Trial of Endovascular Thrombectomy for Large Ischemic Strokes.

BACKGROUND: Trials of the efficacy and safety of endovascular thrombectomy in patients with large ischemic strokes have been carried out in limited populations. METHODS: We performed a prospective, randomized, open-label, adaptive, international trial involving patients with stroke due to occlusion of the internal carotid artery or the first segment of the middle cerebral artery to assess endovascular thrombectomy within 24 hours after onset. Patients had a large ischemic-core volume, defined as an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower scores indicating larger infarction) or a core volume of at least 50 ml on computed tomography perfusion or diffusion-weighted magnetic resonance imaging. Patients were assigned in a 1:1 ratio to endovascular thrombectomy plus medical care or to medical care alone. The primary outcome was the modified Rankin scale score at 90 days (range, 0 to 6, with higher scores indicating greater disability). Functional independence was a secondary outcome. RESULTS: The trial was stopped early for efficacy; 178 patients had been assigned to the thrombectomy group and 174 to the medical-care group. The generalized odds ratio for a shift in the distribution of modified Rankin scale scores toward better outcomes in favor of thrombectomy was 1.51 (95% confidence interval [CI], 1.20 to 1.89; P<0.001). A total of 20% of the patients in the thrombectomy group and 7% in the medical-care group had functional independence (relative risk, 2.97; 95% CI, 1.60 to 5.51). Mortality was similar in the two groups. In the thrombectomy group, arterial access-site complications occurred in 5 patients, dissection in 10, cerebral-vessel perforation in 7, and transient vasospasm in 11. Symptomatic intracranial hemorrhage occurred in 1 patient in the thrombectomy group and in 2 in the medical-care group. CONCLUSIONS: Among patients with large ischemic strokes, endovascular thrombectomy resulted in better functional outcomes than medical care but was associated with vascular complications. Cerebral hemorrhages were infrequent in both groups. (Funded by Stryker Neurovascular; SELECT2 ClinicalTrials.gov number, NCT03876457.).

Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

OBJECTIVE: We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. METHODS: The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). RESULTS: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. INTERPRETATION: Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024;96:356-364.

Anticoagulation Use and Endovascular Thrombectomy in Patients with Large Core Stroke: A Secondary Analysis of the SELECT2 Trial.

Endovascular thrombectomy (EVT) safety and efficacy in patients with large core infarcts receiving oral anticoagulants (OAC) are unknown. In the SELECT2 trial (NCT03876457), 29 of 180 (16%; vitamin K antagonists 15, direct OACs 14) EVT, and 18 of 172 (10%; vitamin K antagonists 3, direct OACs 15) medical management (MM) patients reported OAC use at baseline. EVT was not associated with better clinical outcomes in the OAC group (EVT 6 [4-6] vs MM 5 [4-6], adjusted generalized odds ratio 0.89 [0.53-1.50]), but demonstrated significantly better outcomes in patients without OAC (EVT 4 [3-6] vs MM 5 [4-6], adjusted generalized odds ratio 1.87 [1.45-2.40], p = 0.02). The OAC group had higher comorbidities, including atrial fibrillation (70% vs 17%), congestive heart failure (28% vs 10%), and hypertension (87% vs 72%), suggesting increased frailty. However, the results were consistent after adjustment for these comorbidities, and was similar regardless of the type of OACs used. Whereas any hemorrhage rates were higher in the OAC group receiving EVT (86% in OAC vs 70% in no OAC), no parenchymal hemorrhage or symptomatic intracranial hemorrhage were observed with OAC use in both the EVT and MM arms. Although we did not find evidence that the effect was due to excess hemorrhage or confounded by underlying cardiac disease or older age, OAC use alone should not exclude patients from receiving EVT. Baseline comorbidities and ischemic injury extent should be considered while making individualized treatment decisions. ANN NEUROL 2024;96:887-894.

Mediation of Successful Reperfusion Effect through Infarct Growth and Cerebral Edema: A Pooled, Patient-Level Analysis of EXTEND-IA Trials and SELECT Prospective Cohort.

OBJECTIVE: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship. METHODS: In a pooled, patient-level analysis of the EXTEND-IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift. RESULTS: A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8-48.4), and median midline shift was 0mm (IQR = 0-2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89-4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (ß = -1.19, 95% confidence interval [CI] = -1.51 to -0.88, p < 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23-0.57, p < 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86-3.88, p < 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95-2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results. INTERPRETATION: In this mediation analysis from a pooled, patient-level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793-804.

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

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.

Collateral Circulation in Thrombectomy for Stroke After 6 to 24 Hours in the DAWN Trial.

BACKGROUND AND PURPOSE: Collaterals govern the pace and severity of cerebral ischemia, distinguishing fast or slow progressors and corresponding therapeutic opportunities. The fate of sustained collateral perfusion or collateral failure is poorly characterized. We evaluated the nature and impact of collaterals on outcomes in the late time window DAWN trial (Diffusion-Weighted Imaging or Computed Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo). METHODS: The DAWN Imaging Core Lab prospectively scored collateral grade on baseline computed tomography angiography (CTA; endovascular and control arms) and digital subtraction angiography (DSA; endovascular arm only), blinded to all other data. CTA collaterals were graded with the Tan scale and DSA collaterals were scored by ASITN grade (American Society of Interventional and Therapeutic Neuroradiology collateral score). Descriptive statistics characterized CTA collateral grade in all DAWN subjects and DSA collaterals in the endovascular arm. The relationship between collateral grade and day 90 outcomes were separately analyzed for each treatment arm. RESULTS: Collateral circulation to the ischemic territory was evaluated on CTA (n=144; median 2, 0-3) and DSA (n=57; median 2, 1-4) before thrombectomy in 161 DAWN subjects (mean age 69.8±13.6 years; 55.3% women; 91 endovascular therapy, 70 control). CTA revealed a broad range of collaterals (Tan grade 3, n=64 [44%]; 2, n=45 [31%]; 1, n=31 [22%]; 0, n=4 [3%]). DSA also showed a diverse range of collateral grades (ASITN grade 4, n=4; 3, n=22; 2, n=27; 1, n=4). Across treatment arms, baseline demographics, clinical variables except atrial fibrillation (41.6% endovascular versus 25.0% controls, P=0.04), and CTA collateral grades were balanced. Differences were seen across the 3 levels of collateral flow (good, fair, poor) for baseline National Institutes of Health Stroke Scale, blood glucose <150, diabetes, previous ischemic stroke, baseline and 24-hour core infarct volume, baseline and 24-hour Alberta Stroke Program Early CT Score, dramatic infarct progression, final Thrombolysis in Cerebral Infarction 2b+, and death. Collateral flow was a significant predictor of 90-day modified Rankin Scale score of 0 to 2 in the endovascular arm, with 43.7% (31/71) of subjects with good collaterals, 30.8% (16/52) of subjects with fair collaterals, and 17.7% (6/34) of subjects with poor collaterals reaching modified Rankin Scale score of 0 to 2 at 90 days (P=0.026). CONCLUSIONS: DAWN subjects enrolled at 6 to 24 hours after onset with limited infarct cores had a wide range of collateral grades on both CTA and DSA. Even in this late time window, better collaterals lead to slower stroke progression and better functional outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02142283.

Serial ASPECTS in the DAWN Trial: Infarct Evolution and Clinical Impact.

Background and Purpose: The impact of baseline ischemia on Alberta Stroke Program Early CT Score (ASPECTS) and evolution over 24 hours may be distinct in late thrombectomy. We analyzed predictors of serial ASPECTS and clinical outcomes in the DAWN trial (Diffusion-Weighted Imaging or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo). Methods: The DAWN Imaging Core Laboratory independently scored ASPECTS at baseline and 24 hours. Descriptive statistics characterized ASPECTS on computed tomography/magnetic resonance imaging at baseline and 24 hours, delineating ASPECTS change over 24 hours. Results: 206 subjects (mean age 70.0±13.7 years; 54.9% (n=113) female; baseline National Institutes of Health Stroke Scale median (interquartile range) 17 (13, 21) were included. Baseline ASPECTS was median (interquartile range) 8.0 (7­8), with 92/205 (44.9%) between 0 and 7 and 113/205 (55.1%) 8 and 10. 24-hour ASPECTS was median 6.0 (4­8), with ASPECTS change or infarct evolution having median −1, ranging from −8 to +2. Multivariable logistic regression showed older age (odds ratio [OR] for 10-year interval, 1.26 [95% CI, 1.02­1.55], P=0.030) and dyslipidemia (OR, 1.84 [95% CI, 1.06­3.19], P=0.031) were independently associated with higher baseline ASPECTS. Higher 24-hour ASPECTS was predicted by endovascular treatment (OR, 2.76 [95% CI, 1.58­4.81], P=0.0004), baseline glucose <150 mg/dL (OR, 2.86 [95% CI, 1.50­5.46], P=0.001), lower baseline National Institutes of Health Stroke Scale (OR, 0.93 [95% CI, 0.89­0.98], P=0.010), and older age (OR for 10-year interval, 1.25 [95% CI, 1.01­1.55], P=0.041). Internal carotid artery lesion location (OR, 0.47 [95% CI, 0.24­0.89], P=0.021) was inversely related to 24-hour ASPECTS. Good clinical outcome (day 90 modified Rankin Scale score 0­2) was predicted by 24-hour ASPECTS (OR, 1.46 [95% CI, 1.08­1.96], P=0.014). Extensive infarct evolution (ASPECTS decrease ≥6) occurred in 14/201 (7.0%). Elevated baseline serum glucose ≥150 mg/dL was a predictor of ASPECTS decrease of ≥4 points (OR, 2.78 [95% CI, 1.21­6.35] P=0.016) as was internal carotid artery occlusion (OR, 2.49 [95% CI, 1.05­5.88]; P=0.038). ASPECTS change was influenced by treatment arm (P=0.001 by Wilcoxon), including 0 ASPECTS change in 42/105 (40.0%) of the endovascular arm and only 20/96 (20.8%) of the medical arm. Conclusions: DAWN subjects enrolled with small infarct cores had a broad range of baseline ASPECTS. Twenty-four-hour ASPECTS, strikingly influenced by endovascular therapy, predicted good clinical outcomes. Registration: https://www.clinicaltrials.gov; Unique identifier: NCT02142283.

Early Infarct Growth Rate Correlation With Endovascular Thrombectomy Clinical Outcomes: Analysis From the SELECT Study.

BACKGROUND AND PURPOSE: Time elapsed from last-known well (LKW) and baseline imaging results are influential on endovascular thrombectomy (EVT) outcomes. METHODS: In a prospective multicenter cohort study of imaging selection for endovascular thrombectomy (SELECT [Optimizing Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke], the early infarct growth rate (EIGR) was defined as ischemic core volume on perfusion imaging (relative cerebral blood flow<30%) divided by the time from LKW to imaging. The optimal EIGR cutoff was identified by maximizing the sum of the sensitivity and specificity to correlate best with favorable outcome and to improve its the predictability. Patients were stratified into slow progressors if EIGR2. The primary outcome was 90-day functional independence (modified Rankin Scale score =0-2). RESULTS: Of 445 consented, 361 (285 EVT, 76 medical management only) patients met the study inclusion criteria. The optimal EIGR was <10 mL/h; 200 EVT patients were slow and 85 fast progressors. Fast progressors had a higher median National Institutes of Health Stroke Scale (19 versus 15, P<0.001), shorter time from LKW to groin puncture (180 versus 266 minutes, P<0.001). Slow progressors had better collaterals on computed tomography perfusion: hypoperfusion intensity ratio (adjusted odds ratio [aOR]: 5.11 [2.43-10.76], P<0.001) and computed tomography angiography: collaterals-score (aOR: 4.43 [1.83-10.73], P=0.001). EIGR independently correlated with functional independence after EVT, adjusting for age, National Institutes of Health Stroke Scale, time LKW to groin puncture, reperfusion (modified Thrombolysis in Cerebral Infarction score of ≥2b), IV-tPA (intravenous tissue-type plasminogen activator), and transfer status (aOR: 0.78 [0.65-0.94], P=0.01). Slow progressors had higher functional independence rates (121 [61%] versus 30 [35%], P<0.001) and had 3.5 times the likelihood of achieving modified Rankin Scale score =0-2 with EVT (aOR=2.94 [95% CI, 1.53-5.61], P=0.001) as compared to fast progressors, who had substantially worse clinical outcomes both in early and late time window. The odds of good outcome decreased by 14% for each 5 mL/h increase in EIGR (aOR, 0.87 [0.80-0.94], P<0.001) and declined more rapidly in fast progressors. CONCLUSIONS: The EIGR strongly correlates with both collateral status and clinical outcomes after EVT. Fast progressors demonstrated worse outcomes when receiving EVT beyond 6 hours of stroke onset as compared to those who received EVT within 6 hours. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02446587.

New Class of Radially Adjustable Stentrievers for Acute Ischemic Stroke: Primary Results of the Multicenter TIGER Trial.

[Figure: see text].

Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct.

BACKGROUND: The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS: We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS: A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00). CONCLUSIONS: Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283 .).

A Phase 2 Randomized, Sham-Controlled Trial of Internal Carotid Artery Infusion of Autologous Bone Marrow-Derived ALD-401 Cells in Patients With Recent Stable Ischemic Stroke (RECOVER-Stroke).

BACKGROUND: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow-derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy. METHODS: This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications. RESULTS: There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, -0.3 to 0.8; P=0.330). There were no significant differences between the groups on any of the secondary efficacy measures. CONCLUSIONS: Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337.

Impact of Periprocedural and Technical Factors and Patient Characteristics on Revascularization and Outcome in the DAWN Trial.

Background and Purpose- Because of unique attributes of mechanical thrombectomy performed between 6 and 24 hours after symptom onset in acute ischemic stroke patients, it is not known if predictors of angiographic recanalization and favorable outcome in patients treated with thrombectomy in the late (6-24 hour) time window are similar to those treated in the early time window. Methods- We analyzed data from the DAWN trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) which enrolled patients with symptom onset 6 to 24hours after last known well and occlusion of the intracranial internal carotid artery or proximal middle cerebral artery with a mismatch between severity of clinical deficit and infarct core volume as identified by computed tomography-perfusion or diffusion magnetic resonance imaging. We evaluated the effect of tandem occlusions, periprocedural heparin use, procedural speed (from puncture to procedure completion), general anesthesia, balloon-guide catheters, thrombectomy device size, and number of passes on substantial reperfusion (modified Thrombolysis in Cerebral Infarction 2b/3) and on likelihood of obtaining a modified Rankin Scale at 3 months indicating functional independence. Results- Of 107 patients who underwent MT in the interventional arm of DAWN, substantial reperfusion and modified Rankin Scale score 0 to 2 at 3 months was seen in 90 (84%) and 52 (49%), respectively. In univariate analysis, general anesthesia (odds ratio [OR] 0.27; P=0.042) and ≥3 passes with stent retriever (OR, 0.17; P=0.002) were inversely associated with substantial reperfusion. In multivariate analyses, only ≥3 passes were associated with lack of revascularization (OR, 0.17; P=0.002). in univariate analysis ≥3 passes (OR, 0.24; P =0.003) and baseline National Institutes of Health Stroke Scale score >17 (OR, 0.19; P<0.001) were inversely associated with functional independence at 3 months. In multivariate analyses, ≥3 passes (OR, 0.24; P=0.003) and National Institutes of Health Stroke Scale score >17 (OR, 0.19; P<0.001) remained inversely associated with favorable outcome at 3 months. Conclusions- Patients requiring ≥3 thrombectomy passes had reduced substantial reperfusion and favorable outcome at 3 months in DAWN. Whether or not additional thrombectomy techniques beyond ≥3 thrombectomy passes with the Trevo stent retriever are beneficial for patient outcomes in this patient population remains to be clarified by future studies. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02142283.

Outcome in Direct Versus Transfer Patients in the DAWN Controlled Trial.

Background and Purpose- The impact of transfer status on clinical outcomes in the DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) population is unknown. We analyzed workflow and clinical outcome differences between direct versus transfer patients in the DAWN population. Methods- The following time metrics were analyzed for each group: (1) last known well to hospital arrival, (2) hospital arrival to eligibility imaging, (3) hospital arrival to arterial puncture, (4) qualifying imaging to arterial puncture, (5) last known well to arterial puncture, (6) last known well to reperfusion. The primary end point was the rate of functional independence (90-day modified Rankin Scale [mRS] score, 0-2). Using univariate unconditional logistic regression, we calculated odds ratios and 95% CIs for the association between clinically relevant time metrics, transfer status, and functional independence (mRS 0-2). Results- A total of 206 patients were enrolled. Among these, 121 (59%) patients were transferred, and 85 (41%) patients presented directly to a thrombectomy capable center. Median time last seen well to hospital arrival time was similar between the 2 groups (678 versus 696 minutes). The time from hospital arrival to groin puncture was significantly longer in direct patients compared with transferred patients 140 minutes (interquartile range, 105.5-177.5 minutes) and 88 minutes (interquartile range, 55-125 minutes), respectively (P<0.001). Differences in treatment effect or differences in rates of mRS 0-2 in the thrombectomy treated patients were not statistically significant in direct versus transfer patients (odds ratios for mRS 0-2, thrombectomy versus control, were 5.62 in direct and 6.63 in transfer patients, respectively, Breslow-Day P=0.817). Conclusions- Although transfer patients had a faster door to puncture time, benefits of thrombectomy, and rates of mRS 0 to 2 in the treatment group were similar between direct and transferred patients in the DAWN population. These results may inform prehospital and primary stroke centers triage protocols in patients presenting in the late time window. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02142283.

Noncontrast Computed Tomography Alberta Stroke Program Early CT Score May Modify Intra-Arterial Treatment Effect in DAWN.

Background and Purpose- It is unknown whether noncontrast computed tomography (NCCT) can identify patients who will benefit from intra-arterial treatment (IAT) in the extended time window. We sought to characterize baseline Alberta Stroke Program Early CT Score (ASPECTS) in DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) and to assess whether ASPECTS modified IAT effect. Methods- Core lab adjudicated ASPECTS scores were analyzed. The trial cohort was divided into 2 groups by qualifying imaging (computed tomography versus magnetic resonance imaging). ASPECTS-by-treatment interaction was tested for the trial coprimary end points (90-day utility-weighted modified Rankin Scale (mRS) score and mRS, 0-2), mRS 0 to 3, and ordinal mRS. ASPECTS was evaluated separately as an ordinal and a dichotomized (0-6 versus 7-10) variable. Results- Of 205 DAWN subjects, 123 (60%) had NCCT ASPECTS, and 82 (40%) had diffusion weighted imaging ASPECTS. There was a significant ordinal NCCT ASPECTS-by-treatment interaction for 90-day utility-weighted mRS (interaction P=0.04) and mRS 0 to 2 (interaction P=0.02). For both end points, IAT effect was more pronounced at higher NCCT ASPECTS. The dichotomized NCCT ASPECTS-by-treatment interaction was significant only for mRS 0 to 2 (interaction P=0.04), where greater treatment benefit was seen in the ASPECTS 7 to 10 group (odds ratio, 7.50 [2.71-20.77] versus odds ratio, 0.48 [0.04-5.40]). A bidirectional treatment effect was observed in the NCCT ASPECTS 0 to 6 group, with treatment associated with not only more mRS 0 to 3 outcomes (50% versus 25%) but also more mRS 5 to 6 outcomes (40% versus 25%). There was no significant modification of IAT effect by diffusion weighted imaging ASPECTS. Conclusions- Baseline NCCT ASPECTS appears to modify IAT effect in DAWN. Higher NCCT ASPECTS was associated with greater benefit from IAT. No treatment interaction was observed for diffusion weighted imaging ASPECTS.

Benefit of Endovascular Thrombectomy by Mode of Onset: Secondary Analysis of the DAWN Trial.

Background and Purpose- It is unknown whether the benefit of thrombectomy in late presenting acute stroke patients with imaging evidence of clinical-infarct mismatch is different in patients presenting with wake-up stroke compared with those presenting with witnessed onset or unwitnessed onset. Methods- Prespecified secondary analysis was performed from DAWN (Diffusion Weighted Imaging [DWI] or Computerized Tomography Perfusion [CTP] Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention), a multicenter, prospective, randomized clinical trial with blinded end point assessment comparing thrombectomy with the Trevo device against standard medical therapy in patients with acute stroke and clinical-infarct mismatch presenting 6 to 24 hour after the time last seen well. For the purposes of this study, the primary outcome was the proportion of modified Rankin Scale score 0 to 2 at 90 days. Univariable analysis and multivariable logistic regression was used to assess the relationship between outcome and mode of onset. Results- All 206 enrolled patients were included in the study. Mode of onset was: wake-up stroke (55.3%, n=114), witnessed onset (12.1%, n=25), and unwitnessed onset (32.5%, n=67) with median time last seen well to randomization (13.4±3.7, 10.0±3.7, 14.1±4.9 hours) respectively. Rates of 90-day modified Rankin Scale score of 0 to 2 and symptomatic intracerebral hemorrhage in the thrombectomy arm were not statistically different across patient onset subtypes (P=0.79 and P=0.40, respectively). The benefit of thrombectomy compared with best medical therapy was maintained across all 3 onset modes (rates of 90-day modified Rankin Scale score of 0 to 2 in patients allocated to thrombectomy versus control: wake-up stroke-49.3% versus 10.6%, witnessed onset-63.6% versus 21.4%, UW-41.4% versus 13.2%; P×interaction=0.79). In univariable and multivariable analyses, mode of onset was not identified as a significant predictor of modified Rankin Scale score 0 to 2 at 90 days. Conclusions- In patients with acute ischemic stroke presenting between 6 and 24 hours from time last seen well and harboring clinical-infarct mismatch, the benefit of thrombectomy was similar regardless of the wake-up, unwitnessed, or witnessed mode of onset.

Endovascular therapy after intravenous t-PA versus t-PA alone for stroke.

BACKGROUND: Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. METHODS: We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). RESULTS: The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). CONCLUSIONS: The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).

Predictors of functional dependence despite successful revascularization in large-vessel occlusion strokes.

BACKGROUND AND PURPOSE: High revascularization rates in large-vessel occlusion strokes treated by mechanical thrombectomy are not always associated with good clinical outcomes. We evaluated predictors of functional dependence despite successful revascularization among patients with acute ischemic stroke treated with thrombectomy. METHODS: We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO), and TREVO 2 trials. Successful revascularization was defined as thrombolysis in cerebral infarction score 2b or 3. Functional dependence was defined as a score of 3 to 6 on the modified Rankin Scale at 3 months. We assessed relationship of demographic, clinical, angiographic characteristics, and hemorrhage with functional dependence despite successful revascularization. RESULTS: Two hundred and twenty-eight patients with successful revascularization had clinical outcome follow-up. The rates of functional dependence with endovascular success were 48.6% for Trevo thrombectomy and 58.0% for Merci thrombectomy. Age (odds ratio, 1.04; 95% confidence interval, 1.02-1.06 per 1-year increase), National Institutes of Health Stroke Scale score (odds ratio, 1.08; 95% confidence interval, 1.02-1.15 per 1-point increase), and symptom onset to endovascular treatment time (odds ratio, 1.11; 95% confidence interval, 1.01-1.22 per 30-minute delay) were predictors of functional dependence despite successful revascularization. Symptom onset to reperfusion time beyond 5 hours was associated with functional dependence. All subjects with symptomatic intracranial hemorrhage had functional dependence. CONCLUSIONS: One half of patients with successful mechanical thrombectomy do not have good outcomes. Age, severe neurological deficits, and delayed endovascular treatment were associated with functional dependence despite successful revascularization. Our data support efforts to minimize delays to endovascular therapy in patients with acute ischemic stroke to improve outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00318071, NCT01088672, and NCT01270867.

Intracerebral hemorrhage risk after adjunct intraarterial thrombolysis in thrombectomy-treated acute ischemic stroke.

BACKGROUND AND PURPOSE: Intraarterial thrombolysis as an adjunct to mechanical thrombectomy is increasingly being considered to enhance reperfusion in acute ischemic stroke patients. Intraarterial thrombolysis may increase the risk of post-thrombectomy intracerebral hemorrhage (ICH) in certain patient subgroups. METHODS: We analyzed acute ischemic stroke patients treated with mechanical thrombectomy in a multicenter registry. The occurrence of any (asymptomatic and symptomatic) post-thrombectomy ICH was ascertained using standard definition requiring serial neurological examinations and computed tomographic scans acquired within 48 hours of the thrombectomy. We determined the risk of ICH in subgroups defined by clinical characteristics and the use of intravenous (IV) thrombolysis. RESULTS: A total of 146 (7.5%) patients received intraarterial thrombolysis among 1953 acute ischemic stroke patients who underwent mechanical thrombectomy. The proportion of patients who developed any ICH was 26 (17.8%) and 510 (28.2%) among patients who were and were not treated with intraarterial thrombolysis, respectively (p = .006). The proportion of patients who developed symptomatic ICH was 4 (2.7%) and 30 (1.7%) among patients who were and were not treated with intraarterial thrombolysis, respectively (p = .34). Among patients who received IV thrombolysis (n = 1042), the proportion of patients who developed any ICH was 9 (16.7%) and 294 (30.7%) among patients who were and were not treated with intraarterial thrombolysis, respectively (p = .028). The risk was not different in strata defined by age, gender, location of occlusion, preprocedure National Institutes of Health Stroke Scale score, time interval between symptom onset and thrombectomy, Alberta Stroke Program Early CT Score, systolic blood pressure, and serum glucose concentrations. CONCLUSIONS: In patients undergoing mechanical thrombectomy, the risk of any ICH and symptomatic ICH was not increased with intraarterial thrombolysis, including in those who had already received IV thrombolytics.

Endovascular Thrombectomy Treatment Effect in Direct vs Transferred Patients With Large Ischemic Strokes: A Prespecified Analysis of the SELECT2 Trial.

Importance: Patients with large ischemic core stroke have poor clinical outcomes and are frequently not considered for interfacility transfer for endovascular thrombectomy (EVT). Objective: To assess EVT treatment effects in transferred vs directly presenting patients and to evaluate the association between transfer times and neuroimaging changes with EVT clinical outcomes. Design, Setting, and Participants: This prespecified secondary analysis of the SELECT2 trial, which evaluated EVT vs medical management (MM) in patients with large ischemic stroke, evaluated adults aged 18 to 85 years with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) as well as an Alberta Stroke Program Early CT Score (ASPECTS) of 3 to 5, core of 50 mL or greater on imaging, or both. Patients were enrolled between October 2019 and September 2022 from 31 EVT-capable centers in the US, Canada, Europe, Australia, and New Zealand. Data were analyzed from August 2023 to January 2024. Interventions: EVT vs MM. Main Outcomes and Measures: Functional outcome, defined as modified Rankin Scale (mRS) score at 90 days with blinded adjudication. Results: A total of 958 patients were screened and 606 patients were excluded. Of 352 enrolled patients, 145 (41.2%) were female, and the median (IQR) age was 66.5 (58-75) years. A total of 211 patients (59.9%) were transfers, while 141 (40.1%) presented directly. The median (IQR) transfer time was 178 (136-230) minutes. The median (IQR) ASPECTS decreased from the referring hospital (5 [4-7]) to an EVT-capable center (4 [3-5]). Thrombectomy treatment effect was observed in both directly presenting patients (adjusted generalized odds ratio [OR], 2.01; 95% CI, 1.42-2.86) and transferred patients (adjusted generalized OR, 1.50; 95% CI, 1.11-2.03) without heterogeneity (P for interaction = .14). Treatment effect point estimates favored EVT among 82 transferred patients with a referral hospital ASPECTS of 5 or less (44 received EVT; adjusted generalized OR, 1.52; 95% CI, 0.89-2.58). ASPECTS loss was associated with numerically worse EVT outcomes (adjusted generalized OR per 1-ASPECTS point loss, 0.89; 95% CI, 0.77-1.02). EVT treatment effect estimates were lower in patients with transfer times of 3 hours or more (adjusted generalized OR, 1.15; 95% CI, 0.73-1.80). Conclusions and Relevance: Both directly presenting and transferred patients with large ischemic stroke in the SELECT2 trial benefited from EVT, including those with low ASPECTS at referring hospitals. However, the association of EVT with better functional outcomes was numerically better in patients presenting directly to EVT-capable centers. Prolonged transfer times and evolution of ischemic change were associated with worse EVT outcomes. These findings emphasize the need for rapid identification of patients suitable for transfer and expedited transport. Trial Registration: ClinicalTrials.gov Identifier: NCT03876457.