The Analysis Of Decision-Making For Antiplatelet Regimens And The Efficacy And Safety Of Dual Antiplatelet Therapy For Mild Stroke In Real-World(NIHSS Score ≤ 5)

Part ⅠThe Analysis of Decision-Making for Antiplatelet Regimens Based on Individual Factors in The Real-WorldObjective:Guidelines for ischemic cerebrovascular disease are updated based on the latest RCT results.However,in real clinical practice,doctors make the final antiplatelet regimen not only based on guidelines,but also based on individual patient factors.The purpose of this part of our study was to analyze the individual factors were associated with physicians’antiplatelet decisions in the real world.Methods:This is a prospective,multicenter cohort study.Patients with mild stroke with NIHSS score≤5 and within 72 hours of onset were continuously included in 8 stroke centers in Shanxi Province to collect baseline data.Demographic analysis was performed using intention-to-treat（ITT）.According to the first antiplatelet regimen,patients were divided into two groups:single antiplatelet group and double antiplatelet group.Univariate and/OR multivariate Logistic models will be used to analyze influencing factors for antiplatelet regiments and to report unadjusted and adjusted OR values.Results:We included 3723 patients with a baseline NIHSS score ≤5 within 72 hours of onset,and excluded 662 patients who did not conform to the study,and included 3061 patients for statistical analysis.Compared with the SAPT group,patients in the DAPT group were younger,more male,had higher body mass index,higher baseline diastolic blood pressure and lower serum creatinine level,and had higher rates of current smoking,drinking,hospitalization within 24 hours of onset,and pre-onset mRs Score 0-1.In addition,the proportion of previous atrial fibrillation,ischemic stroke,coronary heart disease,cerebral hemorrhage,new infarction lesions known before medication,gastrointestinal ulcer and gastrointestinal hemorrhage were lower,and the differences were statistically significant（all P<0.05）.Multivariate Logistic regression analysis showed that compared with SAPT regimen,DAPT regimen was 0.62（95%CI（0.52-0.74）,P<0.001）times greater in patients older than 60 years than in patients younger than 60 years.Patients with a NIHSS score of 4-5 were given a DAPT regimen 1.53（95%CI（1.12-2.09）,P=0.007 times higher than those with a baseline NIHSS score of 0-3.Patients with a history of ischemic stroke were 0.74（95%CI（0.60-0.92）,P=0.005）times more likely to receive DAPT than patients without a history of ischemic stroke.Patients with prior intracerebral hemorrhage were 0.28（95%CI（0.16-0.48）,P<0.001）times more likely to receive DAPT than patients without prior history of intracerebral hemorrhage.Patients with a history of digestive tract ulcers were 0.36（95%CI（0.17-0.75）,P=0.007）times more likely to receive DAPT than those without a history of digestive tract ulcers.Patients with known premedication infarct lesions were 0.73（95%CI（0.63-0.86）,P<0.001）times more likely to be treated with DAPT than patients with unknown premedication infarct lesions.Conclusion:In real clinical practice,when doctors make decisions about antiplatelet regimens based on individual patient factors,the factors related to different antiplatelet regimens are different.Regardless of the protocol decision,age and bleeding history may be important factors in the clinician’s decision making.Part ⅡThe Analysis of Decision-Making for Antiplatelet Regimens Based on Stroke Risk Score in The Real-WorldObjective:At present,there are many early stroke risk scales and small bleeding scale for ischemic stroke,and the risk score scale will guide clinicians to conduct secondary prevention treatment.However,it is not known whether the stroke risk scale is relevant to the decision of antiplatelet regimen in real clinical practice.This part of our study is mainly to explore whether the risk score scale is related to the decision of antiplatelet regimen.Methods:Based on the SEACOAST cohort study,the data were collected from mild stroke patients with NIHSS score≤5 and within 72 hours of onset in 8 stroke centers in Shanxi Province,and the baseline data of patients were collected.The current commonly used ischemic recurrence risk scores ABCD2,ESSEN and SPI-II,as well as stroke antiplatelet therapy bleeding score S₂TOP-BLEED score were used.After different antiplatelet therapy groups,the distribution of different risk scores was summarized by group.Restricted Cubic Spline（RCS）analysis was performed with scores as continuous variables and restricted cubic spline（RCS）analysis for different antiplatelet regiments.At the same time,a linear regression analysis was performed between the various scores and the adjusted correlation coefficients were reported.Results:Finally,2828 patients were included in the statistical analysis.There were statistically significant differences in inter-group correlation risk scores（ABCD2,ESSEN,SPI-II and S₂TOP-BLEED）between SAPT group and DAPT group for different risk stratification（P<0.01）.The proportion of high-risk（medium-high-risk）risk stratification of two ischemia scores in SAPT group was higher than that in DAPT group.At the same time,the high-risk ratio in S₂TOP-BLEED in SAPT group was significantly higher than that in DAPT group（48.9%vs 36.1%）,and the difference was statistically significant（all P values<0.001）.There was no curve relationship between ABCD2 score,SPI-Ⅱ score and the decision of anti-platelet regimen（SAPT and DAPT）.There was a curve relationship between the ESSEN score and antiplatelet regimen,that is,the likelihood of patients being given DAPT decreased by 23%for every point increase in ESSEN score（OR[95%CI]=0.77[0.72-0.82],P<0.001）.There was also a curve-like relationship between S₂TOP-BLEED score and antiplatelet regimen,with each point increase in S₂TOP-BLEED score,the likelihood of patients being given DAPT decreased by 10%（OR[95%CI]=0.9[0.88-0.92],P<0.001）.There was an obvious linear relationship between ESSEN scores and S₂TOP-BLEED scores（correlation coefficient[95%CI]=1.75[1.69-1.90],P<0.001）.Cross grouping of different ischemic risk and bleeding risk showed the highest proportion of LAA mechanism and intracranial artery stenosis in the high recurrence group（P<0.001）.Conclusion:In clinical practice,doctors will make antiplatelet decisions based on the stroke risk score,especially the bleeding score of antiplatelet therapy after stroke（S₂TOP-BLEED score）;the increase of bleeding risk increases with the increase of ischemic risk,but Further sample verification and combined outcome event analysis are still needed.Part ⅢEfficacy and safety of dual antiplatelet therapy for non-cardiogenic minor ischemic stroke（NIHSS score ≤5）in the real worldObjective:Current guidelines recommend that dual antiplatelet should be used within 24 hours of onset in patients with a NIHSS score of 3 or less.However,in real world patients with NIHSS≤5 within 72 hours of onset,dual antiplatelet therapy is still superior to single antiplatelet therapy.Our objective in this section is to analyze whether aspirin combined with clopidogrel has spillover effects in this population.Methods:Data analysis was based on the SEACOAST cohort study.3723 patients with mild stroke with NIHSS score≤5 and within 72 hours of onset were enrolled from 8 stroke centers in Shanxi Province.After excluding 746 cases,2977 cases were finally included.After different antiplatelet therapy groups,the baseline characteristics of patients were summarized by group.Multiple interpolation method was used for missing value data,and the data after interpolation was used for final analysis.The end event efficacy was analyzed when the imbalance between patients receiving DAPT and SAPT was analyzed using propensity score weighting,a model with treatment-weighted inverse probability（IPTW）and standardized mortality ratio weighting（SMRW）to reduce the influence of treatment selection bias and other potential confounding factors.The primary efficacy endpoint event was a 90-day complex vascular event（ischemic stroke,TIA,symptomatic intracranial hemorrhage,myocardial infarction or angina,and vascular death）.The main security event was severe bleeding.Demographic analysis was performed using intention-to-treat（ITT）.Results:A total of 2977 patients were included in this analysis,including 1163 patients（39.1%）in the SAPT group and 1814 patients（60.9%）in the DAPT group receiving aspirin combined with clopidogrel.After weighted by propensity score,the difference between the two baseline data groups was basically balanced（SMD<0.1）.The mean follow-up time was 85.5 ± 16.9 days,and 97.3%of the patients completed the 90-day follow-up.Complex vascular events occurred in 257 patients,including 154 patients（8.5%）in the DAPT group and 103 patients（8.9%）in the SAPT group.The DAPT group was associated with a 29%lower risk of 90-day complex vascular events（HRSMRW[95%CI]=0.71[0.77-0.90],P=0.004）and a 28%lower risk of ischemic stroke recurrence（HRSMRW[95%CI]=0.72[0.77-0.90],P=0.01）and significantly did not increase the risk of symptomatic intracranial hemorrhage（HR[95%CI]=0.64[0.69-4.55],P=0.656）.There were no statistically significant differences in other secondary endpoints.Conclusion:In the real world,compared with SAPT,DAPT regimen of aspirin combined with clopidogrel may reduce the risk of 90-day complex vascular events in non-cardiogenic ischemic stroke patients with NIHSS less than or equal to 5 points within 72 hours of onset,and does not increase the risk of bleeding.The above results still need to be further supported by large sample data.Part ⅤSubgroup（Sensitivity）AnalysisObjective:Although the results of the previous analysis suggest that aspirin combined with clopidogrel dual antiplatelet regimen may benefit people with NIHSS score≤5 within 72 hours of onset.But we still want to find the subgroup of people with the greatest benefit and the best treatment in this population.Methods:Based on the valid subgroup analysis and sensitivity analysis of the SEACOAST study,intention-to-treat（ITT）was used for population statistical analysis.We set up subgroups based on the results of previous studies and previous studies:Age younger than 65 years and age greater than or equal to 65 years,male and female,smoking status（non-smokers,former smokers,and current smokers）,presence or absence of hypertension,diabetes,dyslipidemia,ischemic stroke,previous antiplatelet therapy,baseline NIHSS score（0-3 and 4-5 points）,time of onset to hospital arrival（0-24 hours and 24-72 hours）,TOAST classification:Whether there is intracranial artery stenosis and whether it is similar to the RCT population（NIHSS score less than or equal to 3 points and within 24 hours of onset,NIHSS score 0-5 points and 24-72 hours of onset,and NIHSS score 4-5 points and 0-72 hours of onset）,baseline blood pressure is divided into three groups:Systolic blood pressure levels（<140 mmHg,≥140 and<180 mmHg and ≥180 mmHg）and diastolic blood pressure levels（<90 mmHg,≥90 and<110 mmHg and ≥110 mmHg）were measured.Antiplatelet drug use time was divided into three groups（less than 10 days,10-21 days,and more than 21 days）.Long-term secondary prophylaxis was divided into four groups:no medication,single aspirin therapy,single clopidogrel therapy,and aspirin combined with clopidogrel therapy.When the P-value is less than 0.1,evidence of therapeutic heterogeneity is considered present,suggesting a possible interaction.Adjusted Kaplan-Meier estimates were used to construct survival curves simulating the cumulative risk of complex vascular events at 90 days of follow-up,and Cox proportional hazard regression models were used to estimate HR and its 95%confidence interval.Results:Subgroup analysis plots for the entire population showed an interaction between baseline diastolic blood pressure and antiplatelet regimen in the unadjusted model（P interaction=0.007）.In a subgroup analysis performed in the post-IPTW model,an interaction between baseline blood pressure and antiplatelet regimen was found（P interaction<0.05）:patients with baseline systolic blood pressure between 140-180 mmHg and diastolic blood pressure between 90-110 mmHg Can benefit significantly from DAPT treatment（8.0%vs 8.9.%,HR[95%CI]=0.73[0.53-0.99]）and（7.5%vs 11.2%,HR[95%CI]=0.48[0.32-0.70]）.There was an interaction between the previous history of hypertension and the efficacy of DAPT（P interaction<0.05）:patients without previous history of hypertension benefited more from DAPT 7.3%vs.8.7%,HR[95%CI]=0.64[0.43-0.95]）.Patients with large artery atherosclerosis and other etiologies in the TOAST classification with intracranial arterial stenosis also seem to benefit from DAPT.The stratified analysis of the risk score suggested that the effect of DAPT may be the most obvious in the high recurrence and low-bleeding risk population,and the high recurrence and high-bleeding（medium-high bleeding）DAPT treatment may be harmful.The subgroup analysis of different medication times showed:patients who took DAPT for 10 days but not more than 21 days could benefit significantly from the dual antiplatelet therapy（9.6%vs.11.5%,HRIPTW[95%CI]=0.66[0.46-0.94],P=0.022）,the results were consistent in the PSM model.Patients treated with DAPT for more than 21 days did not reduce the risk of 90-day recurrence of ischemic stroke（10.5%v.s 7.6%,HRIPTW[95%CI]=1.44[1.03-2.0],P=0.031）.The drug analysis of the long-term drug regimen for secondary prevention after stroke showed that compared with the non-medication group,taking antiplatelet drugs can significantly reduce the risk of 90-day composite vascular events,and aspirin monotherapy can reduce the risk by 74%（HR[95%CI]=0.29[0.16-0.42],P-value<0.001）.Compared with aspirin monotherapy,clopidogrel monotherapy or aspirin combined with clopidogrel dual therapy may increase the risk of 90-day recurrence of composite vascular events（HRCM[95%CI]=1.86[1.32-2.62],P value<0.001 and HRDAPT[95%CI]=1.95[1.44-2.65],P-value<0.001）.Conclusion:Our subgroup（sensitivity）analysis found an interaction between baseline blood pressure and antiplatelet efficacy,specifically baseline diastolic blood pressure levels;Subgroup analysis based on risk score found that patients with high recurrence and low bleeding risk were more likely to benefit from dual antibody.For patients with NIHSS less than or equal to 5 points and 72 hours of onset,oral aspirin combined with clopidogrel for 10 days and no more than 21 days can reduce the risk of recurrence of 90-day complex vascular events by 34%;After short-term dual antibody therapy,aspirin monotherapy was superior to clopidogrel monotherapy and DAPT as long-term secondary preventive maintenance therapy.Conclusion1.In real clinical practice,when doctors make decisions on antiplatelet regimens based on individual patient factors,factors related to different antiplatelet regimens are different.Regardless of the protocol decision,age and bleeding history may be important factors in the clinician’s decision.2.In clinical practice,doctors will make anti-platelet decisions based on stroke risk scores,especially the S₂TOP-BLEED score for post-stroke anti-platelet therapy;The increase of bleeding risk increases with the increase of ischemia risk,but further sample verification and combined with outcome event analysis are still needed,and further optimization of stroke score scale tools is reasonable.3.Compared with SAPT in the real world,DAPT regimen of aspirin combined with clopidogrel may reduce the risk of 90-day complex vascular events in non-cardiogenic ischemic stroke patients with NIHSS less than or equal to 5 points within 72 hours of onset and does not increase the risk of bleeding;The above results still need to be further supported by large sample data.4.Our subgroup（sensitivity）analysis found an interaction between baseline blood pressure and antiplatelet efficacy,particularly baseline diastolic blood pressure levels;Subgroup analysis based on risk score found that patients with high recurrence and low bleeding risk were more likely to benefit from dual antibody.For patients with NIHSS less than or equal to 5 points and 72 hours of onset,oral aspirin combined with clopidogrel for 10 days and no more than 21 days can reduce the risk of recurrence of 90-day complex vascular events by 34%.After short-term dual therapy,aspirin monotherapy was superior to clopidogrel monotherapy or aspirin combined with clopidogrel.