| Great progress has been made in the treatment of acute anterior circulation intracranial large vessel occlusive stroke since 2015.Compared with conventional drug treatment,mechanical thrombectomy could achieve instant successful recanalization of more than 80% occluded vessels and significantly improve the 90-day good prognosis of patients.However,there are still many critical issues unresolved about the reperfusion treatment strategy of acute anterior circulation intracranial large vessel occlusive stroke.Firstly,the efficacy and safety of intravenous tirofiban combined with endovascular therapy for acute anterior circulation intracranial large vessel occlusive stroke within 24 hours from symptom onset remains uncertain.Secondly,among patients with acute anterior circulation intracranial large vessel occlusive stroke within 4.5 hours from symptom onset,which patients are more likely to benefit from alteplase intravenous thrombolysis combined with mechanical thrombectomy or direct mechanical thrombectomy.Thirdly,the effect of intravenous thrombolysis with alteplase combined with mechanical thrombectomy and direct mechanical thrombectomy on the long-term functional prognosis of patients remains unclear;Therefore,this study will explore the above-mentioned key scientific issues on the basis of the national multi-center clinical research,in order to provide data support for the optimization of recanalization treatment strategy for acute anterior circulation intracranial large vessel occlusive stroke.Part 1 A multicenter,Randomized,Controlled Clinical Study on The Safety and Efficacy of Early Endovascular Therapy Combined with Tirofiban for Acute Anterior Circulation Intracranial Large vessel occlusive strokeBackground and purpose: Tirofiban has a potent anti-platelet aggregation effect and is currently frequently used in endovascular treatment of acute intracranial large vessel occlusive stroke.Several studies have suggested that it can reduce vascular reocclusion and improve patient functional outcomes.However,the efficacy and safety of intravenous tirofiban combined with endovascular therapy for acute anterior circulation intracranial large vessel occlusive stroke within 24 hours from symptom onset remains uncertain.The purpose of this study was to evaluate the efficacy and safety of intravenous tirofiban combined with endovascular therapy in acute anterior circulation intracranial large vessel occlusive stroke within 24 hours from symptom onset.Methods: This trial is an investigator-initiated,prospective,multicenter,randomized,placebo-controlled,double-blind clinical trial design initiated by researchers.Eligible patients were randomized to tirofiban or placebo in a 1:1 ratio prior to mechanical thrombectomy.The primary outcome was the level of disability at 90 days,measured from 0(asymptomatic)to 6(death)according to the overall distribution of the modified Rankin Scale score.The main safety outcome events were the incidence of symptomatic intracranial hemorrhage within 48 hours and 90-day mortality.Results: The trial finally included 948 patients,463 in the tirofiban group and 485 in the placebo group.All patients completed 90-day m RS follow-up.According to the randomization,the intention-to-treat set analysis focused on 463 patients in the tirofiban group and 485 patients in the placebo group.The median 90-day m RS score was 3(IQR: 1 ~ 4)in the tirofiban group and that of placebo group was 3(IQR: 1 ~ 4).The adjusted common odds ratio for comparing the distribution of 90-day m RS scores between tirofiban and placebo was 1.08(95% CI,0.86 ~ 1.36;P = 0.50).Among the patients randomized into tirofiban group,there were 99 protocol violations and 100 protocol violations in the placebo group.A total of 364 patients in the tirofiban group and 385 patients in the placebo group were finally included in the per-protocol set analysis.Among the patients who entered the placebo group due to randomization,58 patients used remedial drugs and were classified into tirofiban group in the analysis of as-treated set.Finally,a total of 521 patients were included in the tirofiban group and 427 patients in the placebo group.The comparison results of 90-day m RS distribution between tirofiban and placebo in the per-protocol set and as-treated set were similar to those in the intention-to-treat set.These results showed that tirofiban was not more effective than placebo.However,among patients with large arteriosclerotic stroke,90-day functional outcomes were significantly improved in the tirofiban group compared with the placebo group(adjusted c OR 1.40,95% CT,1.00 ~ 1.97).There were no statistically significant differences in the incidence of symptomatic intracranial hemorrhage and mortality between the two groups in the intention-to-treat set.Conclusions: In patients with acute anterior circulation intracranial large vessel occlusive stroke within 24 hours from symptom onset,tirofiban combined with endovascular therapy did not significantly improve the 90-day disability level compared with endovascular therapy alone.In the subgroup of patients with large artery atherosclerotic stroke,tirofiban combined with endovascular therapy can significantly improve the 90-day disability level of patients,which needs to be further confirmed in randomized controlled trials.Part 2: Post Hoc Analysis of The Efficacy and Safety of Direct Mechanical Thrombectomy versus Intravenous Alteplase Combined with Mechanical Thrombectomy in Acute Anterior Circulation Intracranial Large Vessel Occlusive StrokeBackground and purpose: At present,there are still disagreement on whether the acute anterior circulation intracranial large vessel occlusive stroke within 4.5 hours can cross the intravenous thrombolysis of alteplase and adopt direct mechanical thrombectomy.The summary results of six randomized controlled trials showed that the proportion of 90-day good prognosis(m RS 0~2)in direct mechanical thrombectomy group and intravenous thrombolysis combined with mechanical thrombectomy group were 49.2% and 50.9%,respectively.The absolute difference between the two treatment strategies was weak.In the era of precision medicine,it will be more meaningful to explore which patients are more suitable for direct mechanical thrombectomy or intravenous thrombolysis combined with mechanical thrombectomy,so as to provide patients with more beneficial individualized treatment.The purpose of this study was to explore the predictors of good functional prognosis in patients received direct mechanical thrombectomy or bridging thrombectomy within 4.5 hours from symptom onset,and compare the therapeutic effects of two treatment strategies in important subgroups.Methods: This study is mainly based on the post hoc analysis of a multi-center,randomized and parallel controlled trial(DEVT trial)database.The included patients are patients with anterior circulation intracranial large vessel occlusion confirmed by craniocerebral CTA or MRA within 4.5 hours from symptom onset.They were randomly assigned to the direct mechanical thrombectomy group or the bridging thrombectomy group.The bridging thrombectomy group needs to receive intravenous thrombolysis with alteplase and mechanical thrombectomy quickly after randomization.The primary efficacy outcome event was the proportion of 90-day good functional outcomes(defined as m RS 0~2).Multivariate Poisson regression model with Huber white robust variance estimator was used to analyze the predictors of 90-day good functional outcomes in direct mechanical thrombectomy group or bridging thrombectomy group,and to explore the effects of two treatment methods on functional outcomes in important subgroups.Results: Multivariate analysis showed that a higher baseline NIHSS score(adjusted RR 0.97,95% CI,0.94 ~ 0.99;P = 0.03)was an independent risk factor for 90-day good functional prognosis in patients with direct thrombectomy and in patients with bridging thrombectomy(adjusted RR 0.93,95% CI,0.90 ~ 0.96;P < 0.001),Middle cerebral artery occlusion was an independent predictor of 90 day good functional prognosis in patients with bridging thrombectomy(adjusted RR 3.57,95% CI,1.11 ~ 11.48;P = 0.03).In the subgroup with baseline NIHSS score ≥16,direct mechanical thrombectomy was an independent predictor of good prognosis at 90 days(adjusted RR 1.55,95% CI,1.01 ~ 2.38;P = 0.04);In patients with internal carotid artery occlusion,multivariate analysis found that direct mechanical thrombectomy was an independent predictor of good functional prognosis at 90 days(adjusted RR 4.65,95% CI,1.57 ~ 13.77;P = 0.006).Conclusions: In patients with middle cerebral artery occlusion within 4.5 hours from symptom onset may be more suitable for intravenous thrombolytic bridging mechanical thrombectomy,while patients with intracranial internal carotid artery occlusion and NIHSS score ≥ 16 may be more suitable for direct mechanical thrombectomy.Part 3 Comparison of Long-term Prognosis between Direct Mechanical Thrombectomy and Alteplase Intravenous Thrombolysis Combined with Mechanical Thrombectomy in Acute Anterior Circulation Intracranial Large Vessel Occlusive StrokeBackground and purpose: At present,the results of six randomized controlled studies on whether acute anterior circulation intracranial large vessel occlusive stroke within 4.5 hours from symptom onset can cross Alteplase intravenous thrombolysis and use direct mechanical thrombectomy have been published.The results of these studies are based on the 90-day functional prognosis of patients,and pay less attention to the long-term impact of the two treatment strategies.Methods: This study is based on the randomized cases of DEVT trial.After the patients have completed 90 days of follow-up,the follow-up will be extended to 18 months after randomization.The group at the end of follow-up was based on the randomized grouping information of DEVT trial,that is,the direct mechanical thrombectomy group in DEVT trial was still the direct mechanical thrombectomy group in the current study,and the alteplase intravenous thrombolysis combined with mechanical thrombectomy group in DEVT trial was still classified as the bridging thrombectomy group.Main outcome event: the proportion of good functional prognosis(defined as m RS 0~2)at 18 months of randomization.Secondary outcome events were mainly the proportion of m RS score 0~1 at 18 months,the overall distribution of m RS score,all-cause mortality,stroke recurrence rate and the incidence of sever vascular events.Results: At 18 months after randomization,60 patients(51.7%)in the direct mechanical thrombectomy group achieved good functional independence,and 56 patients(47.5%)in the bridging thrombectomy group achieved functional independence(rate difference,4.2%;one-sided 97.5% confidence interval,-8.4% to ∞),and the lower limit of 95% CI was-8.4%,which was greater than the preset non inferiority limit of-10%.At 18 months of follow-up,the proportion of patients with m RS 0~1 in the direct mechanical thrombectomy group was similar to that in the bridging thrombectomy group,and there was no significant difference after multivariate adjustment(38.8% vs 39.0%;adjusted or 0.96,95% CI,0.53 ~ 1.74).Ordered logistic regression analysis showed that direct mechanical thrombectomy did not increase the 18-month m RS score of patients compared with bridging thrombectomy group(adjusted c OR0.96,95% CI,0.60 ~ 1.54).No significant difference was observed between the two treatment groups when using the EQ-5D-5L assessment to assess patients 18-month healthy quality of life(mean health utility score 0.81 vs 0.73,adjusted β coefficient is 0.004;95% CI,-0.01 ~ 0.11).Conclusions: For adult patients with acute ischemic stroke caused by anterior circulation large vessel occlusion within 4.5 hours of symptom onset,direct mechanical thrombectomy 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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