Remote Ischemic Conditioning Combined With Intravenous Thrombolysis For Ischemic Stroke:A Multicenter,Randomized,Controlled Trial(SERIC-IVT Trial)

Part one: The safety of remote ischemic conditioning combined with intravenous thrombolysis for acute ischemic strokeBackground and objective: Studies have shown that remote ischemic conditioning(RIC)has neuroprotective effects on acute ischemic stroke.RIC combined with intravenous thrombolysis(IVT)has a potential role in improving the clinical outcomes of acute ischemic stroke,and RIC is expected to become a new adjuvant treatment for patients with IVT.However,there is insufficient evidence for the safety of RIC in patients with IVT.Therefore,we designed a multi-center,randomized controlled clinical trial on the safety and efficacy of RIC combined with IVT for acute ischemic stroke(SERIC-IVT trial).In this part of the study,the safety of RIC combined with IVT for acute ischemic stroke was explored to provide new evidence for the clinical application of RIC.Methods: This study was a prospective,multicenter,randomized controlled,blindedendpoint clinical trial.From August 2021 to February 2023,558 consecutive patients with acute ischemic stroke treated with IVT with alteplase within 4.5 hours of onset were enrolled from 18 hospitals in Jilin Province.Patients were randomly assigned in a 1:1 ratio to RIC(n = 279)group or sham RIC(n = 279)group.Patients in both groups were treated with RIC or sham RIC for 7 consecutive days after IVT.Safety outcomes were collected at 24 hours,7 days,and 90 days after IVT,as follows: 1)the incidence of hemorrhagic transformation(HT)within 24 hours after IVT;2)the incidence of all adverse events within 90 days;3)total mortality at 90 days;4)The incidence of RICrelated adverse events during the intervention;5)Blood pressure and heart rate at 24 hours and 7 days after IVT.Results: Safety analyses were performed for all subjects who received at least one RIC treatment.Finally,274 patients were included in the RIC group and 273 patients in the sham RIC group.The median age(interquartile range)of the RIC group was 64(54-71)years old,and 188(68.6%)were male.The median age(interquartile range)of Sham RIC group was 65(56-70)years old,and 191(70.0%)were male.There was no significant difference in baseline clinical data between the two groups.There was no significant difference between the RIC group and the Sham RIC group in the incidence of HT within 24 hours after IVT(RIC group 6.0% vs.Sham RIC group 5.6%,P=0.845).There was no significant difference between the RIC group and the sham RIC group in the total mortality at 90 days(RIC group 4.1% vs.Sham RIC group 1.9%,P=0.136).The incidence of all adverse events at 90 days was similar between the RIC group and Sham RIC group(11.2% vs.8.1%,P=0.221),and no serious adverse events occurred in either group.RIC related adverse events included: local skin changes(including petechiae,redness or cyanosis,5 patients),allergic dermatitis(1 patient),pain(4 patients),and dizziness(1 patient).There was no significant difference between the RIC group and the sham RIC group in the RIC related adverse events.The generalized estimating equations showed that RIC had no significant effect on blood pressure and heart rate.Conclusions: RIC combined with IVT is safe and tolerable for acute ischemic stroke.RIC does not increase the incidence of HT within 24 hours after IVT,the total mortality and the incidence of all adverse events at 90 days after IVT.RIC has no effect on blood pressure and heart rate during hospitalization.Part two: Efficacy of remote ischemic conditioning combined with intravenous thrombolysis for acute ischemic strokeBackground and objective: Intravenous thrombolysis(IVT)was indicated as currently the highest level of evidence and recommendation for the treatment of acute ischemic stroke.However,more than half of patients with acute ischemic stroke still do not have a favorable outcome after IVT.The reason may be that IVT may cause ischemia-reperfusion injury,hemorrhagic transformation and other complications,which even can lead to death.Therefore,IVT combined with neuroprotective therapy may be one of the effective methods to improve the prognosis.Previous studies have shown that Remote Ischemic Conditioning(RIC)combined with IVT may improve the clinical outcomes of patients.Our team has found that RIC can reduce blood-brain barrier(BBB)damage,oxidative stress and inflammatory response in IVT animal models,thereby improving neurobehavioral function.However,the results of previous studies on the efficacy of RIC combined with IVT for acute ischemic stroke are not consistent.Therefore,we designed a multicenter,randomized controlled clinical trial on the safety and efficacy of RIC combined with IVT for acute ischemic stroke(SERICIVT trial).In this part of the study,we explore the efficacy of RIC combined with IVT for acute ischemic stroke.Methods: A total of 558 subjects included in the SERIC-IVT study were enrolled in this part of the study.Patients were randomly assigned in a 1:1 ratio to RIC(n = 279)group or sham RIC(n = 279)group.Patients in both groups were treated with RIC or sham RIC for 7 consecutive days after IVT,and patients were followed up at 24 hours,7 days,and 90 days after IVT.The primary efficacy outcome was the proportion of patients with a favorable outcome(modified Rankin Scale [mRS] score of ≤1)at 90 days.The secondary efficacy outcome included: 1)the difference in the National Institutes of Health Stroke Scale(NIHSS)score at 24 hours and 7 days after IVT;2)differences in the incidence of early neurological deterioration after IVT;3)The difference in the distribution of mRS Scores between the two groups at 90 days after IVT;4)The proportion of mRS Score 0-2 at 90 days after IVT;5)the difference in recurrent stroke rate at 90 days,after IVT.The modified intention-to-treat(mITT)analysis set was used for all subjects who received at least one RIC,and the per-protocol(PP)analysis set was used for subjects who received RIC at least 10 times.Primary and secondary outcomes were analyzed by Poisson regression or Win Ratio method,as appropriate,with adjustment for affecting outcome(age,sex,baseline NIHSS score,mRS Score before stroke onset,time from onset to RIC treatment,cites).Results: A total of 274 patients in the RIC group and 273 patients in the sham RIC group were included in the mITT analysis set,and the loss rate at 90 day was 2.74%(15/547).A total of 231 patients in the RIC group and 247 patients in the Sham RIC group were entered into the PP analysis set.There was no significant difference in the baseline clinical data between the two groups in mITT analysis set and PP analysis set.For the primary outcome,the RIC group compared with the sham RIC group in the mITT analysis set,the proportion of 90-day mRS 0-1 was not statistically significant(62.7% vs.56.8%,Risk ratio [RR] 1.10,95% confidence interval [CI]: 0.96-1.27,P=0.169).After adjustment,the results were still not statistically significant,and the results in PP analysis set were also not statistically significant.For the secondary outcomes,there was no significant difference in the proportion of mRS 0-2 at 90 days between the RIC group and the sham RIC group in the mITT analysis set(78.7% vs.79.5%,RR 0.99,95% CI: 0.91-1.08,P=0.817),and the distribution of mRS Scores at 90 days was not statistically significant(Win Ratio [WR] 0.92,95% CI: 0.72–1.17,P=0.482).The 90-day recurrence rate was not statistically significant(13.0% vs.12.8%,RR 1.01,95% CI: 0.65-1.58,P=0.950),and the results were not statistically significant after adjustment.For short-term outcomes,in the mITT analysis set,the RIC group compared with the sham RIC group had no statistically difference in incidence of early neurological deterioration after IVT(6.9% vs.7.0%,RR 1.00,95%CI: 0.54-1.84,P=0.991).RIC had no significant impact on NIHSS score at 24 hours(WR 0.87,95% CI:0.70–1.07,P=0.186),7-day NIHSS score(WR 0.95,95% CI:0.76–1.18,P=0.645),BI at 24 hours(WR 1.12,95% CI:0.91–1.39,P=0.278)and 7-day BI(WR 1.14,95% CI:0.91–1.42,P=0.263)after IVT and the results were also not statistically significant in the PP analysis set.Conclusion: RIC combined with IVT has no significant effect on the short-term and long-term prognosis for patients with acute ischemic stroke,but there is a trend of 5.9% increase in patients with long-term excellent outcome(mRS 0 or 1).Part three: The effect of remote ischemic conditioning on blood pressure variability in patients with acute ischemic stroke receiving intravenous thrombolysisBackground and objective: blood pressure variability(BPV)reflects the fluctuation of blood pressure level in a certain period of time,which is one of the basic physiological characteristics of human beings.Elevated BPV is closely related to the occurrence,recurrence and poor clinical outcomes of cardiovascular or cerebrovascular diseases.Regulating BPV is an important part of the prevention and treatment of cardiovascular and cerebrovascular diseases.Some studies have shown that improving autonomic nerve function in patients with acute ischemic stroke may be one of the mechanisms of RIC’s neuroprotective effect,but whether RIC affects BPV in patients with acute ischemic stroke is currently unknown.Therefore,in this part of the study,we intend to investigate the effect of RIC on BPV in patients with acute ischemic stroke receiving intravenous thrombolysis(IVT).Methods: Based on the SERIC-IVT trial,this part of the study included patients from the First Hospital of Jilin University.Patients in both groups were treated with RIC or sham RIC for 7 consecutive days after IVT.The two groups of patients underwent noninvasive continuous fingertip blood pressure monitoring at 1-3 days and 7-10 days after thrombolysis,respectively.Systolic blood pressure(SBP),Diastolic blood pressure(DBP)and mean arterial pressure(MAP)were obtained.BPV parameters,including standard deviation(SD)and variation independent of mean(VIM),were calculated by MATLAB software according to the formula.The effect of RIC on BPV indexes was analyzed by multivariate linear regression model.Results: A total of 66 subjects were enrolled in the First Hospital of Jilin University,including 33 in the RIC group and 33 in the sham RIC group.After excluding subjects who did not complete 2 times of BPV monitoring,14 times of RIC treatment,and ectopic beats more than 20%,22 subjects in each group were finally included in the statistical analysis.There was no significant difference in baseline data between the two groups,and there was no significant difference in BPV indicators between the two groups at 1-3 days after IVT.Compared with the sham RIC group,SBP-SD,MAP-SD,SBP-VIM and MAP-VIM in the RIC group decreased significantly than sham RIC group at 7-10 days after IVT(P=0.026,P=0.038,P=0.044,P=0.045).After adjusting the influencing factors,RIC had a significant improvement effect on SBP-SD and SBPVIM(P=0.044,P=0.042).Conclusions: RIC treatment for 7 consecutive days after IVT can improve BPV in patients with acute ischemic stroke with IVT.