The Efficacy And Safety Of Intravenous Tirofiban In Acute Ischemic Stroke

The treatment of acute ischemic stroke has evolved rapidly within the last few decades.Two randomized controlled clinical trials have established intravenous thrombolysis as the preferred modality for the treatment of acute ischemic stroke within 4.5 hours of onset.However,strict time windows and contraindications limited the use of intravenous thrombolysis.In addition,more than half of patients treated with intravenous thrombolysis still experienced neurological deterioration or no neurological improvement within 24 hours,with less than 10% benefited from intravenous thrombolysis.Since 2015,five clinical trials confirmed the safety and efficacy of endovascular thrombectomy as the standard treatment for acute large vessel occlusion within 6 hours of presentation.Followed by the DAWN and DEFUSE 3 studies,which extended the time window for endovascular thrombectomy for patients after imaging screening was extended to 24 hours.The wave of endovascular thrombectomy in large vessel occlusive stroke has been accompanied by the gradual introduction of endovascular thrombectomy in patients with medium vessel occlusive stroke.However,nearly 30% of patients with ischemic stroke without large and medium size vessel occlusion still cannot be treated by endovascular thrombectomy,and a large number of these patients still suffered significant disability from ischemic stroke.To date,there were still a number of critical issues that need to be addressed in acute disabling ischemic stroke without large or medium size vessel occlusion.First,whether antithrombotic therapy with tirofiban was preferable to oral low-dose aspirin therapy in acute disabling ischemic stroke without large or medium size vessel occlusion.Second,the effect of tirofiban on outcomes in acute disabling ischemic progressive stroke without large or medium size vessel occlusion Third,the association between treatment with adjunct intravenous tirofiban and outcomes following successful reperfusion in patients with acute large artery atherosclerotic stroke.This study was based on nationwide multicenter clinical trials,and provided data to support the treatment of acute ischemic stroke.Part 1 A multicenter,Randomized,Controlled Clinical Trial on The Safety and Efficacy of Tirofiban for Disabling Stroke Without Large or Medium Size Vessel OcclusionBackground and purpose: Tirofiban,the most potent current antiplatelet agent,has been widely used in the treatment of acute ischemic stroke.Several previous studies have shown that tirofiban was safe for the treatment of acute ischemic stroke without large and medium vessel occlusion,but its efficacy was unclear.The purpose of this study was to compare the efficacy and safety of tirofiban with aspirin in the treatment of patients with acute ischemic stroke without large and medium size vessel occlusion.Methods: This clinical trial was an investigator-initiated,nationwide,multicenter,prospective,double-blind,double-dummy,randomized controlled clinical trial.Participants who met the enrollment criteria were randomized in a 1:1 ratio to the tirofiban or aspirin group and received intravenous tirofiban or oral aspirin for 48 hours,respectively,followed by aspirin for 90 days in both groups.The primary efficacy outcome was the proportion of excellent outcomes at 90 days,defined as a 90-day modified Rankin Scale score of 0 or 1(mRS,ranging from 0 [asymptomatic] to 6 [death]).The primary safety outcomes included90-day mortality and incidence of symptomatic intracranial hemorrhage.Results: The trial ultimately enrolled 1177 patients,606 in the tirofiban group and 571 in the aspirin group,and all but 6 patients were lost to follow-up(2 in the tirofiban group and 4in the aspirin group)and completed 90-day mRS follow-up.The proportion of mRS 0-1 at 90 days was 29.1% in the tirofiban group and 22.2% in the aspirin group(adjusted risk ratio,1.26;95% confidence interval [95%CI]: 1.04-1.53,P = 0.02).There was no significant difference in 90-day mortality between the two groups,whereas the incidence of symptomatic intracranial hemorrhage was 0.99% in the tirofiban group and 0% in the aspirin group.Conclusions: Compared with oral low-dose aspirin,intravenous tirofiban treatment significantly improved the neurological outcome of patients with acute disabling stroke and without large or medium size vessel occlusion.Rates of intracranial hemorrhages were low but slightly higher with tirofiban.Part 2 The Effect of Tirofiban on Outcomes in Patients with Acute Progressive Ischemic Stroke without Large or Medium Size Vessel OcclusionBackground and purpose: The treatment for progressive stroke was a challenge in current clinical practice,and there was no standard treatment up to now.Previous studies have shown that treatment with tirofiban in progressive stroke was associated with favorable outcome,but the association between tirofiban treatment and clinical outcome in acute progressive stroke without large or medium size vessel occlusion was unclear.The aim of this study was to investigate the association between treatment with tirofiban and aspirin and outcomes in acute progressive stroke patients without large or medium size vessel occlusion.Methods: This study was a secondary analysis of the RESCUE BT2 trial and included patients with onset within 24-96 hours,but with progressive stroke occurring within 24 hours and who could not be treated with reperfusion therapy.Patients were divided into the tirofiban and aspirin groups according to randomized grouping.The primary efficacy outcome was the proportion of excellent outcomes(mRS 0-1)at 90 days,and the primary safety outcome were 90-day mortality and incidence of symptomatic intracranial hemorrhage.Results: A total of 379 eligible patients were included in this study for analysis,including 199 in the tirofiban group and 180 in the aspirin group.At follow-up to 90 days,2 patients were lost to follow-up,both in the aspirin group.The primary efficacy outcome was achieved in 49(19.7%)patients in the tirofiban group and only 35(19.7%)in the aspirin group obtained mRS 0-1 at 90 days(adjusted risk ratio: 1.19;95% CI,0.81-1.73;P = 0.38).There were no statistically significant differences between the two groups for secondary efficacy outcomes and primary safety outcomes.Conclusions: Intravenous tirofiban treatment was not associated with improved neurological outcomes of patients with acute non-large or non-medium size vessel occlusive stroke within 24-96 hours of onset but progressing within 24 hours and not amenable to intravenous thrombolysis and endovascular thrombectomy,and no association was observed between tirofiban and the risk of symptomatic intracranial hemorrhage.Part 3 Effect of Intravenous Tirofiban Following Successful Endovascular Thrombectomy on Functional Outcomes in Large Artery Atherosclerotic StrokeBackground and purpose: Although the recanalization rates of endovascular thrombectomy have reached 90%,only one half of patients achieved functional independence at 90 days,or even catastrophic outcomes,also referred to clinically as futile recanalization.Intravenous tirofiban might enhance macrocirculatory and microcirculatory reperfusion in these patients,especially in those with large artery atherosclerotic stroke.The aim of this study was to investigate whether treatment with adjunct intravenous tirofiban is associated improved outcomes following successful reperfusion in patients with acute large artery atherosclerotic stroke.Methods: The RESCUE BT trial was a prospective,multicenter,double-blind,randomized controlled clinical trial that enrolled patients with acute anterior circulation large vessel occlusion within 24 hours of onset between October 31,2018 and October 21,2021.The study was a secondary analysis of the RESCUE BT trial and included patients with large artery atherosclerotic stroke who were successfully recanalized after endovascular thrombectomy(successful recanalization defined as: e TICI 2b50-3).The patients were divided into the tirofiban and placebo groups according to randomized grouping.The primary efficacy outcome was the proportion of independent functional outcome at 90 days,defined as a 90-day mRS score of 0-2.The primary safety outcomes included the incidence of symptomatic intracranial hemorrhage and 90-day mortality.Results: Among the 382 patients with intracranial large artery atherosclerosis stroke and successful reperfusion,175 patients were treated with intravenous tirofiban and 207 with placebo.The proportion of patients with independent functional outcome at 90 days was 54.3%(95/175)with tirofiban and 44.0%(91/207)with placebo(adjusted odds ratio,1.59;95% CI,1.03-2.45;P = 0.04).Intravenous tirofiban was not significantly associated with an increased risk of symptomatic intracranial hemorrhage within 48 hours(12/175 [6.9%] vs.11/207 [5.3%];adjusted odds ratio,1.41;95% CI,0.59–3.34;P = 0.44)or 90-day mortality(21/175 [12.0] vs.34/207 [16.4%];adjusted odds ratio,0.71;95% CI,0.38–1.31;P = 0.27).Conclusions: Among patients with acute large artery atherosclerotic stroke and successful reperfusion following endovascular thrombectomy,adjunct intravenous tirofiban was associated with a higher rate of independent functional outcome,without higher rates of symptomatic intracranial hemorrhage or mortality.Confirmatory randomized trials in these patients are desirable.