| BackgroundCerebral infarction is a kind of cerebrovascular event with high fatality and disability rate.Although the current western medicine conventional treatment plan is relatively mature in improving objective indicators and improving patient’s prognosis,patients are still always accompanied by limb movement disorders,cognitive disorders,and other symptoms that seriously affect the quality of life,such as skewed tongue and unfavorable speech.Traditional Chinese medicine has obvious advantages in the treatment of cerebral infarction convalescence and sequelae,and has accumulated abundant clinical research evidence.As the main traditional Chinese medicine treatment method for the treatment of cerebral infarction,Chinese patent medicine has a wide variety and each has its own characteristics.However,the number of previous clinical studies on Chinese patent medicines is uneven,and the guiding role of the research results on the comprehensive and standardized use of Chinese patent medicines under real clinical conditions still needs to be improved.In addition,the clinical treatment of cerebral infarction involves many links.How to optimize the treatment plan,reflect the characteristics of Chinese patent medicine,and give full play to the advantages of integrated Chinese and Western medicine is also worth studying.Mixed methods research and real-world research,which have gradually emerged in recent years,provide new evaluation ideas for solving these problems.Xuesaitong soft capsule uses Panax notoginseng extract-Panax notoginseng saponins as active ingredients.It is a drug commonly used in clinical treatment of cerebral infarction,especially in improving related accompanying symptoms and has good security.At the same time,as a class of compounds extracted from natural medicines,the basic research on Xuesaitong preparations has been relatively sufficient,the clinical research has formed a certain scale,and it has the demand and feasibility to further improve the standardization of clinical use.The characteristics of oral dosage forms,soft capsules are the most widely used dosage forms in clinical practice.Compared with other dosage forms,they can maximize the preservation of volatile substances,maintain the stability of active ingredients,improve bioavailability,and have good economy,is a kind of representative specie,with the value of further research.However,due to the complicated diagnosis and treatment of cerebral infarction,there are differences in clinicians’ cognition attitude and standard use of Xuesaitong soft capsule,and its real clinical application and practical application have not been fully recognized and studied.For this reason,it is necessary to conduct in-depth research on its application in the real world environment from multiple perspectives,and standardize the details of its clinical use through the development of clinical consensus.ObjectiveThe purpose of this study is to clarify the dosing schedule,timing of administration,characteristics of dosage and course of treatment,and safety issues of Xuesaitong soft capsules in the treatment of cerebral infarction through the application of explanatory design,so as to promote rational drug use,reduce drug risks,and clarify the advantages steps of the drug use,thereby improving clinical efficacy.At the same time,exploring advantages and the possibility of applying the new method to better solve complex clinical problems.Methods1.Real-world study data analysis of Xuesaitong soft capsule intervention for cerebral infarction1.1 Cross-sectional survey:Clinical medication characteristics of Xuesaitong soft capsule for cerebral infarction based on real-world study and its correlation with patient prognosis.Select the patients with "cerebral infarction(I63)"(classified according to ICD-10 code)as the first diagnosis in the inpatient database(HIS)from October 8,2014 to November 22,2020 in 8 grade-A tertiary hospital of traditional Chinese medicine.Collect the relevant information of the electronic medical records of patients who use Xuesaitong soft capsules during hospitalization,including:basic information of patients,usage of Xuesaitong soft capsules(time of medication,duration of medication,frequency of medication,dose,total daily dose),cerebral infarction relevant outcome indicators(such as the improvement of NIHSS score after treatment),etc.SPSS20.0 statistical software was used to carry out descriptive statistical analysis based on frequency and rate of count data(general information of patient admission,condition,combined diagnosis,combined medication,etc.),and chi-square test or nonparametric test was used to explore and screen Xuesaitong soft capsule Influencing factors between the changes of NIHSS scores of patients with different use time points,courses of treatment,comorbid diseases,symptoms,and TCM diagnostic factors,and the selected variables were statistically analyzed by logistic regression model.1.2 Qualitative research:the cognition and attitude of clinicians in a grade-A tertiary hospital of traditional Chinese medicine in Beijing on the use of Xuesaitong soft capsules.Based on the quantitative research results above,semi-structured interviews were carried to investigate the timing and dosage of Xuesaitong soft capsule for the treatment of cerebral infarction by the chief physician,deputy chief physician,attending physician,and resident physician of the encephalopathy department of a grade-A tertiary hospital of traditional Chinese medicine in Beijing,medication duration,concomitant medication,and clinicians’ attitudes were also interviewed.Use Nvivo12 software to summarize the interview data through thematic analysis method,and then summarize the specific advantages of Xuesaitong soft capsule in the treatment of cerebral infarction to further interpret and supplement the results of the quantitative study.2.Construction of expert consensus on clinical application of Xuesaitong soft capsule in intervention of cerebral infarctionThe expert consensus on clinical application of Xuesaitong soft capsule was constructed according to the formulation procedure of "Technical Requirements for Revision of Chinese Patent Medicine Clinical Application Expert Consensus of Chinese Association of Traditional Chinese Medicine(Trial)".Firstly,by sorting out the instructions of Xuesaitong soft capsules,pre-retrieve literature and interviewing with experts,design the clinical question questionnaire of "Expert Consensus on Clinical Application of Xuesaitong soft capsules in Intervention of Cerebral Infarction",and collect questions.After the list,a second round of questionnaire survey was conducted,and the importance of the questionnaire list collected in the first round was scored to obtain the final clinical questions.The expert group voted by the nominal group method,and constructed the PICO logic for the final included clinical questions to form a consensus question.Then,7 databases commonly used were systematically searched to include randomized controlled trials on Xuesaitong soft capsule in the treatment of cerebral infarction.The risk of bias assessment of the included literature was carried out using the Cochrane Handbook version 5.1.0 RCT risk of bias assessment tool.Review Manager 5.4 software was used for meta-analysis to comprehensively evaluate the evidence-based evidence of Xuesaitong soft capsules in the treatment of cerebral infarction.Then,the quality of evidence formed by a clinical problem and the strength of recommendation are combined to form a recommendation.For clinical problems without high-quality research(RCT)support,other types of research and expert opinions are referred to to form consensus recommendations.The qualitative research steps are mainly:expert interviews,clinical investigations,etc.;the quantitative research steps are mainly evidence synthesis and evaluation.Results1.Real-world study data analysis of Xuesaitong soft capsule intervention for cerebral infarction1.1 Cross-sectional surveyThe HIS system derived a total of 471 patients with cerebral infarction first diagnosed by western medicine and stroke diagnosed by traditional Chinese medicine,among which 37 patients were diagnosed as cerebral infarction(acute phase)by western medicine,12 were diagnosed as cerebral infarction(convalescent phase),and the remaining 422 were diagnosed as cerebral infarction.1.1.1 Analysis of medication characteristicsAmong the 471 patients with cerebral infarction,155 patients had clear medication timing,medication days,medication dosage and medication frequency.Statistics found that the timing of cerebral infarction patients using Xuesaitong soft capsules was 1 day after admission has the highest proportion of 69.67%(108 cases),followed by cerebral infarction patients who started taking Xuesaitong soft capsules 2-5 days after admission,accounting for 12.30%(19 cases);the number of patients taking Xuesaitong soft capsule 7-14 days has the highest proportion of 50.82%(79 cases),followed by patients taking 15-30 consecutive days,accounting for 24.59%(38 cases);the highest proportion was 59.84%(93 cases)taking 1 capsule each time,followed by 2 capsules each time accounted for 38.52%(60 cases),taking 3 capsules each time was the least;the frequency of medication twice a day(BID)accounted for 81.29%(126 cases),followed by three times a day(TID)of 17.42%(27 cases),with the least number of cases once a day(QD).1.1.2 Prognosis correlation analysisAmong the 471 patients with cerebral infarction,there were 155 valid data on admission and discharge NIHSS scores(316 cases had incomplete medication data).Univariate analysis chi-square test and nonparametric test were used to screen out five significant independent variables,including medication time,diabetes,limb movement disorders,logoplegia,and blood stasis.Incorporated them into the logistic regression equation,the diabetes and blood stasis two factors were associated with changes in NHISS.Compared with non-diabetic patients,diabetic patients were more likely to have NIHSS score changes(OR=2.968,95%CI 1.381-6.379,P<0.05);compared with non-blood stasis patients,blood stasis patients were more likely to have NIHSS score changes(OR=2.414,95%CI 1.199-4.861,P<0.05).1.2 Qualitative interviewsAmong the 11 encephalopathy clinicians who participated in the interviews,2 had senior titles,1 had deputy senior titles,3 had intermediate titles,and 2 had primary titles;2 had master’s degrees,6 had doctoral degrees;5people with background of traditional Chinese medicine,3 people with background of integrative medicine.The results of qualitative data showed that a total of 5 subjects and 27 codes were obtained.1.2,1 The main issues that clinicians are concerned about are:①Anti-platelet aggregation;②Whether it can be used in the acute phase of cerebral infarction;③Adverse reactions of clinical use,etc.1.2.2 The main conclusions of the interview are as follows:①Xuesaitong soft capsule can be used for acute and convalescent treatment of cerebral infarction,especially for patients with TCM blood stasis syndrome;②The drug has few adverse reactions,and the treatment cycle should be used according to the instructions;③The outcome indicators of Xuesaitong soft capsule intervention for cerebral infarction are mainly inhibiting α2-AP,anti-platelet aggregation,improving vascular inflammation,and improving the recovery of neurological function of patients;④The advantages of Xuesaitong soft capsule are mainly reflected in its economy and convenience and has high bioavailability cause of the soft capsule dosage form.2.Development of expert consensus on clinical application of Xuesaitong soft capsule2.1 Through carding the instructions of Xuesaitong soft capsule,literature pre-retrieval,expert interview,design clinical questions survey questionnaire,after two round of questionnaire survey,expert group voting and PICO logic,finally formed 10 consensus questions.Respectively:(1)the appropriate usage,dosage and course of treatment of Xuesaitong soft capsule for patients with cerebral infarction?(2)Xuesaitong soft capsule in syndrome differentiation(blood stasis obstruction of the arteries of cerebral infarction),compared with only for symptoms,whether the effect is better?(3)Xuesaitong soft capsule is used in patients with cerebral infarction sequela for a long time,compared with short-term application,how safe is it?(4)Xuesaitong soft capsule combined with conventional treatment and cerebral infarction patients,compared with the simple application of conventional treatment,whether can improve neurological function,improve long-term quality of life and other rehabilitation effects?(5)Whether long-term application of Xuesaitong soft capsule in patients with cerebral infarction can improve the prognosis,including reducing the recurrence rate of cerebral infarction,compared with short-term application?If it improves the prognosis of patients with cerebral infarction,is it related to the duration of medication?(6)Is there a synergic effect between Xuesaitong soft capsule and dual antibody(aspirin/clopidogrel)in the treatment of patients with cerebral infarction compared with dual antibody alone?(7)The medication timing of Xuesaitong soft capsule for patients with cerebral infarction?(8)When Xuesaitong soft capsule is combined with common drugs for the indication,is the curative effect superior to conventional treatment compared with the simple application of conventional treatment?(9)When Xuesaitong soft capsule combined with aspirin and other antiplatelet drugs are used in patients with cerebral infarction,can they reduce the risk of bleeding compared with aspirin and other antiplatelet drugs alone?(10)Whether there are definite precautions for Xuesaitong soft capsule,such as medication(compatibility)contraindications,medication for special groups and other clinical medication precautions?2.2 A total of 2715 literatures were obtained through literature retrieval of 7 common databases in Chinese and English.After reviewing,reading titles and removing irrelevant literatures,12 clinical studies on the intervention of Xuesaitong soft capsule in cerebral infarction were finally included,with a total of 1297 subjects,including 692 in experimental group and 605 in control group.A completed but not unpublished RCT study of 3,072 cases and a more comprehensive economic evaluation report were also included.The bias risks of the included studies were all low.Meta-analysis shows,combined with Xuesaitong soft capsule could reduce the recurrence rate of patients within 1 year compared with conventional drugs,NIHSS and CSS scores were decreased,ESS and BI scores were increased,and neurological function was improved,ORR was improved,and Xuesaitong soft capsule combined with conventional treatment group has advantages in reducing the incidence of adverse reactions.The GRADE tool was used to evaluate the GRADE of evidence for 26 outcome indicators in the included literature from 5 aspects(risk of bias,inconsistency,indirection,inaccuracy and publication bias),and it was found that the GRADE of evidence was scattered from very low to medium,and the quality was mainly very low and low.Then,the quality of evidence formed by a certain clinical problem constitutes a recommendation;for the clinical problems without evidence to recommend,refer to other types of studies and expert opinions to form consensus recommendations.2.3 Finally,based on the comprehensive evaluation of the evidence,the recommendation/consensus recommendation and strength formed by the nominal group method:(1)Xuesaitong Soft Capsules combined with conventional western medicine treatment are recommended to improve neurological deficits in patients with cerebral infarction.(Strong recommendation evidence grade:very low)(2)Xuesaitong Soft Capsules combined with conventional western medicine treatment are recommended to improve the daily living ability of patients with ischemic stroke.(Strong recommendation evidence grade:high)(3)It is recommended to use Xuesaitong Soft Capsule in combination with antiplatelet drugs such as aspirin,which has not been found to increase the risk of bleeding in patients with ischemic stroke.(Strong recommendation evidence grade:high)(4)The adverse reactions in the drug insert only mention that a small number of patients may experience mild nausea and stomach bloating after taking the drug.The existing data show that Xuesaitong Soft Capsule has less "serious" adverse reactions,and most of the adverse reactions are "average".,mainly for gastrointestinal system symptoms,skin and nervous system symptoms,can pay attention to monitoring in clinical use.(Strong recommendation evidence grade:low)(5)The economic advantage of Xuesaitong Soft Capsule depends on the patient’s willingness to pay for healthy output.When the patient’s willingness to pay is greater than 95.6 yuan,the Xuesaitong Soft Capsule combined with the conventional Western medicine treatment program for cerebral infarction has cost-effectiveness advantages.Recommended to use.(Strong recommendation evidence grade:high)(6)It is recommended that Xuesaitong Soft Capsules combined with conventional western medicine treatment be used for acute ischemic stroke,stroke recovery period and sequelae period.(consensus proposal)(7)It is recommended that Xuesaitong Soft Capsules be used for ischemic stroke patients with blood stasis closed choroids according to the drug instructions.(consensus proposal)(8)For stroke patients,Xuesaitong Soft Capsules combined with conventional western medicine treatment can be considered to reduce the recurrence of stroke within 1 year.(consensus proposal)(9)For stroke patients,the usage and dosage of Xuesaitong soft capsules should follow the instructions,2 capsules at a time,twice a day.It is recommended that 4-8 weeks be a course of treatment,and the duration of the course of treatment should be selected according to the patient’s condition.(consensus proposal)(10)Except for the use with caution in pregnant women and contraindicated in pregnant women mentioned in the drug insert,the following patients are advised to use with caution:①Patients with bleeding tendency and patients with coagulation dysfunction should be used with caution.②Pregnant women and menstruating women should be used with caution.③People with allergic constitution and abnormal liver and kidney function should use it with caution.④Pay attention to the detection of liver function during use.⑤For those with severe and long-lasting heartache,electrocardiogram and myocardial enzyme examination should be done,and corresponding medical measures should be taken.If used with other drugs at the same time,drug interactions may occur,please consult a physician or pharmacist before use.(consensus proposal)(11)In addition to the precautionary use for pregnant women and the contraindication for pregnant women mentioned in the drug insert,it is recommended to add contraindications to those who are allergic to ginseng and Panax notoginseng;those who are allergic to this product and its components;acute bleeding disorders.(consensus proposal)Conclusion1.explanatory mixed method design is suitable for Xuesaitong soft capsule intervene cerebral infarction real world data and related clinical problems,can prompt Xuesaitong soft capsule intervene cerebral infarction has good curative effect and safety,its advantages are:to a certain extent,it can make up for the shortcomings of retrospective real-world research with many confounding and bias,high statistical analysis difficulty,and high complexity of result interpretation,improve the utilization of data,and analyze and explain the influencing factors related to clinical diagnosis and treatment as much as possible.The results of the real-world data analysis suggest that the patients with cerebral infarction combined with diabetes mellitus or blood stasis syndrome will have a more significant improvement in the neurological deficit after the treatment.2.Through the development of clinical application consensus,it is clear that Xuesaitong soft capsule has the advantages of intervening cerebral infarction in that it can improve clinical symptoms and neurological deficits,and improve the quality of life of patients;long-term medication can improve symptoms and reduce the recurrence rate of cerebral infarction.In clinical application,it is recommended to be used in convalescent cerebral infarction patients with syndrome of blood stasis and obstruction of collaterals,and it is also recommended for supplementary adjuvant therapy in acute and subacute phases.The medication regimen should follow the usage and dosage of the instructions,and the length of the course of treatment should be adjusted by the decision maker according to the patient’s condition.It should be used in combination with conventional treatment regimens to better improve neurological function and activities of daily living.It can be used in combination with aspirin to stabilize carotid plaque and better improve neurological deficits.When combined with aspirin or clopidogrel,no increase in bleeding risk was found,and the gastrointestinal mucosa could be protected,showing good safety. |
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