Dual Antiplatelet Therapy For Improving Functional Status After Minor Ischemic Stroke With NIHSS ≤5 In Real World

According to the China National Stroke Registry III,approximately 50%of acute ischaemic stroke patients present minor neurologic deficits(National Institutes of Health Stroke Scale score,NIHSS score ≤5)in China.Several studies have shown that 15-20%of minor stroke patients are dead or disabled during follow-up despite their minor or even no symptoms at presentation.Post hoc exploratory analysis of both the CHANCE(clopidogrel in high-risk patients with acute nondisabling cerebrovascular events)trial and POINT(plateletoriented inhibition in new TIA and minor ischaemic stroke)trial revealed that dual antiplatelet therapy might reduce the incidence of stroke-related disability and risk of recurrent stroke in patients with acute minor stroke and transient ischaemic attack(TIA).As a major antithrombotic method against early vascular events,combined antiplatelet therapy with clopidogrel plus aspirin for 21 days has been suggested by Chinese and AHA/ASA guidelines for minor stroke with a NIHSS score≤3 and TIA patients.However,DAPT is widely used in stroke patients with a broader NIHSS score(4-5)and with a longer time span of symptom onset(24-72 hours)by some clinicians in the real world.Therefore,clinical practice in the real world is not the same as guidelines recommendation.However,it remains unknown whether DATP within 72 hours could reduce disability if a stroke patient has a higher NIHSS score of 4-5.To date,several point-based risk scores have been developed to predict clinical outcomes after ischemic stroke.Of these,3 point-based stroke prognostic scores including acute stroke registry and analysis of Lausanne(ASTRAL)score,Houston intraarterial recanalization therapy(HIAT)score,and the totaled health risks in vascular events(THRIVE)score were the most used models,which have the potential for clinical application.However,most of the predictive models are developed from patients who received intravenous thrombolysis,endovascular thrombectomy or the whole stroke population,specific predictive models for minor ischemic stroke are rare.We explored the question through a real-world clinical data-based registry study,SEACOAST(Safety and efficacy of aspirin plus clopidogrel in patients with acute noncardiogenic minor ischemic stroke).SEACOAST included data of acute non cardiogenic stroke patients with minor-moderate stroke(NIHSS score ≤5)within 72 hours of symptom onset.Therefore,in this study,we first investigate the differences of the real-world clinical practice and guideline recommendation among minor ischemic stroke patients.Secondly,we evaluate the association between different antiplatelet regimen and disability and bleeding complications among minor stroke patients with NIHSS score≤5.Finally,we develop and validate a prognostic nomogram to predict 90day disability among patients with acute minor stroke.Trial registration number:http://www.chictr.org.cn/(ChiCTR1900025214)Part Ⅰ Differences between real-world clinical practice and guideline recommendation regarding antiplatelet therapy among non-cardiogenic minor ischemic stroke patientsObjective:Combined antiplatelet therapy is a major antithrombotic method against early vascular events by guidelines recommendations.The purpose of this study was to investigate the differences of the real-world clinical practice and guideline recommendation regarding antiplatelet therapy among minor ischaemic stroke patients.Methods:We used data from the SEACOAST trial(Safety and efficacy of aspirinclopidogrel in acute noncardiogenic minor ischaemic stroke)to analyse patients with mild-to-moderate stroke within 72 hours of onset who were treated with aspirin or clopidogrel alone(MAPT)or combination of clopidogrel and aspirin(DAPT)from September 2019 to November 2021.We investigate the implementation of antiplatelet therapy,including the detailed antiplatelet regimen,discontinuation within 90 days,and the duration of the initial antiplatelet therapy.Results:A total of 2822 minor ischaemic stroke patients were treated either with DAPT(n=1726,61.2%)or MAPT(n=1096,38.8%).1)842(65.8%)patients within 24 hours of onset with NIHSS≤3 received DAPT,while 34.2%received MAPT.In addition,for patients with a NIHSS score of 4-5,202(38.5%)patients were treated with MAPT and 322(62.5%)patients were treated with DAPT.For patients of onset within 24-72 hours,541(43.5%)patients were treated with MAPT and 703(56.5%)were still treated with DAPT.2)In the DAPT group,65.5%patients received the guideline-recommended loading dose of clopidogrel(300 mg)on day 1,while 34.4%received the usual 75 mg on day 1.3)In the MAPT group,381 patients switched antiplatelet regimens within 90 days.In the DAPT group,1404 patients(81.3%)switched their original regimen within 90 days.The mean duration of the MAPT regimen was 63.03 days,and that of the DAPT regimen was 29.83 days.58.2%and 17.8%of patients in the DAPT group were given DAPT lasting for 10-21 days and 90 days as recommended by the guideline,respectively.Conclusion:There is a gap between the guideline recommendation and real-world clinical practice.DAPT is widely used in patients within 24-72 hours of onset and with NIHSS scores of 4-5,which is not recommended from the guidelines.In addition,the doses of clopidogrel on day 1 and the duration of DAPT differed from those of the guideline recommendation.Part Ⅱ Dual antiplatelet therapy reduces disability after minor ischemic strokeObjective:The purpose of this study was to evaluate the association between different antiplatelet regimen and disability and bleeding complications among minor ischaemic stroke patients based on real-world data.Methods:We used data from the SEACOAST trial(Safety and efficacy of aspirin-clopidogrel in acute noncardiogenic minor ischaemic stroke)to analyse patients with minor stroke within 72 hours of onset who were treated with aspirin or clopidogrel alone or combination of clopidogrel and aspirin from September 2019 to November 2021.Propensity score matching(PSM)was used to balance the differences between groups.We performed an analysis to evaluate the association of different antiplatelet regimen and 90-day disability,which was defined as a modified Rankin Scale score≥2,as well as disability ascribed to index or recurrent stroke by the local investigator.From the safety point of view,we then compared the bleeding events between the two groups.Results:A total of 2822 minor ischaemic stroke patients were treated either with clopidogrel plus aspirin(n=1726,61.2%)or aspirin/clopidogrel(n=1096,38.8%).1350 of 1726 patients(78.5%)in the dual antiplatelet group received a duration of less than or equal to 30 days combined therapy.At 90 days,433(15.3%)patients were disabled.There was a trend favouring a lower overall disability rate in patients receiving combined therapy(13.7%versus 17.9%;OR,0.78(0.6～1.01);P=0.064).However,there were significantly fewer patients in the dual antiplatelet group with disability attributed by the investigators to index stroke(8.4%versus 12%;OR,0.72(0.52-0.98);P=0.038).There was no statistically difference in moderate to severe bleeding complications between the dual and mono antiplatelet drug regimens(0.4%versus 0.2%;HR,1.5(0.25,8.98);P=0.657).Conclusion:Aspirin plus clopidogrel was associated with a reduction of disability attributed to index stroke.There was no statistically difference in moderate to severe bleeding complications between the two antiplatelet drug regimens.Part Ⅲ The prognostic accuracy of the THRIVE、HIAT and the ASTRAL models in non-cardiogenic minor stroke patients treated with antiplatelet therapy:an external validation studyObjective:To validate the predictive performance of the ASTRAL,HIAT and THRIVE predictive scores for predicting 3-month poor outcome in acute non-cardiogenic minor ischemic stroke patients.Methods:We used data from the SEACOAST study(Safety and efficacy of aspirinclopidogrel in acute noncardiogenic minor ischaemic stroke)to analyse patients with minor stroke within 72 hours of onset who were treated with aspirin or clopidogrel alone or combination of clopidogrel and aspirin from September 2019 to November 2021.The outcome measure was a 3-month poor outcome,defied as modified Rankin Scale 3-6,which was consistent with the original cohort study of the models.These three models were evaluated in terms of discrimination and calibration.Discrimination was assessed using the area under the receiver operating characteristic(AUROC),and calibration was evaluated graphically with calibration plots.Then,we compare the AUROC of the predictive models.Results:In this section,2822 patients were used to validate the THRIVE model,and 2249 patients were used to validate the HIAT and the ASTRAL model.The AUROC of THRIVE model for predicting 3-month poor prognosis(mRS 3-6)was 0.663(95%CI:0.625-0.700);The AUROC of the HIAT model predicting 3-month poor prognosis(mRS 3-6)was 0.715(95%CI:0.654-0.776);The AUROC of ASTRAL score for predicting 3month poor prognosis(mRS 3-6)was 0.722(95%CI:0.677-0.767)ASTRAL was superior to the THRIVE and the HIAT models.The calibration curves show that there is a strong correlation between the predicted values and the real values of the three models.Conclusion:In our cohort,the ASTRAL score was superior to the THRIVE and the HIAT models in predicting 3-month poor functional outcomes,and all of the models were well calibrated.Part Ⅳ Early prediction of the 3-month functional outcome for noncardiogenic minor ischemic stroke patients who received antiplatelet therapy using a nomogram modelObjective:To develop and validate a prognostic nomogram to predict 3-month functional outcome for non-cardiogenic minor ischemic stroke patients who received antiplatelet therapy.Methods:In this section,2249 patients with baseline glucose data were included in the analysis.We used 1476 patients from 7 stroke centres as development cohort and 773 patients from another stroke centre as validation cohort.The outcome measure was 3month disability,defied as modified Rankin Scale 2-6.Logistic regression model was employed to develop the nomogram to predict 3-month disability in patients with minor stroke using demographic,medical,and serological information.We then validated the nomogram externally.The predictive discrimination and calibration of the nomogram were assessed in the development and validation cohorts by area-under-the-curves(AUC)and calibration plots.Results:Logistic multivariate analysis showed that age,baseline systolic blood pressure,history of ischemic stroke or TIA,baseline NIHSS score,NIHSS score on arm weakness,NIHSS score on leg weakness,and abnormal blood glucose were independent predictors of adverse outcome in patients with minor stroke.We develop a nomogram model by using these predictive factors.The nomogram demonstrated adequate calibration and discrimination(AUC=0.770),which was validated among the validation cohort(AUC=0.773).Our nomogram was determined to be superior to the ASTRAL score in discrimination in the validation cohort(P=0.001).Conclusion:A prognostic nomogram for predicting the 3-month disability among patients after acute minor stroke was constructed and validated externally.The nomogram demonstrated adequate calibration and discrimination in both the development and validation cohort.Conclusion1.There is a gap between the guideline recommendation and real-world clinical practice.DAPT is widely used in patients within 24-72 hours of onset and with NIHSS scores of 4-5,which is not recommended from the guidelines.In addition,the doses of clopidogrel on day 1 and the duration of DAPT differed from those of the guideline recommendation.2.Aspirin plus clopidogrel was associated with a reduction of disability attributed to index stroke.There was no statistically difference in moderate to severe bleeding complications between the two antiplatelet drug regimens.3.In our cohort of minor non-cardiogenic ischemic stroke,the ASTRAL model was determined to be superior to the THRIVE and the HIAT models in predicting 3-month poor functional outcomes,and all of the models were well calibrated.A prognostic nomogram for predicting the 3-month disability among patients after acute minor stroke was constructed and validated externally.The nomogram demonstrated adequate calibration and discrimination in both the development and validation cohort.Our nomogram was determined to be superior to the ASTRAL score in discrimination in the validation cohort(P=0.001).