Recent evidence suggests a beneficial effect of endovascular thrombectomy in acute ischaemic stroke with large infarct; however, previous trials have relied on multimodal brain imaging, whereas non-contrast CT is mostly used in clinical practice.In a prospective multicentre, open-label, randomised trial, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and a large established infarct indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3-5 were randomly assigned using a central, web-based system (using a 1:1 ratio) to receive either endovascular thrombectomy with medical treatment or medical treatment (ie, standard of care) alone up to 12 h from stroke onset. The study was conducted in 40 hospitals in Europe and one site in Canada. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days, assessed by investigators masked to treatment assignment. The primary analysis was done in the intention-to-treat population. Safety endpoints included mortality and rates of symptomatic intracranial haemorrhage and were analysed in the safety population, which included all patients based on the treatment they received. This trial is registered with ClinicalTrials.gov, NCT03094715.From July 17, 2018, to Feb 21, 2023, 253 patients were randomly assigned, with 125 patients assigned to endovascular thrombectomy and 128 to medical treatment alone. The trial was stopped early for efficacy after the first pre-planned interim analysis. At 90 days, endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better outcome (adjusted common OR 2·58 [95% CI 1·60-4·15]; p=0·0001) and with lower mortality (hazard ratio 0·67 [95% CI 0·46-0·98]; p=0·038). Symptomatic intracranial haemorrhage occurred in seven (6%) patients with thrombectomy and in six (5%) with medical treatment alone.Endovascular thrombectomy was associated with improved functional outcome and lower mortality in patients with acute ischaemic stroke from large vessel occlusion with established large infarct in a setting using non-contrast CT as the predominant imaging modality for patient selection.EU Horizon 2020. 

Endovascular thrombectomy for acute ischaemic stroke with established large infarct: multicentre, open-label, randomised trial

Stroke affects up to one in five people during their lifetime in some high-income countries, and up to almost one in two in low-income countries. Globally, it is the second leading cause of death. Clinically, the disease is characterised by sudden neurological deficits. Vascular aetiologies contribute to the most common causes of ischaemic stroke, including large artery disease, cardioembolism, and small vessel disease. Small vessel disease is also the most frequent cause of intracerebral haemorrhage, followed by macrovascular causes. For acute ischaemic stroke, multimodal CT or MRI reveal infarct core, ischaemic penumbra, and site of vascular occlusion. For intracerebral haemorrhage, neuroimaging identifies early radiological markers of haematoma expansion and probable underlying cause. For intravenous thrombolysis in ischaemic stroke, tenecteplase is now a safe and effective alternative to alteplase. In patients with strokes caused by large vessel occlusion, the indications for endovascular thrombectomy have been extended to include larger core infarcts and basilar artery occlusion, and the treatment time window has increased to up to 24 h from stroke onset. Regarding intracerebral haemorrhage, prompt delivery of bundled care consisting of immediate anticoagulation reversal, simultaneous blood pressure lowering, and prespecified stroke unit protocols can improve clinical outcomes. Guided by underlying stroke mechanisms, secondary prevention encompasses pharmacological, vascular, or endovascular interventions and lifestyle modifications. 

Stroke

RATIONALE
Mechanical thrombectomy (MT), the standard of care for acute ischemic stroke secondary to large vessel occlusion (LVO), is generally not offered to patients with large baseline infarct (core). Recent studies demonstrated MT benefit in patients with anterior circulation stroke and large core (i.e. Alberta Stroke Program Early CT Score, ASPECTS, 3-5). However, its benefit in patients with the largest core (ASPECTS 0-2) remains unproven.


AIM
To compare the efficacy and safety of MT plus best medical treatment (BMT) and of BMT alone in patients with ASPECTS 0-5 (baseline CT or MRI) and anterior circulation LVO within 7 hours of last-seen-well. Sample size estimate: To detect with a two-sided test at 5% significance level (80% power) a common odds ratio of 1.65 for 1-point reduction in the 90-day mRS score in the MT+BMT arm versus BMT arm, and to anticipate 10% of patients with missing primary endpoint, 450 patients are planned to be included by 36 centers in France, Spain and USA.


METHODS AND DESIGN
LASTE is an international, multicenter, Prospectively Randomized into two parallel (1:1) arms, Open-label, with Blinded Endpoint (PROBE design) trial. Eligibility criteria are diagnosis of acute ischemic stroke within 6.5 hours of last-seen-well (or negative FLAIR if unknown stroke onset time), ASPECTS 0-5 (ASPECTS 4-5 for ≥80-year-old patients), and LVO in the anterior circulation (intracranial internal carotid artery, M1 or M1-M2 segment of the middle cerebral artery (MCA).


STUDY OUTCOMES
The primary endpoint is the day-90 mRS score distribution (shift analysis) with mRS categories 5 and 6 coalesced into one category. Secondary endpoints include day-180 mRS score, rates of 90-day and 180-day mRS score=0-2 and 0-3, rates of decompressive craniectomy, NIHSS score change, revascularization and infarct volume growth at 24 hours, and quality of life at day 90 and 180. Safety outcomes (90-day all-cause mortality, procedural complications, symptomatic intracerebral hemorrhage, and early NIHSS score worsening) are recorded. A dynamic balanced randomization (1:1) is used to distribute eligible patients into the experimental arm and control arm, by incorporating the center and these pre-specified factors: baseline ASPECTS (0-3 vs 4-5), age (≤70 vs >70 years), baseline NIHSS (<20 vs ≥20), intravenous thrombolysis (no vs yes), admission mode (Drip-and-Ship vs Mothership), occlusion site (intracranial ICA vs MCA-M1 or M1-M2), intravenous fibrinolysis (no vs yes), and last-seen-well to randomization time (0-4.5 vs >4.5-6.5 hours).


DISCUSSION
The LASTE trial will determine MT efficacy and safety in patients with ASPECTS 0-5 and LVO in the anterior circulation.


TRIAL REGISTRATION
LASTE Trial NCT03811769.

EXPRESS: Evaluation of acute mechanical revascularization in large stroke (ASPECT score ≤5) and large vessel occlusion within 7 hours of last-seen-well: the LASTE multicenter, randomized, clinical trial protocol.

BACKGROUND
Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA).


METHODS
MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220.


FINDINGS
Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20-2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44-1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49-14·10]).


INTERPRETATION
In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow.


FUNDING
Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

Endovascular treatment versus no endovascular treatment after 6–24 h in patients with ischaemic stroke and collateral flow on CT angiography (MR CLEAN-LATE) in the Netherlands: a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial

Importance
Whether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain.


Objective
To describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect.


Design, Setting, and Participants
An exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 and September 2022.


Intervention
EVT vs MM.


Main Outcomes and Measures
Primary outcome was functional outcome-90-day mRS score (0, no symptoms, to 6, death) assessed by adjusted generalized OR (aGenOR; values >1 represent more favorable outcomes). Benefit of EVT vs MM was assessed across levels of ischemic injury defined by noncontrast CT using ASPECTS score and by the volume of brain with severely reduced blood flow on CT perfusion or restricted diffusion on MRI.


Results
Among 352 patients randomized, 336 were analyzed (median age, 67 years; 139 [41.4%] female); of these, 168 (50%) were randomized to EVT, and 2 additional crossover MM patients received EVT. In an ordinal analysis of mRS at 90 days, EVT improved functional outcomes compared with MM within ASPECTS categories of 3 (aGenOR, 1.71 [95% CI, 1.04-2.81]), 4 (aGenOR, 2.01 [95% CI, 1.19-3.40]), and 5 (aGenOR, 1.85 [95% CI, 1.22-2.79]). Across strata for CT perfusion/MRI ischemic core volumes, aGenOR for EVT vs MM was 1.63 (95% CI, 1.23-2.16) for volumes ≥70 mL, 1.41 (95% CI, 0.99-2.02) for ≥100 mL, and 1.47 (95% CI, 0.84-2.56) for ≥150 mL. In the EVT group, outcomes worsened as ASPECTS decreased (aGenOR, 0.91 [95% CI, 0.82-1.00] per 1-point decrease) and as CT perfusion/MRI ischemic core volume increased (aGenOR, 0.92 [95% CI, 0.89-0.95] per 10-mL increase). No heterogeneity of EVT treatment effect was observed with or without mismatch, although few patients without mismatch were enrolled.


Conclusion and Relevance
In this exploratory analysis of a randomized clinical trial of patients with extensive ischemic stroke, EVT improved clinical outcomes across a wide spectrum of infarct volumes, although enrollment of patients with minimal penumbra volume was low. In EVT-treated patients, clinical outcomes worsened as presenting ischemic injury estimates increased.


Trial Registration
ClinicalTrials.gov Identifier: NCT03876457.

Endovascular Thrombectomy for Large Ischemic Stroke Across Ischemic Injury and Penumbra Profiles.

BACKGROUND
The role of endovascular therapy for acute stroke with a large infarction has not been extensively studied in differing populations.


METHODS
We conducted a multicenter, prospective, open-label, randomized trial in China involving patients with acute large-vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower values indicating larger infarction) or an infarct-core volume of 70 to 100 ml. Patients were randomly assigned in a 1:1 ratio within 24 hours from the time they were last known to be well to undergo endovascular therapy and receive medical management or to receive medical management alone. The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability), and the primary objective was to determine whether a shift in the distribution of the scores on the modified Rankin scale at 90 days had occurred between the two groups. Secondary outcomes included scores of 0 to 2 and 0 to 3 on the modified Rankin scale. The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours after randomization.


RESULTS
A total of 456 patients were enrolled; 231 were assigned to the endovascular-therapy group and 225 to the medical-management group. Approximately 28% of the patients in both groups received intravenous thrombolysis. The trial was stopped early owing to the efficacy of endovascular therapy after the second interim analysis. At 90 days, a shift in the distribution of scores on the modified Rankin scale toward better outcomes was observed in favor of endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval, 1.11 to 1.69; P = 0.004). Symptomatic intracranial hemorrhage occurred in 14 of 230 patients (6.1%) in the endovascular-therapy group and in 6 of 225 patients (2.7%) in the medical-management group; any intracranial hemorrhage occurred in 113 (49.1%) and 39 (17.3%), respectively. Results for the secondary outcomes generally supported those of the primary analysis.


CONCLUSIONS
In a trial conducted in China, patients with large cerebral infarctions had better outcomes with endovascular therapy administered within 24 hours than with medical management alone but had more intracranial hemorrhages. (Funded by Covidien Healthcare International Trading [Shanghai] and others; ANGEL-ASPECT ClinicalTrials.gov number, NCT04551664.).

Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct.

Background Stress hyperglycemia frequently occurs in patients with acute ischemic stroke (AIS). The influence of stress hyperglycemia on the outcomes of patients with AIS remains ambiguous. Methods Data from our institution on patients with AIS between June 2020 and June 2021 were retrospectively analyzed. The severity of the stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS) at admission, and the primary endpoint was functional outcomes. Stress hyperglycemia was measured by the glucose-to-HbA1c ratio. In the multivariable analysis, two models that retained or excluded the NIHSS were adopted to explore the relationship between stress hyperglycemia and outcomes. The receiver operating characteristic curve (ROC) was calculated to determine an optimized cutoff value. Results The optimal cutoff value was 1.135. When all patients were included, model 1 did not find an association between the glucose-to-HbA1c ratio and functional outcomes. In model 2, the glucose-to-HbA1c ratio×10 (Glucose-to-HbA1c ratio ×10) was the independent predictor of functional outcomes (OR 1.19, 95% CI 1.07–1.33, p < 0.01). Separately, in patients without diabetes, the glucose-to-HbA1c ratio×10 was the independent predictor of functional outcomes in both model 1 (OR 1.37, 95% CI 1.08–1.73, p = 0.01) and model 2 (OR 1.48, 95% CI 1.22–1.79, p < 0.01), but not in patients with diabetes. In addition, the glucose-to-HbA1c ratio×10 was the independent predictor of stroke severity (OR 1.16, 95% CI 1.05–1.28, p < 0.01). Conclusion The glucose-to-HbA1c ratio was associated with more severe AIS. Specifically, the glucose-to-HbA1c ratio was associated with the functional outcomes in patients without diabetes but not in patients with diabetes.

/pdf/fasting-blood-glucose-to-glycated-hemoglobin-ratio-for-3i0hxqfe.pdf

Fasting blood glucose-to-glycated hemoglobin ratio for evaluating clinical outcomes in patients with ischemic stroke

AIMS
The role of cilostazol after intracranial or extracranial artery stent implantation is still unclear. Therefore, we designed this trial to explore the efficacy and safety of cilostazol in this particular population.


METHODS
In this retrospective study, patients were divided into the cilostazol or clopidogrel group by the antiplatelet therapy received after artery stent implantation. The primary efficacy endpoint was ischemic stroke. Bleeding events and other antiplatelet drug-related adverse reactions (ADRs) were also recorded. Neurological function prognosis was evaluated by the modified Rankin Scale (mRS) after discharge.


RESULTS
A total of 156 patients were enrolled; 56 underwent intracranial artery stenting, 95 underwent extracranial artery stenting, and 5 underwent intracranial combined with extracranial artery stenting. Any stroke and bleeding events in the hospital of the two groups were comparable (P=0.38, P=0.34, respectively). The incidence of stroke recurrence tended to be lower in the cilostazol group, although not significant (cilostazol vs. clopidogrel, 1.35% vs. 4.88%, P=0.25). There was a significant difference of any bleeding events between the two groups (cilostazol vs. clopidogrel, 5.41% vs. 20.73%, P=0.02). During follow-up, we did not observe an apparent increase of ADRs in the cilostazol group (cilostazol vs. clopidogrel, palpitation 4.05% vs. 2.44%, P=0.58; gastrointestinal discomfort events 8.11% vs. 12.20%, P=0.80). There were no differences between the two groups of neurological function prognosis (P=0.29).


CONCLUSIONS
Cilostazol-based dual antiplatelet therapy could be recommended as an effective and safe therapy regimen among patients undergoing intracranial or extracranial artery stent implantation.

Comparison of Cilostazol versus Clopidogrel in Addition to Aspirin in Patients with Ischemic Stroke who Underwent Intracranial or Extracranial Artery Stent Implantation.

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Papers

Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct.

Fasting blood glucose-to-glycated hemoglobin ratio for evaluating clinical outcomes in patients with ischemic stroke

Comparison of Cilostazol versus Clopidogrel in Addition to Aspirin in Patients with Ischemic Stroke who Underwent Intracranial or Extracranial Artery Stent Implantation.