| Since 2015,at least 7 high-quality randomized controlled trials have consistently demonstrated that endovascular treatment combined with standard medical treatment is significantly superior to standard medical treatment alone in acute anterior large vessel occlusion within 24 hours of stroke onset.However,there are still many problems in cerebrovascular recanalization treatment strategies that need to be resolved.For example,the posterior circulation is different from the anterior circulation due to its anatomical structure and physiological functions.It is still unclear whether acute posterior large vessel occlusion can benefit from endovascular treatment.Furthermore,among thrombolysis eligible stroke patients with acute anterior large vessel occlusion within 4.5 hours of symptom onset,it also urgently needs to be confirmed by high-quality randomized controlled trials whether intravenous thrombolysis before endovascular treatment brings additional benefits and/or increases risks.This article focuses on the above two scientific issues,and cooperates with multiple stroke centers across the country to conduct collaborative research.Part 1: Endovascular Treatment for Acute Posterior Large Vessel Occlusion: A Multi-center Observational RegistryBackground and purpose: Several multi-center randomized controlled clinical trials showed that endovascular treatment administrated within 24 hours of symptom onset could significantly improve the clinical functional outcome of stroke patients with acute anterior large vessel occlusion.Because the posterior circulation is different from the anterior circulation in anatomical structure and physiological function,these trials did not include patients with acute posterior large vessel occlusion.It is not clear whether endovascular treatment can improve the functional outcome of stroke patients with posterior large vessel occlusion.This study aims to investigate whether standard medical treatment combined with endovascular treatment can reduce the disability level and mortality in stroke patients with acute posterior large vessel occlusion within 24 hours of symptom onset compared with standard medical treatment alone.Methods: This study was an investigator-initiated,non-randomized controlled,multi-center observational study.It was planned to consecutively enroll adult patients with symptomatic posterior large vessel occlusion confirmed by computed tomographic angiography(CTA)/ magnetic resonance angiography(MRA)/ digital substraction angiography(DSA)within 24 hours of stroke onset.Patients were divided into two groups according to whether they received endovascular treatment.Those who only received standard medical treatment were allocated into standard medical treatment alone group(control group),and those who received endovascular treatment on the basis of standard medical treatment were the standard medical treatment combined with endovascular treatment group(interventional group).The primary outcome was the modified Rankin scale(m RS,7levels from 0 to 6,0 indicates asymptomatic,higher score means more severe disability,and the 6 indicates death)to assess the patient's 90-day disability level.The main effect variable was adjusted common odds ratio(c OR),and was estimated by the use of ordinal logistics regression model taking the pre-specified factors into account.Secondary outcome included the favorable functional outcome(defined as m RS score 0 to 3,manifested as independent walking without assistance)at 90 days.The safety outcomes included the incidence of symptomatic intracerebral hemorrhage and 90-day mortality.Results: From January 2014 to May 2019,51 stroke centers in 15 provinces,municipalities and autonomous regions in China screened 1254 patients for this study.Finally,829 cases were successfully enrolled.Among them,612(73.8%)were male,and the median age was 65(interquartile range [IQR]: 57?74)years old.182 patients only received standard medical treatment,and the remaining 647 patients received standard medical treatment combined with endovascular treatment.The 90-day m RS score in the interventional group was dramatically lower than that in the control group(5 [IQR,2?6] vs 6 [IQR,5?6] with an adjusted c OR,3.08 [95% confidence interval(CI): 2.09?4.55];P < 0.001).In addition,compared with the control group,patients in the interventional group had a significantly higher proportion of 90-day favorable functional outcome(32% [207/647] vs 9.3% [17/182]with an adjusted OR,4.70 [95% CI: 2.53?8.75];P < 0.001),and a substantial lower rate of90-day mortality(46.2% [299/647] vs 71.4% [130/182] with an adjusted OR,2.93 [95% CI:1.95?4.40];P < 0.001),but the incidence of symptomatic intracerebral hemorrhage increased significantly(7.1% [45/636] vs 0.5% [1/182];P < 0.001).Conclusions: This was the first database of early recanalization management for acute posterior large vessel occlusion in China.The results showed that endovascular treatment administrated within 24 hours of stroke onset was significantly associated with lower disability level and mortality.Although the incidence of symptomatic cerebral hemorrhage increased significantly,endovascular treatment was still a very promising treatment in terms of benefit-risk ratio.The findings of this study need to be further verified by multi-center randomized controlled trials.Part 2 Endovascular Treatment Alone versus Intravenous Alteplase Plus Endovascular Treatment for Stroke Patient with Acute Anterior Large Vessel Occlusion: A Multi-center,Randomized Controlled Clinical Trial Background and purpose: Several high-quality randomized controlled clinical trials consistently demonstrated that intravenous thrombolysis combined with endovascular treatment was superior to intravenous thrombolysis alone in improving the functional outcome of stroke patient with acute anterior large vessel occlusion,and no significant difference was detected in terms of safety between the two treatment strategies.Related domestic and foreign stroke management guidelines recommended intravenous thrombolysis combined with endovascular treatment as the first-line standard treatment for patients with acute ischemic stroke due to anterior large vessel occlusion.However,intravenous thrombolysis before endovascular treatment was a double-edged sword,with both potential benefits and risks.It may recanalize the vessels in some patients to avoid endovascular treatment,and may also increase the risk of intracerebral hemorrhage.This trial aimed to investigate whether intravenous thrombolysis could be omitted,and directly underwent endovascular treatment,and whether endovascular treatment alone could achieve a similar efficacy to intravenous thrombolysis combined with endovascular treatment.At the same time,this trial aimed to explore whether there are differences in the safety of the two treatment strategies.Methods: This was a multi-center,randomized controlled,open-label,blinded endpoint assessment,and non-inferiority clinical trial.Eligible subjects were adult stroke patients who were diagnosed by CTA/MRA of intracranial internal carotid artery or the first segment of middle cerebral artery occlusion within 4.5 hours of symptom onset,thrombolysis eligible,and were scheduled for endovascular treatment.Using a Web-based randomization software system and block randomization method,qualified subjects were randomly assigned to endovascular treatment alone group(direct thrombectomy group)and intravenous alteplase combined with endovascular treatment group(bridging thrombectomy group)at a ratio of 1:1.The follow-up period of all enrolled subjects is 90 days.The primary outcome was the proportion of 90-day functional independence(defined as a score of 0~2 on m RS).The safety outcomes included the incidence of symptomatic cerebral hemorrhage within 48 hours and the mortality within 90 days.The non-inferiority margin was-10%.A 5-stage group sequential design was adopted,and the Pocock function was used to determine the efficacy termination boundary value of each stage.The non-inferiority test for the difference of two independent proportions was used to estimate the Z value and the corresponding P value,and the lower limit of the 1-sided 97.5% confidence interval for the difference between the two groups' rates was calculated.Results: Up to 970 subjects were planned to randomize in this trial.However,after 234 subjects were randomized,the first interim analysis indicated that the prespecified efficacy termination boundary required by the statistical analysis plan was reached,and the trial was terminated early.From May 20,2018 to May 2,2020,33 stroke centers in China screened 509 subjects,and 234 eligible subjects were randomized in this trial.All enrolled subjects had 90-day follow up results.There were no missing or cross-over cases,and the follow-up date for the final subject was July 22,2020.Among the 234 patients,102(43.6%)were female,with a median age of 70(IQR,60~78)years old.There were 116 subjects randomly assigned to the direct thrombectomy group and 118 subjects to the bridging thrombectomy group.At the 90-day follow-up,63(54.3%)patients in the direct thrombectomy group and 55(46.6%)patients in the bridging thrombectomy group achieved functional independence(difference: 7.7%;1-sided 97.5% CI:-5.1% ~ ?).The lower boundary of the 1-sided 97.5% confidenceinterval was-5.1%,and was greater than the prespecified non-inferiority margin of-10%.The Z value and the corresponding P value of the non-inferiority test of the two independent proportions were 2.7157 and 0.003,respectively,which crossed the prespecified first-interim analysis efficacy boundary(Z = 2.35826 and P = 0.00918).The two treatment groups had similar proportions in terms of symptomatic intracerebral hemorrhage(6.1% vs 6.8%;difference:-0.8%,95% CI:-7.1% ~ 5.6%)and 90-day mortality(17.2% vs 17.8%;difference:-0.5%,95% CI:-10.3% ~ 9.2%).Conclusions: For adult patients with acute ischemic stroke caused by anterior circulation large vessel occlusion within 4.5 hours of symptom onset,endovascular treatment alone was not inferior to intravenous alteplase combined with endovascular treatment in terms of achieving 90-day functional independence.There was no significant difference in the incidence of symptomatic intracerebral hemorrhage and mortality between the two treatment strategies.Endovascular treatment alone can be an alternative treatment strategy for intravenous thrombolysis combined with endovascular treatment.These findings should be interpreted in the context of acceptable non-inferiority thresholds. |
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