The Study Of The Development Of A Core Outcome Set(COS) For Ischemic Stroke In Clinical Trials Of Chinese Medicine

ObjectiveThe objective of this study is to establish the core outcome set(COS)for clinical studies of CM in the treatment of Ischemic Stroke(IS)referring to the COMET Handbook(version 1.0)by The COMET(Core Outcome Measures in Effectiveness Trials)Initiative,and provide a reference for the selection of outcomes of future CM researches on the treatment of IS.It could enrich the methodology research on the evaluation of CM effectiveness for IS.Methods(1)A systematic review to find existing outcomes:the Chinese and English databases were searched to identify outcomes currently used in the TCM randomized controlled trials of IS.International Clinical Trials Registry Platform and The Chinese Clinical Trial Register were also searched.(2)A patient survey:the patients with ischemic stroke were interviewed to collect patient-related outcomes.(3)A list of candidate outcomes:outcomes sorted out from the systematic review and semi-structured interview were divided into outcome domains.(4)Selecting outcomes:the Delphi survey was conducted to assess the importance of outcomes.(5)Establishing a COS:the consensus method was used to estimate whether outcomes excluded in the Delphi survey could enter the COS.Results(1)This study finally included 719 published articles and 196 clinical research registration schemes.A total of 277 outcome indicators were collected.They were classified into 11 categories:clinical/primary endpoint outcomes,body functions,body structures,activities and participation,quality of life,outcomes related to CM syndrome,outcomes related to imaging findings,laboratory indicators,safety evaluations,health-economic indicators,and other outcomes.The National Institutes of Health Stroke Scale(NIHSS)was the most frequently reported(reported 569 times,percentage is 62.19%).The clinical response rate was following NIHSS.The reporting frequency of the clinical response rate was 448(53.88%),The evaluation criteria and methods of the clinical response rate were varied.(2)Nine categories of outcomes were collected through a survey of 472 stroke patients:patient satisfaction,activities of daily living,body functions,total cost during hospitalization,depression or anxiety,and nursing satisfaction,recurrence rate,complications,quality of life.(3)After the initial screening,66 outcomes entered the first round of the Delphi survey.(4)56 experts participated in the first round of the Delphi survey.Questionnaire recovery rate and effective rate are both 100%,with a high positive coefficient.The authority is 0.804>0.7,Kendall’s W is 0.5,and the coefficient of variation(CV)is 0.28>0.25.According to expert reliability analysis,it was believed that the credibility of the first round of the Delphi survey was good.After the first round of the Delphi survey,the remaining 24 outcomes entered the second round of the Delphi survey:all-cause mortality,mortality,recurrence rate(within one year after the stroke onset),deterioration of nervous system function at its early stage,incidence of cardiovascular and cerebrovascular events(myocardial infarction,cerebral hemorrhage,etc.),symptomatic intracranial hemorrhage(SICH),the Modified Rankin Scale(mRS),the National Institutes of Health Stroke Scale(NIHSS),the Glasgow Coma Scale(GCS),the Minimal Fugl-Meyer Motor Function Score(FMA),Mini-Mental Sate Examination(MMSE),Infarct area,Infarct volume,Thrombolysis in myocardial infarction(TIMI),Barthel index(BI),LDL,MRI,CT,DSA,Carotid color ultrasonography,Adverse events,Incidence of adverse reactions,Incidence of bleeding events(non-intracranial hemorrhage),Blood pressure.(5)A total of 48 experts participated in the second round of the Delphi survey.The expert positive coefficient was 85.71%.The authority was 0.794>0.7.Kendall’s W was 0.672.The coefficient of variation(CV)was 0.17<0.25.According to the expert reliability analysis,it was believed that the credibility of the second round of the Delphi survey was good.After the second round of the Delphi survey,the outcomes included in the preliminary COS were:all-cause mortality,mortality,recurrence rate(within one year after the stroke onset),incidence of cardiovascular and cerebrovascular events(myocardial infarction,cerebral hemorrhage,etc.),symptomatic intracranial hemorrhage(SICH),the Essen scale,the ABCD2 scale,the Modified Rankin Scale(mRS),the National Institutes of Health Stroke Scale(NIHSS),the Glasgow Coma Scale(GCS),the Minimal Fugl-Meyer Motor Function Score(FMA),Mini-Mental Sate Examination(MMSE),Infarct volume,ASPECTS,Thrombolysis in myocardial infarction(TIMI),Barthel index(BI),LDL,MRI,CT,DSA,Carotid color ultrasonography,Adverse events,Incidence of adverse reactions,Incidence of bleeding events(non-intracranial hemorrhage).(6)A total of 11 experts were invited to participate in the questionnaire survey of the consensus meeting.The final core outcome set included six outcome fields:clinical/primary endpoint outcomes,body functions,body structures,activities and participation,outcomes related to CM syndrome(without indexes recommended currently),safety evaluations.12 outcomes:all-cause mortality,mortality,recurrence rate,deterioration of nervous system function at its early stage,incidence of cardiovascular and cerebrovascular events,level of disability,neurological deficit,motor dysfunction,cognitive impairment,cerebrovascular disease,carotid and vertebral artery disease,assessment of activities of daily living,adverse events.ConclusionsThere are various types of outcome indicators used in clinical studies of CM for IS,without adequate reporting in published literature.According to the COS-STAD recommendations(Core Outcome Set-STAndards for Development),the established COS in this study met the 11 minimum reporting standards,so the methodology of the this study is reasonable.This study has limitations:the quality evaluation of the included literature was not conducted,which could affect reporting frequency of outcomes.Due to the short time,patients were not interviewed.Questionnaires could affect the types of patient-related outcomes collected.Selection criteria and scoring methods for Delphi survey and consensus meeting need to be improved.It is suggested that related studies in the future explore more reasonable methods and standards in the source and selection of outcomes.The evaluation outcomes related to CM syndromes and symptoms were not included into the initial COS.The evaluation outcomes related to CM syndromes may need to be scored separately,for it is generally considered important to establish a core outcome set for CM syndromes for the final COS.