Multicenter Clinical Studies On Optimizing Endovascular Treatment Strategies For Acute Anterior Circulation Large Vessel Occlusion Stroke

Background and Purpose—Acute ischemic stroke(AIS)possesses high morbidity and mortality.Timely and effectively recanalizing the occlusion artery and then salvaging the ischemic penumbra is the key to treatment for AIS with anterior circulation large-vessel occlusion(LVO).Before 2015,intravenous thrombolysis(IVT)was the only effective way to reach recanalization.Following the publication of five randomized controlled trials(RCTs)in 2015,comparing with IVT only,endovascluar treatment(EVT)(in particular mechanical thrombectomy)bridging with IVT,initiated in 6 hours from onset,was confirmed to significantly increase the rate of successful recanalization,improve functional outcome at 90 days.The rate of symptomatic intracranial hemorrhage(s ICH)and mortality at 90 days did not significantly differ.So it becomes the second effective way to reach recanalization and the milestone of early treatment for AIS.However,there are some open questions related to EVT in clinical practice,especially in the matter of EVT strategies.Some problems are as follows: First,the current results related to EVT derived from RCTs based on the Occident population.It remains unclear what the real world results of EVT based on Chinese population are,and as yet there is no relevant published research.Second,it is well known that IVT has some limitations.The narrow time window(3–4.5 hours),potential risk of hemorrhage transformation,ineffectiveness in the majority of patients with LVO and large thrombus burden,and expensive drug costs restrain the effectiveness of IVT.And there is no siginificant difference of intracranial hemorrhage rate between the bridging therapy and the IVT only,which means the hemorrhage transformation mainly from IVT.Hence,it becomes the hot point whether direct EVT could be performed without prior IVT use.Until now,no related RCTs are published yet.Only a few retrospective studies found direct EVT could obtain similar effectiveness to bridging therapy,which denoted IVT did not play a dominant role in bridging therapy.However,in such studies,the majority of patients in direct EVT group were ineligible for IVT,and the times from onset to treatment between both groups were not comparable.So the selection bias inevitably existed.The rate of performing IVT in our country is markedly lower than that in Occident owing to various reasons,which,in turn,provides us an opportunity to compare the effectiveness and safety of direct EVT with that of bridging therapy.Third,in clinical practice,a subset of patients,who meet the criteria for EVT recommended in the guidelines,obtained unfavorable functional outcome at 90 days,even disastrous consequence,despite successful recanalization of occluded artery.The so-called “futile recanalization”(FR)attenuated the effectiveness of EVT.The sporadic published studies only involved with some predictors for FR,with scarce of including some important variables(e.g.collateral flow and laboratory findings),which are closely associated with functional outcome.In addition,there is no study involving with preoperative evaluation of FR and quantification of the risk of FR to provide reference for performing EVT.For exploring above mentioned problems,we design the present studies.By collecting the data of patients with acute anterior circulation LVO stroke from multiple stroke centers in China and building a database,we can get to know the real world results of EVT in our country.Then,based on the database,we can compare the effectiveness and safety of direct EVT with that of bridging therapy in the study population who are all eligible for IVT.Finally,based on the screened preoperative predictors for FR,we can derive a preoperative evaluation scale.On account of the scale score,we can quantify and stratify the risk of FR to find who are most,and least,likely to benefit from EVT,providing reference for the clinician’s making treatment strategies.Methods—From 21 stroke centers across 10 provinces in China,we retrospectively enrolled acute ischemic stroke patients older than 18 years with anterior circulation proximal LVO,who all received endovascular treatment with or without IVT between January 2014 and June 2016.Demographic data,medical history,clinical and laboratory findings,procedure-related indices,and follow-up data were collected,and then an endov As Cular Treatment for ac Ute Anterior circu Lation(ACTUAL)ischemic stroke registry were bulit.The functional outcome at 90 days,the rate of s ICH,and mortality within 90 days of overall patients were assessed and the predictors for unfavorable functional outcome were screened.Then,from the database,the patients without contraindications for IVT were selected,who all underwent stent retriever thrombectomy with time from onset to IVT(bridging therapy)/groin puncture(direct EVT)≤4.5 h.By proponsity score matching analysis,certain patients from both groups were matched,then we compared the effectiveness and safety of direct EVT to those of bridging therapy.Finally,we selected the patients from the database who met the criteria for EVT recommended in the guidelines and obtained successful recanalization.Patients were randomly divided into a derivation group(60%)and validation group(40%).Multivariable logistic regression was used to determine the pre-operative independent predictors for FR,and to derive a PReoperative Evaluation for Determ Ination of endovas Cular Therapy (PREDICT)scale.The discrimination and calibration of the scale were assessed by the area under the curve(AUC)and Hosmer-Lemeshow goodness-of-fit test,respectively.And based on the scale score,we stratified the risk of FR.Results—A total of 698 patients were enrolled in the ACTUAL registry,and 304(43.6%)patients had functional independence at 90 days.s ICH rate was 15.5%(108/698)and mortality rate at 90 days was 25.4%(177/698).Age(odds ratio [OR] 1.04,95% confidence interval [CI]: 1.02–1.07),NIHSS score at admission(11–20 vs.≤10,OR 2.38:1.23–4.59;≥21 vs.≤10,OR 3.66: 1.72–7.80),glucose(OR 1.09: 1.01–1.18),onset to groin puncture >6 hours(OR 1.88: 1.06–3.31),s ICH(OR 15.49: 5.16–46.43),and pneumonia(OR 3.15: 1.86–5.32)were independent predictors of poor functional outcomes,while good recanalization(OR 0.26: 0.13–0.54),preoperative ASPECTS 8–10(OR 0.48: 0.28–0.83)and good collateral flow(OR 0.50: 0.32–0.79)were protective factors.Of 363 patients who were eligible for IVT and underwent stent retriever thrombectomy with time from onset to IVT(bridging therapy)/groin puncture(direct EVT)≤4.5 h,276 patients were matched(138 patients in each group)by propensity score matching analysis.Good functional outcome at 90 days in the direct EVT group(40.6% [56/138])did not significantly differ from that in the bridging group(44.9% [62/138])(P=0.53).Rates of s ICH(13.8% [19/138] vs 13.0% [18/138],P=1.00)and mortality(25.4% [35/138] vs 23.9% [33/138],P=0.88)within 90 days were also not significantly different.Patients in the direct EVT group had a lower rate of asymptomatic intracranial hemorrhage(a ICH)(28.3% [39/138] vs 44.9% [62/138],P=0.01)and a higher rate of successful reperfusion(92.0% [127/138] vs 81.9% [113/138],P=0.02).Among 332 patients who underwent EVT with successful recanalization(m TICI 2b/3),47.2%(94/199)of patients in the derivation group and 56.4%(75/133)of patients in the validation group had a poor functional outcome(m RS 3–6)at 90 days.The 19-point PREDICT scale consisted of 5 items(prior IVT,collateral status,blood glucose,neutrophil to lymphocyte ratio,and baseline NIHSS score).The AUC of the scale in derivation group and validation group was 0.76(95% CI 0.70–0.83)and 0.74(95% CI 0.65–0.82),respectively.The scale was well calibrated in derivation group(P=0.14)and validation group(P=0.25).The risk of FR was stratified into very low(PREDICT scale score ≤5),low(6–8),moderate(9–11),and high(≥12).Compared to those with a score of ≤5,patients with score of ≥12 had an 18.33-fold(95% CI 6.36–52.89)increased risk of FR.Conclusions—Our study contributes evidence in real world to support the performance of EVT for acute anterior circulation stroke patients in Chinese population.Patients with small infarct core,successful recanalization,good collateral status,and short treatment delay without s ICH or pneumonia may benefit from EVT.Our results suggest that,in Chinese patients with anterior circulation LVO stroke,direct endovascular mechanical thrombectomy initiated within an IVT time window carries similar effectiveness to that of bridging therapy and a decreased a ICH risk.DEVT may be an alternative for bridging therapy.Future RCTs are warranted.In our study population,the PREDICT scale is a concise and practical tool for rapidly predicting FR after EVT in our patients and,if validated in other patient populations,may serve as a preprocedural scale for identifying which patients are most,and least,likely to benefit from EVT.By means of above studies,we can provide reference for optimizing EVT strategies in clinical practice,so as to enhance the effectiveness of EVT.