Study Of Ultra-Early Therapeutic Strategy For Mild Non-Disabling Ischemic Stroke And The Construction Of Clinical Prediction Model

Part Ⅰ: Comparison of efficacy and safety of ultra-early Non-Intravenous Thrombolysis and Intravenous Thrombolysis for mild non-disabling ischemic stroke Objective: Studies have shown that more than 50% of patients with acute ischemic stroke(AIS)are Mild Ischemic Stroke(MIS),which can be divided into disabling and non-disabling.Ultra-early Intravenous Thrombolysis(IVT)treatment has been widely used in the treatment of mild disabling ischemic stroke.However,there is still a lack of research on the ultra-early treatment of Mild Non-Disabling Ischemic Stroke(MNDIS).It was observed that part of MNDIS patients with Non-Intravenous Thrombolysis(NonIVT)treatment within 4.5 hours of onset also achieved a favorable outcome in the in the real-world clinical center.Therefore,this study screened MNDIS patients within 4.5hours of onset in the real-world clinical center for clinical research,to explore whether non IVT treatment is safe and effective for MNDIS within 4.5 hours of onset,and the efficacy is not inferior to IVT treatment,To provide basis for individual treatment of MNDIS patients.Methods:Data of all AIS patients admitted to Hospital were prospectively registered between March 2018 and February 2022.A total of 1072 patients who met the MNDIS diagnostic criteria within 4.5 hours of onset were included.They were divided into NonIVT treatment group(n = 359)and IVT treatment group(n = 713).Baseline parameters collected for analysis included demographic information,medical history,medications prior to onset,blood pressure,blood glucose,baseline NIHSS score and stroke etiology,(modified Rankin Scale)m RS score.The treatments for Non-IVT group and IVT group were registered.NIHSS score at 24 hours,Hemorrhagic Transformation(HT)at 36 hours,m RS at 90 days and all-cause mortality were collected during follow-up.The primary outcome was favorable outcome of MNDIS patients.The secondary outcome measures included HT,symptomatic Intracranial Hemorrhage(s ICH),asymptomatic Intracranial Hemorrhage,and the type of HT,Early Neurologic Deterioration(END)and all-cause mortality at 90 days.Measurement data were described by mean ± standard deviation,median and interquartile range,and comparison between groups was performed by t-test or Mann-Whitney U test(Wilcoxion rank sum test).For the primary outcome,twosample rate comparison of noninferiority was used for statistical inference.Subgroup analyses were performed for age,sex,stroke history,blood glucose,admission NIHSS score,cardiogenic embolism,and large-artery atherosclerosis.Interactions were considered to assess the heterogeneity of association between subgroups.Poisson regression was used to analyze secondary outcome indicators.Binary Logistic regression was used to predict and analyze the influencing factors of 90-day favorable outcome.Age,blood glucose,admission to NIHSS,smoking,hypertension,previous stroke,total cholesterol,high density protein-cholesterol,triglycerides,and TOAST classification were adjusted for covariates.In the IVT treatment group,chi-square analysis was used to compare the efficacy differences between the dose subgroups.All statistics were performed using SAS 9.4 and R software version 4.0.3,and Graph Pad Prism 7 was used for plotting.P< 0.05 was considered statistically significant.Results:1.Demographic and clinical characteristics.From March 2018 through February 2022 a total of consecutive 7449 patients were enrolled in the AIS registry of hospital.A total of 1072 patients with MNDIS were included in the analysis.359 patients received NonIVT and 713 patients received IVT.Patients who received IVT had a higher prevalence of smoking(P=0.010),were significantly younger than those who received Non-IVT(P=0.000),fewer previous strokes(P=0.001),higher baseline blood glucose(P=0.001),and higher NIHSS scores(P=0.000).Total cholesterol >5mmol/L(P=0.0.026),high density lipoprotein cholesterol <1mmol/L(P=0.012)and triglyceride level>1.68mmol/L(P=0.000)were higher in IVT treatment group.There were statistically significant differences in the proportion distribution of TOAST classification between the two groups(P=0.040).2.Favorable outcome at three months after stroke.307 patients(307/359,85.520%)of favorable results were obtained in the Non-IVT treatment group and 622 patients(622/713,87.24%)in the IVT treatment group.The Non-IVT treatment group was noninferior to the IVT treatment group(RD,-1.72%;95%CI,-6.11%-2.67%,P<0.0001),the lower limit of 95%CI was-6.11%,which was higher than the pre-set non-inferiority margin of-7.5%,Non-IVT treatment was noninferior to IVT treatment.After Bonferroni’s correction for multiple comparisons,Non-IVT treatment was compared with the doses group,and Non-IVT treatment group was non-inferior to IVT with low-dose group(RD,-1.35%;95%CI,-6.24% to 3.54%,P=0.0006),The Non-IVT treatment group was non-inferior to the standard IVT dose group(RD,-2.23%;95%CI,-7.42% to 2.96%,P=0.0003),both groups achieved noninferiority.3.Effects of Non-IVT only as compared with IVT on the primary efficacy outcome,according to prespecified subgroups.In prespecified subgroups based on age,sex,previous stroke history,blood glucose,baseline NIHSS score,cardioembolism,and causes of large-artery atherosclerosis,there was a statistically significant difference between the two groups when stratified at age 18 to 60 years(P=0.0124),Others interactions were not significant.Non-IVT treatment group was more sensitive to the age of 18-60 years than the IVT treatment group for noninferiority.4.Safety assessment after stroke.Compared with the IVT treatment group,hemorrhagic transformation(RR,4.56;95% CI,4.33 to 4.81;P<0.0001)is statistically significant.For s ICH(RR,5.32;95% CI,2.94 to 9.60;P<0.0001),also asymptomatic intracranial hemorrhage(RR,4.42;95% CI,4.42 to 4.42;P<0.0001),HI-1 type(RR,5.47;95% CI,3.15 to 9.50;P<0.0001),HI-2(RR,2.73;95% CI,1.73 to 4.29;P<0.0001)were all statistically different between the two groups.END(RR,1.22;95% CI,0.48 to3.06;P=0.679)had no significant difference.90-day mortality(RR,0.93;95% CI,0.28 to 3.08;P=0.907)was no significant difference between the two groups.5.Multiple regression analysis for favorable outcome(m RS ≤ 1)at 90 days in NonIVT treatment group and IVT treatment group.Multiple regression analysis showed that age(OR,924;95% CI,0.892 to 0.958;P< 0.0001)and admission NIHSS score(OR,0.682;95% CI,0.538 to 0.863;P=0.002)was an independent prognostic factor for 90-day favorable outcome in Non-IVT treatment group.Admission NIHSS score(OR,0.585;95% CI,0.484 to 0.706;P<0.0001),hypertension(OR,0.552;95% CI,0.323 to 0.928;P<0.0001)were independent prognostic factors for favorable outcome at 90 days in the IVT treatment group.Age(OR,0.964;95% CI,0.945 to 0.984;P=0.000)and admission NIHSS score(OR,0.623;95% CI,0.540 to 0.720;P<0.000)and hypertension(OR,0.648;95% CI,0.426 to 0.987;P=0.043)was an independent prognostic factor for the overall favorable outcome of patients with MNDIS at 90 days.6.Efficacy and safety of low-dose versus standard-dose IVT in MNDIS patients.There were 357 patients with m RS 0-1scores(357/411,86.86%)and 54 patients with m RS > 1 scores in the low-dose group,265 patients with m RS0-1 scores(265/302,87.75%)and 37 patients with m RS >1 scores in the standard-dose group.There was no significant difference in 90-day functional outcomes between the low-dose group and the standard dose group(P=0.726).Similarly,there was no significant difference in HT(P=0.737),END(P=0.982)and 90-day mortality(P=0.523).There was no significant difference in 90-day functional outcome over 80 years old(P=0.406).All 6 cases of bleeding were in the standard dose group,with 1 case of END and 1 case of death in each group.Conclusion:1.In MNDIS patients within 4.5 hours of onset,the Non-IVT therapy was not inferior to IVT therapy.Non-IVT treatment group was more sensitive to the age of 18-60 years than the IVT treatment group for noninferiority.2.Among MNDIS patients with within 4.5 hours of onset,END and mortality did not increase in the Non-IVT treatment group compared with IVT treatment group,the IVT treatment group had an increased tendency to bleed compared with the Non-IVT group.Non IVT treatment is safer.3.Age and admission NIHSS score were independent prognostic factors for 90-day favorable outcome in non-IVT treatment group,while admission NIHSS score and hypertension were independent prognostic factors for 90-day favorable outcome in IVT treatment group.Age,admission NIHSS score and hypertension were independent prognostic factors for the overall favorable outcome of MNDIS patients at 90 days.4.IVT dose subgroup analysis showed that there was no significant difference in efficacy and safety between low-dose and standard dose IVT in the treatment of MNDIS patients.There was no difference in the efficacy over 80 years old,but the standard dose group had increased bleeding tendency.Part Ⅱ: Construction of a Predictive Model For Unfavorable Outcome In Mild Non-Disabling Ischemic Stroke with Intravenous Thrombolysis Objective: The aim of this part was to analyze the influencing factors of unfavorable outcome in MNDIS patients with IVT therapy,to construct a nomogram model based on the influencing factors for 90-day unfavorable outcome.The accuracy and clinical practicability of the established nomogram model were analyzed.The risk degree of each patient can be obtained through the nomogram model,hoping to help doctors identify high-risk patients in clinical practice,so as to guide the individualized treatment of MNDIS patients.Methods:The clinical data of 713 patients who met the MNDIS diagnostic criteria and received intravenous thrombolysis within 4.5 hours in a medical center from March 2018 to February 2022 were retrospectively collected.According to the m RS score at 90 days after discharge,713 patients were divided into two groups: Unfavorable outcome group(m RS≥2 points)and favorable outcome group(m RS≤1 point).Demographic data,clinical data,laboratory and imaging datas in hospital and follow-up were collected after discharge.Univariate analysis and multivariate analysis were used to screen the influencing factors of unfavorable outcome at 90 days after discharge.The nomogram model was constructed by R language package based on the above independent influencing factors.The Receiver Operating Characteristic(ROC)ROC curve,Bootstrap method and clinical decision curve were used to verify the accuracy of the model and the benefit of clinical decision.Statistical analysis was performed using R language 4.1.1.Continuous variable with a normal distribution is expressed as mean ± standard deviation;Statistical description of data that do not conform to normal distribution is expressed as median(Inter-Quartile Range(IQR));Categorical variables are expressed as frequency(percentage).Multivariate Logistic regression was performed by stepwise method,with inclusion criteria of 0.05 and exclusion criteria of 0.10.P < 0.05 was considered statistically significant.Results:1.A total of 713 MNDIS patients with thrombolysis were included in this study for statistical analysis.There were 91 cases in the unfavorable outcome group and 622 cases in the favorable outcome group.The baseline characteristics between the two groups were compared,and the results showed that the hypertension(p=0.033),diabetes(p=0.044),age(p=0.049),admission NIHSS score(p<0.001),24-hour NIHSS score(p<0.001)in unfavorable outcome group were higher than those in the favorable outcome group,the difference is statistical significance;Hyperlipidemia(p=0.037)and highdensity lipoprotein cholesterol(p=0.049)in the unfavorable outcome group were lower than those in the favorable outcome group,which is significantly different.2.Multivariate logistics analysis was used to analyze the influencing factors of unfavorable outcome in MNDIS patients after thrombolysis.Statistical analysis results showed that NIHSS score on admission(OR,1.37;95% CI,1.1 to 1.72;P=0.006)and24-hour NIHSS score(OR,1.78;95% CI,1.52 to 2.1;P<0.001),diastolic blood pressure(OR,1.02;95% CI,1.00 to 1.05;P=0.026),coronary heart disease(OR,1.88;95% CI,1.05 to 3.35;P=0.033)were found to be risk factors for unfavorable outcome.3.The nomogram has a strong ability to predict the unfavorable outcome of MNDIS patients after thrombolysis at 90 days,AUC = 0.835,95% CI,0.805 to 0.861;P<0.001,sensitivity is 71.43%,specificity is 84.08%,Youden index is 0.5551.The nomogram was verified by repeated sampling for 1000 times,and it was found that the average absolute error of the calibration curve was 0.014,indicating that the calibration curve fitted the ideal curve well.The Nomogram model is the most suitable for predicting the unfavorable outcome of MNDIS patients after thrombolysis at 90 days,when the threshold of occurrence is between 0.10 and 0.98.Conclusion:The risk factors affecting the unfavorable outcome of MNDIS patients after thrombolysis were NIHSS score on admission,24-hour NIHSS score,diastolic blood pressure and coronary heart disease.The nomogram model constructed based on the factors has good clinical predictive value.The model can identify the risk probability of unfavorable outcome,which is helpful for clinicians to evaluate and diagnose patients.