routine western medicine treatment consisting of thrombolysis or thrombectomy, antiplatelet therapy, neuroprotective therapy, blood pressure and glucose control, nutritional supplementation, and rehabilitation.
In addition, the combined treatment group will receive the following traditional Chinese medicine treatments: stroke initial state decoction (SISD, Beijing Tcmages Pharmaceutical Co., Ltd., China), orally administered 250 mL 0.9% normal saline and 0.6 g Gastrodin injection (State Medical Permission No. H20013046; KPC Pharmaceuticals, Inc., Kunming, China), intravenously administered; and 250 mL 0.9% normal saline and 20 mL Tanreqing injection (State Medical Permission No. Z20030054; Shang Hai Kai Bao Pharmaceutical Co., Ltd., China), intravenously administered. 250 mL 0.9% normal saline and 20 mL Xingnaojing injection (State Medical Permission No. Z32020563; Wuxi Jimin Kexin Shanhe Pharmaceutical Co., Ltd., China) will also be administered intravenously.
Primary outcome measures
- National Institute of Health Stroke Scale (NIHSS) score on days 1, 3, 7, and 14 after treatment. The NIHSS is used to evaluate neurological deficits, including level of consciousness, cognitive function, sensory function, visual field test, and reflex, and has been widely used for evaluating neurological deficits in patients with AIS (Kwah and Diong, 2014).
- Traditional Chinese medicine stroke scale score on days 1, 3, 7, and 14 after treatment. This scale is used to evaluate the severity of neurological deficits based on the severity of traditional Chinese medicine syndromes (Gao et al., 2011).
Secondary outcome measures
- Barthel index on days 1, 3, 7, and 14 after treatment. Barthel index can reflect the severity of stroke (Quinn et al., 2011).
- Modified Rankin scale score on days 1, 3, 7, and 14 after treatment. The Modified Rankin scale is used to reflect the severity of stroke (Bruno et al., 2013).
- Glasgow coma scale score before treatment and on days 1, 3, 7, and 14 after treatment. The Glasgow coma scale is used to evaluate patient consciousness (Teasdale and Jennett, 1974).
- Serum matrix metalloproteinase-9 and vascular endothelial growth factor levels before treatment and on day 3 after treatment. Previous studies have shown that these factors are associated with infarct volume and clinical prognosis in patients with AIS (Abdelnaseer et al., 2017; Geiseler and Morland, 2018).
To ensure patient safety, routine blood and urine testing, routine stool analysis, liver and kidney function, coagulation function, D-dimer level, and electrocardiogram assessment will be performed after treatment. Key indicators will be monitored throughout the trial.
The onset time, symptoms and signs, duration, severity, treatment measures, treatment efficacy, and causal relationship of any adverse events occurring during the 3-day treatment period and the 2-week follow-up period will be recorded. Serious adverse events will be reported in the case report forms and promptly to the institutional ethics committee.
Timing of outcome measure evaluation and adverse events is shown in [Table 2].
Trial flow chart is shown in [Figure 1].
Sample size calculation
With reference to a previous study (Zeng and Zhao, 2016), we assumed an NIHSS score for the combined treatment and control groups of 9.49 ± 4.98 and 12.32 ± 4.43 points, respectively. Taking α = 0.05 and β = 0.1, an effective sample size of n = 53/group was calculated according to superiority and non-inferiority design formulae. Assuming a withdrawal rate of 10%, a final sample size of n = 60/group will be used. Therefore, a total of 120 patients (60 patients in each group) will be included in this study.
Designated researchers will generate a random digital sequence using Excel 2007 software (Microsoft Corporation, Redmond, WA, USA), and sequence numbers will be printed onto digital cards and sealed in opaque envelopes printed with a serial number corresponding to the random digital sequence numbers. Eligible patients who have provided written informed consent will be randomized to the combined treatment group (n = 60) or the control group (n = 60) according to the assigned digital sequence.
It is difficult to perform blinding to investigators and participants, so only assessors will be blinded to grouping.
This study will be performed in accordance with the Declaration of Helsinki developed by the World Medical Association. This study was approved by Hospital Ethics Committee, Dongfang Hospital, Beijing University of Chinese Medicine (approval No. JDF-IRB-2016033602) on November 2, 2016 (Additional file 1 [Additional file 1]). The whole study process will be supervised by the research committee. Any severe adverse events will be reported to the research committee immediately. Changes to the study design can only be made with the permission of the research committee.
It is the responsibility of the investigators to provide the patient or his or her legal guardian with a complete and comprehensive introduction about the purpose, procedure, and possible benefits and risks of this study. Each patient or his or her legal guardian will sign the informed consent (Additional file 2[Additional file 2]) and he or she will understand that they have the right to withdraw from the study at any time. The participant’s personal privacy and data confidentiality will be protected during the study period. The manuscript was prepared in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statements (Additional file 3[Additional file 3]). Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal.
SPSS 20.0 software (IBM Corp., Armonk, NY, USA) will be used for data analysis. Continuous variables are expressed as the mean ± SD. Categorical variables are expressed as frequency or percentage. The t-test (if normally distributed) or nonparametric test (if abnormally distributed) will be used for comparison of continuous variables between groups. The chi-square test or nonparametric test will be used for comparison of categorical variables between groups. A level of P < 0.05 will be considered statistically significant. Efficacy will be analyzed according to the intention-to-treat principle. Missing values will be imputed by the last observation carried forward method.
All data will be recorded in case report forms by trained investigators. To ensure data reality, all investigators participating in this trial will receive training regarding how to fill in case report form prior to initiation of this trial. All data will be collected on site and input in real-time using a double data entry strategy with Epi-Data 3.0 data management software.
After data entry, real-time quality control and online error correction will be performed by investigators responsible for data entry using a two-pass verification method. The missing data or special errors will be detected by the software program and resolved by the investigators. Transparency in the research process should be ensured, the research progress and the existing problems should be managed at any time and rationally solved under the permission of protocol principle.
Before the study protocol put into practice, a series of training sessions will be performed to ensure that all the investigators have a full understanding of the study protocol and mastery of the standard operating procedures. The case report forms will be regularly checked by the supervisors, and the investigators will be notified of any problems in a timely manner. The members of research team will meet regularly to discuss problems that they have confronted and share their experience with others. Moreover, a telephone will be established for the participants who have been discharged. Patients enrolled in the clinical trial will be able to receive a certain amount of traditional Chinese medicine for combined treatment group and some related examination subsidies for both groups.
The clinical monitors will be the persons who come from the department of neurology but do not participate in this study and be responsible for reviewing trial data, extracting medical records, visiting the trial site, and inquiring about relevant personnel once every 6 months during the study period. The clinical monitors will report the progression of the trial to the Medical Ethics Committee. Trial registration will be updated simultaneously.
All electronic data will be password-protected.
Results will be available at ResMan Research Manager (http://www.medresman.org/) within 6 months after the completion of the trial without any charge and disseminated by publication through publication in a peer-reviewed journal.
| Discussion|| |
This study will not evaluate the long-term efficacy of traditional Chinese medicine combined with western medicine in the treatment of AIS, and the study will be conducted at a one center only.
Traditional Chinese medicine has been widely used in China for the treatment of AIS (Zhang et al., 2016), although most studies examining combination treatment with traditional Chinese medicine and western medicine focus only on the effects of the specific drugs (Venketasubramanian et al., 2009, 2013; Young et al., 2010; Chen et al., 2013; Venketasubramanian et al., 2013; Wan et al., 2015; Du et al., 2016; Zhang et al., 2016). To date, few studies have reported the efficacy of traditional Chinese medicine combined with western medicine in the early phase of AIS.
This study will be the first to investigate the efficacy and safety of traditional Chinese medicine combined with western medicine for the treatment of AIS based on the primary syndrome elements of traditional Chinese medicine theory.
Traditional Chinese medicine has been widely used for the clinical treatment of acute ischemic stroke in China (Zhang et al., 2016). Gastrodin injection (Yu et al., 2007), Tanreqing injection (He, 2007), and Xingnaojing injection (Peng et al., 2014) are described in the Chinese Pharmacopoeia for the clinical treatment of AIS via an intravenous administration routes. In this study, oral stroke initial state decoction will be administered alongside intravenous Gastrodin injection and Tanreqing injection. This study will investigate the efficacy and safety of 3-day comprehensive intensive therapy by assessing neurological deficits, traditional Chinese medicine stroke scale score, quality of life in patients with acute ischemic stroke. Results of this study will provide evidence for the use of traditional Chinese medicine in combination with western medicine for the treatment of AIS.
| Trial Status|| |
Patient recruiting is ongoing.
Additional file 1: Hospital ethics approval (Chinese).
Additional file 2: Informed consent form (Chinese).
Additional file 3: SPIRIT Checklist.
Design of study: XLF, FSL; manuscript writing: FSL, JL; concept and implementation of study: FSL, ZRC, CCS, ZL, LS, HJ; approval of final manuscript for publication: all authors.
Conflicts of interest
The authors declare that they have no conflicts of interest.
This work was supported by the National Special Scientific Research Project for the Construction of Traditional Chinese Medicine Clinical Research, No. JDZX2015289; the Central University Basic Scientific Research Foundation of China, No. 2016-JYB-JSPY-047. The funders had no role in the study design, data collection, management, analysis, and interpretation; paper writing; or decision to submit the manuscript for publication.
Institutional review board statement
All experimental procedures will be performed in strict accordance with the Declaration of Helsinki and relevant ethical requirement of the Dong Fang Hospital, Beijing University of Chinese Medicine, China (approval No. JDF-IRB-2016033602) on November 2, 2016.
Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms from the patients or their legal guardians. In the forms, the patients or their legal guardians will give their consent for patients’ images and other clinical information to be reported in the journal. The patients or their legal guardians understand that the patients’ names and initials will not be published and due efforts will be made to conceal the patients’ identity.
This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.
The statistical methods of this study were reviewed by the biostatistician of the Dongfang Hospital, Beijing University of Chinese Medicine, China.
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Individual participant data that underlie the results reported in this manuscript, after deidentification (text, tables, figures, and appendices) will be available indefinitely at ResMan Research Manager () within 6 months after the completion of the trial without any charge. Other raw data can be achieved through contact with the corresponding author. Results will be disseminated by publication in a peer-reviewed journal.
Checked twice by iThenticate.
Externally peer reviewed.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribu-tion-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
C-Editor: Zhao M; S-Editor: Yu J, Li CH; L-Editors: Clare C, Song LP, Wang L; T-Editor: Jia Y
| References|| |
Abdelnaseer MM, Elfauomy NM, Esmail EH, Kamal MM, Elsawy EH (2017) Matrix metalloproteinase-9 and recovery of acute ischemic stroke. J Stroke Cerebrovasc Dis 26:733-740.
Bakheet MF, Pearce LA, Hart RG (2015) Effect of addition of clopidogrel to aspirin on subdural hematoma: meta-analysis of randomized clinical trials. Int J Stroke 10:501-505.
Bruno A, Close B, Gomadam A, Akinwuntan AE, Switzer JA (2013) The simplified mRS questionnaire reflects stroke severity. Int J Stroke 8:E55.
Catanese L, Tarsia J, Fisher M (2017) Acute ischemic stroke therapy overview. Circ Res 120:541-558.
Chang CC, Chen TL, Chiu HE, Hu CJ, Yeh CC, Tsai CC, Lane HL, Sun MF, Sung FC, Liao CC, Lin JG, Shih CC (2016) Outcomes after stroke in patients receiving adjuvant therapy with traditional Chinese medicine: a nationwide matched interventional cohort study. J Ethnopharmacol 177:46-52.
Chen CL, Young SH, Gan HH, Singh R, Lao AY, Baroque AC 2nd
, Chang HM, Hiyadan JH, Chua CL, Advincula JM, Mueng-taweepongsa S, Chan BP, de Silva HA, Towanabut S, Suwanwela NC, Poungvarin N, Chankrachang S, Wong KS, Eow GB, Navarro JC, et al. (2013) Chinese medicine neuroaid efficacy on stroke recovery: a double-blind, placebo-controlled, ran-domized study. Stroke 44:2093-2100.
Cheng NT, Kim AS (2015) Intravenous thrombolysis for acute ischemic stroke within 3 hours versus between 3 and 4.5 hours of symptom onset. The Neurohospitalist 5:101-109.
Du X, Wang J, Bao C, Jiao Z, Dong G (2016) Immediate effects of twirling reinforcing-reducing manipulation at head acupoints on muscle force in patients with acute ischemic stroke: a randomized controlled trial. Zhongguo Zhen Jiu 36:43-47.
Gao Y, Ma B, Liu Q, Wang YY (2011) Methodological study and establishment of the diagnostic scale for TCM syndromes of ischemic stroke. Zhongyi Zazhi 52:2097-2101.
Geiseler SJ, Morland C (2018) The Janus face of VEGF in stroke. Int J Mol Sci 19:E1362.
He H (2007) Clinical observation of pulmonary infection in patients with acute stroke treated by tanreqing injection. Zhongguo Zhongxiyi jiehe Jijiu Zazhi 14:158.
Kwah LK, Diong J (2014) National Institutes of Health Stroke Scale (NIHSS). J Physiother 60:61.
Ly J, Maquet P (2018) Clinical management of acute stroke. Rev Med Liege 73:333-337.
Peng W, Yang J, Wang Y, Wang W, Xu J, Wang L, Xing Z (2014) Systematic review and meta-analysis of randomized controlled trials of xingnaojing treatment for stroke. Evid Based Complement Alternat Med 2014:210851-210851.
Phan K, Zhao DF, Phan S, Huo YR, Mobbs RJ, Rao PJ, Mortimer AM (2016) Endovascular therapy including thrombectomy for acute ischemic stroke: A systematic review and meta-analysis with trial sequential analysis. J Clin Neurosci 29:38-45.
Quinn TJ, Langhorne P, Stott DJ (2011) Barthel index for stroke trials: development, properties, and application. Stroke 42:1146-1151.
Rabinstein AA (2017) Treatment of acute ischemic stroke. Continuum (Minneap Minn) 23:62-81.
Raphael C, Briscoe C, Davies J, Ian Whinnett Z, Manisty C, Sutton R, Mayet J, Francis DP (2007) Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure. Heart 93:476-482.
Song Y, Pei J, Liu ZD, Li HY, Cai YF, Guo JW, Huang Y (2009) Dynamic changes in traditional Chinese medicine syndromes in patients with ischemic stroke treated by acupuncture. Zhong Xi Yi Jie He Xue Bao 7:334-341.
Sun W, Ou Q, Zhang Z, Qu J, Huang Y (2017) Chinese acute ischemic stroke treatment outcome registry (CASTOR): protocol for a prospective registry study on patterns of real-world treatment of acute ischemic stroke in China. BMC Complement Altern Med 17:357.
Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81-84.
Venketasubramanian N, Young S, Tay SS, Chang HM, Umapathi T, Chan B, de Silva A, Wong L, Navarro J, Zhao YD, Tan SB, Chen C (2013) Chinese medicine NeuroAiD efficacy stroke recovery-extension study (CHIMES-E study): an observational multicenter study to investigate the longer-term efficacy of NeuroAiD in stroke recovery. Cerebrovasc Dis 35 Suppl 1:18-22.
Venketasubramanian N, Chen CL, Gan RN, Chan BP, Chang HM, Tan SB, Picard D, Navarro JC, Baroque AC 2nd
, Poungvarin N, Donnan GA, Bousser MG; CHIMES Investigators (2009) A double-blind, placebo-controlled, randomized, multicenter study to investigate CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES Study). Int J Stroke 4:54-60.
Wan HT, Bie XD, Yao Z, Xu B, Liu H, Yang JH, Zhang Y, He Y, Zhou HF (2015) Treating ischemic stroke patients of deficiency of qi and yin syndrome and static blood obstructing collaterals syndrome by Yangyin Yiqi Huoxue Recipe: a clinical study of therapeutic effect. Zhongguo Zhong Xi Yi Jie He Za Zhi 35:281-286.
Yan X, Hu HT, Liu S, Sun YH, Gao X (2015) A pharmacoeconomic assessment of recombinant tissue plasminogen activator therapy for acute ischemic stroke in a tertiary hospital in China. Neurol Res 37:352-358.
Yin X, Wang D (2018) Antiplatelet agents in acute stroke and TIA. N Engl J Med 379:e29.
Young SH, Zhao Y, Koh A, Singh R, Chan BP, Chang HM, Venketasubramanian N, Chen C, CHIMES Investigators (2010) Safety profile of MLC601 (Neuroaid) in acute ischemic stroke patients: A Singaporean substudy of the Chinese medicine neuroaid efficacy on stroke recovery study. Cerebrovasc Dis 30:1-6.
Yu SR, Wang LX, Chen Y (2007) Therapeutic effect of gastrodin injection on acute ischemic stroke. Zhongguo Zhongxiyi Jiehe Zazhi 27:377-378.
Zeng Q, Zhao LB (2016) Clinical effect of Xingnaojing injection on acute ischemic stroke and on inflammatory factors. Zhongguo Shiyong Shenjing Jibing Zazhi 19:26-27.
Zhang X, Liu XT, Kang DY (2016) Traditional Chinese patent medicine for acute ischemic stroke: an overview of systematic reviews based on the GRADE approach. Medicine (Baltimore) 95:e2986.
Chinese Society of Neurology and Chinese Society of Neurology Cerebrovascular Disease Section (2015) 2014 Chinese guidelines on the diagnosis and treatment of acute ischemic stroke. Zhonghua Shenjing Ke Zazhi 48:246-257.
[Table 1], [Table 2]