Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).

For stroke patients treated 3 to 6 hours after onset, baseline MRI findings can identify subgroups that are likely to benefit from reperfusion therapies and can potentially identify subgroups that are unlikely to benefit or may be harmed.

Background It is uncertain if endovascular stroke therapy leads to improved clinical outcomes due to a paucity of data from randomized placebo-controlled trials. The aim of this study was to determine if MRI can be used to identify patients who are most likely to benefit from endovascular reperfusion. Methods Consecutive patients, scheduled to undergo endovascular therapy within 12 hours of stroke onset, were enrolled in a multi-center prospective cohort study. Aided by an automated image analysis software program, investigators interpreted the baseline MRI. They determined, prior to endovascular treatment, if the patient had an MRI profile (Target Mismatch) that suggested salvageable tissue was present. Reperfusion was assessed on an early follow-up MRI and defined as a >50% reduction in the volume of the baseline perfusion lesion. A favorable clinical response was defined as a ≥8 point improvement on the NIH Stroke Scale (NIHSS) between baseline and day 30 or an NIHSS score of 0–1 at 30 days. Findings Following endovascular therapy reperfusion occurred in 46 of 78 (59%) Target Mismatch patients and in 12 of 21 (57%) No Target Mismatch patients. The adjusted odds ratio for favorable clinical response associated with reperfusion was 8·5 (95% CI 2·6 – 28) in the Target Mismatch group and 0·2 (95% CI 0·0 – 1·6) in the No Target Mismatch group (p=0·003 for difference between odds ratios). Reperfusion was associated with an increased odds of good functional outcome at 90 days (OR is 5.2, 95% CI 1.4–19) and attenuation of infarct growth at 5 days (30 ml of median growth with reperfusion vs. 73 ml without reperfusion, p=0·01) in the Target Mismatch group but not in patients without Target Mismatch. Interpretation Target Mismatch patients who achieved early reperfusion following endovascular stroke therapy had more favorable clinical outcomes and less infarct growth. No association between reperfusion and favorable outcomes was present in patients without Target Mismatch. These data support a randomized controlled trial of endovascular treatment in patients with the Target Mismatch profile.

Background and Purpose-We sought to assess whether the volume of the ischemic penumbra can be estimated more accurately by altering the threshold selected for defining perfusion-weighting imaging (PWI) lesions. Methods-DEFUSE is a multicenter study in which consecutive acute stroke patients were treated with intravenous tissue-type plasminogen activator 3 to 6 hours after stroke onset. Magnetic resonance imaging scans were obtained before, 3 to 6 hours after, and 30 days after treatment. Baseline and posttreatment PWI volumes were defined according to increasing Tmax delay thresholds (Ͼ2, Ͼ4, Ͼ6, and Ͼ8 seconds). Penumbra salvage was defined as the difference between the baseline PWI lesion and the final infarct volume (30-day fluid-attenuated inversion recovery sequence). We hypothesized that the optimal PWI threshold would provide the strongest correlations between penumbra salvage volumes and various clinical and imaging-based outcomes. Results-Thirty-three patients met the inclusion criteria. The correlation between infarct growth and penumbra salvage volume was significantly better for PWI lesions defined by Tmax Ͼ6 seconds versus Tmax Ͼ2 seconds, as was the difference in median penumbra salvage volume in patients with a favorable versus an unfavorable clinical response. Among patients who did not experience early reperfusion, the Tmax Ͼ4 seconds threshold provided a more accurate prediction of final infarct volume than the Ͼ2 seconds threshold. Conclusions-Defining PWI lesions based on a stricter Tmax threshold than the standard Ͼ2 seconds delay appears to provide more a reliable estimate of the volume of the ischemic penumbra in stroke patients imaged between 3 and 6 hours after symptom onset. A threshold between 4 and 6 seconds appears optimal for early identification of critically hypoperfused tissue.

Background and Purpose We evaluate associations between the severity of magnetic resonance perfusion-weighted imaging abnormalities, as assessed by the hypoperfusion intensity ratio (HIR), on infarct progression and functional outcome in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2). Methods Diffusion-weighted magnetic resonance imaging and perfusion-weighted imaging lesion volumes were determined with the RAPID software program. HIR was defined as the proportion of TMax >6 s lesion volume with a Tmax >10 s delay and was dichotomized based on its median value (0.4) into low versus high subgroups as well as quartiles. Final infarct volumes were assessed at day 5. Initial infarct growth velocity was calculated as the baseline diffusion-weighted imaging (DWI) lesion volume divided by the delay from symptom onset to baseline magnetic resonance imaging. Total Infarct growth was determined by the difference between final infarct and baseline DWI volumes. Collateral flow was assessed on conventional angiography and dichotomized into good and poor flow. Good functional outcome was defined as modified Rankin Scale ≤2 at 90 days. Results Ninety-nine patients were included; baseline DWI, perfusion-weighted imaging, and final infarct volumes increased with HIR quartiles (P<0.01). A high HIR predicted poor collaterals with an area under the curve of 0.73. Initial infarct growth velocity and total infarct growth were greater among patients with a high HIR (P<0.001). After adjustment for age, DWI volume, and reperfusion, a low HIR was associated with good functional outcome: odds ratio=4.4 (95% CI, 1.3–14.3); P=0.014. Conclusions HIR can be easily assessed on automatically processed perfusion maps and predicts the rate of collateral flow, infarct growth, and clinical outcome.

Rationale Early reperfusion in patients experiencing acute ischemic stroke is effective in patients with large vessel occlusion. No randomized data are available regarding the safety and efficacy of endovascular therapy beyond 6 h from symptom onset. Aim The aim of the study is to demonstrate that, among patients with large vessel anterior circulation occlusion who have a favorable imaging profile on computed tomography perfusion or magnetic resonance imaging, endovascular therapy with a Food and Drug Administration 510 K-cleared mechanical thrombectomy device reduces the degree of disability three months post stroke. Design The study is a prospective, randomized, multicenter, phase III, adaptive, blinded endpoint, controlled trial. A maximum of 476 patients will be randomized and treated between 6 and 16 h of symptom onset. Procedures Patients undergo imaging with computed tomography perfusion or magnetic resonance diffusion/perfusion, and automated software (RAPID) determines if the Target Mismatch Profile is present. Patients who meet both clinical and imaging selection criteria are randomized 1:1 to endovascular therapy plus medical management or medical management alone. The individual endovascular therapist chooses the specific device (or devices) employed. Study outcomes The primary endpoint is the distribution of scores on the modified Rankin Scale at day 90. The secondary endpoint is the proportion of patients with modified Rankin Scale 0–2 at day 90 (indicating functional independence). Analysis Statistical analysis for the primary endpoint will be conducted using a normal approximation of the Wilcoxon–Mann–Whitney test (the generalized likelihood ratio test).

Background MRI-based selection of patients for acute stroke interventions requires rapid accurate estimation of the infarct core on diffusion-weighted MRI (DWI). Typically used manual methods to delineate DWI lesions are subjective and time-consuming. These limitations would be overcome by a fully automated method that can rapidly and objectively delineate the ischemic core. An automated method would require pre-defined criteria to identify the ischemic core. Aim To determine Apparent Diffusion Coefficient (ADC) based criteria that can be implemented in a fully automated software solution for identification of the ischemic core. Methods Imaging data from patients enrolled in the DEFUSE study who had early revascularization following tPA treatment, was included. The patients’ baseline DWI and 30-day FLAIR lesions were manually delineated after co-registration. Parts of the DWI lesion that corresponded with 30-day infarct were considered ischemic core, whereas parts that corresponded with normal brain parenchyma at 30 days were considered non-core. The optimal ADC threshold to discriminate core from non-core voxels was determined by voxel-based ROC analysis using the Youden index. Results 51045 DWI positive voxels from 14 patients who met eligibility criteria were analyzed. The mean DWI lesion volume was 24(±23) mL. Of this, 18(±22) mL was ischemic core and 3(±5) mL was non-core. The remainder corresponded to pre-existing gliosis, CSF, or was lost to post-infarct atrophy. The ADC of core was lower than that of non-core voxels (p<0.0001). The optimal threshold for identification of ischemic core was an ADC ≤620 ×10−6 mm2/s (sensitivity 69% and specificity 78%). Conclusions Our data suggests the ischemic core can be identified with an absolute ADC threshold. This threshold can be implemented in image analysis software for fully automated segmentation of the ischemic core.

We hypothesized that automated assessment of collaterals on computed tomography perfusion can predict the rate of infarct growth during transfer from a primary to a comprehensive stroke center for endovascular stroke treatment. We identified consecutive patients (N = 28) and assessed their collaterals based on the hypoperfusion intensity ratio (HIR) prior to transfer. Infarct growth rate was strongly correlated with HIR (r = 0.78, p < 0.001). Receiver operating characteristic analysis identified HIR ≥ 0.5 as optimal for predicting infarct growth. Patients with HIR ≥ 0.5 had a median infarct growth rate of 10.1ml/h (interquartile range [IQR] = 6.4-18.4) compared with 0.9ml/h (IQR = 0-2.8; p < 0.001) in patients with HIR < 0.5. Patients with HIR ≥ 0.5 had an 83% probability of significant core growth, whereas patients with HIR < 0.5 had an 88% probability of core stability. These preliminary data have the potential to guide decision making regarding whether repeat brain imaging should be performed after transfer to a comprehensive stroke center. Ann Neurol 2018;84:616-620.