The biological pathways involved in lesion formation after an acute ischemic stroke (AIS) are poorly understood. Despite successful reperfusion treatment, up to two thirds of patients with large vessel occlusion remain functionally dependent. Imaging characteristics extracted from DWI and T2-FLAIR follow-up MR sequences could aid in providing a better understanding of the lesion constituents. We built a fully automated pipeline based on a tree ensemble machine learning model to predict poor long-term functional outcome in patients from the MR CLEAN-NO IV trial. Several feature sets were compared, considering only imaging, only clinical, or both types of features. Nested cross-validation with grid search and a feature selection procedure based on SHapley Additive exPlanations (SHAP) was used to train and validate the models. Considering features from both imaging modalities in combination with clinical characteristics led to the best prognostic model (AUC = 0.85, 95%CI [0.81, 0.89]). Moreover, SHAP values showed that imaging features from both sequences have a relevant impact on the final classification, with texture heterogeneity being the most predictive imaging biomarker. This study suggests the prognostic value of both DWI and T2-FLAIR follow-up sequences for AIS patients. If combined with clinical characteristics, they could lead to better understanding of lesion pathophysiology and improved long-term functional outcome prediction.

Noninferiority trials aim to prove that the efficacy, defined in terms of a key clinical outcome, of a new treatment is not meaningfully worse than that of an established active control. Noninferiority trials are important when other aspects of care can be improved, such as convenience, toxicity, costs, and safety (nonefficacy benefits). While the motivation for a noninferiority trial is straightforward, the design, execution, and interpretation of these trials is not a trivial task. Several safeguards that protect superiority trials from incorrect conclusions do not apply or even work in reverse for noninferiority trials. This review aims to provide stroke clinicians and researchers with a general overview of noninferiority trials and a deeper understanding of 10 pitfalls they should consider when designing and interpreting such trials.

More than half of the endovascularly treated ischemic stroke patients with incomplete reperfusion (expanded Thrombolysis in Cerebral Infarction [eTICI] <3) show delayed reperfusion (DR) on 24-hour perfusion imaging, which is associated with favorable clinical outcome. The effect of intravenous thrombolysis (IVT) on the rates of DR remains unclear. This study aimed to assess the treatment effect of IVT on the occurrence of DR. Pooled data from 3 randomized controlled trials (EXTEND-IA and EXTEND-IA TNK parts 1 and 2) and 2 comprehensive stroke centers (University Hospitals Graz and Bern) were analyzed. Only patients with a final reperfusion score of eTICI 2a-2c and available perfusion imaging at follow-up of 24 ± 12 hours were included. The primary outcome was the presence of DR on 24-hour follow-up CT/MRI perfusion imaging, defined as the absence of any focal perfusion deficit on perfusion imaging, despite incomplete reperfusion on the final angiography series during thrombectomy. For the secondary analysis, we explored the association between the primary outcome (DR) and the time elapsed between start of IVT and the end of an intervention. To address confounding in observational data, we performed a target trial emulation. Of 832 included patients with eTICI 2a-2c (median age 74 years, 49% female), 511 (61%) had DR. There was an independent treatment effect of IVT on DR (standardized risk ratio [sRR] 1.1, 95% CI 1.0-1.3; standardized risk difference [sRD] 8.2%, 95% CI 0.2%-16.1%), after adjusting for age, sex, atrial fibrillation, number of device passes, collateral score, and eTICI. Among those patients who have received IVT (n = 524/832, 63%), when adjusting for the aforementioned covariates, there was a causal effect of shorter time between administration of thrombolytics and end of the intervention on DR (sRR 0.93%, 95% CI 0.87-0.98; sRD -5.2%; 95% CI -9.1% to -1.3%, per hour increase). Exposure to thrombolytics showed independent treatment effect on the occurrence of DR among patients with incomplete reperfusion after thrombectomy who undergo perfusion imaging at the 24-hour follow-up. The effect of thrombolytics on DR was observed if there was a high chance of therapeutic concentrations of thrombolytics at the time point when the proximal vessel was recanalized, but distal occlusions persisted and/or occurred. This study is rated Class III because it is a nonrandomized study and there are substantial differences in baseline characteristics of the treatment groups.

(1) Background: For acute ischemic strokes caused by large vessel occlusion, manually assessed thrombus volume and perviousness have been associated with treatment outcomes. However, the manual assessment of these characteristics is time-consuming and subject to inter-observer bias. Alternatively, a recently introduced fully automated deep learning-based algorithm can be used to consistently estimate full thrombus characteristics. Here, we exploratively assess the value of these novel biomarkers in terms of their association with stroke outcomes. (2) Methods: We studied two applications of automated full thrombus characterization as follows: one in a randomized trial, MR CLEAN-NO IV (n = 314), and another in a Dutch nationwide registry, MR CLEAN Registry (n = 1839). We used an automatic pipeline to determine the thrombus volume, perviousness, density, and heterogeneity. We assessed their relationship with the functional outcome defined as the modified Rankin Scale (mRS) at 90 days and two technical success measures as follows: successful final reperfusion, which is defined as an eTICI score of 2b-3, and successful first-pass reperfusion (FPS). (3) Results: Higher perviousness was significantly related to a better mRS in both MR CLEAN-NO IV and the MR CLEAN Registry. A lower thrombus volume and lower heterogeneity were only significantly related to better mRS scores in the MR CLEAN Registry. Only lower thrombus heterogeneity was significantly related to technical success; it was significantly related to a higher chance of FPS in the MR CLEAN-NO IV trial (OR = 0.55, 95% CI: 0.31–0.98) and successful reperfusion in the MR CLEAN Registry (OR = 0.88, 95% CI: 0.78–0.99). (4) Conclusions: Thrombus characteristics derived from automatic entire thrombus segmentations are significantly related to stroke outcomes.

BACKGROUND: Equipoise persists whether patients with stroke with carotid tandem lesions undergoing endovascular treatment (EVT) should undergo acute carotid stenting, and whether intravenous thrombolysis (IVT) before EVT should influence this decision. We assessed functional and safety outcomes of acute carotid stenting in patients with carotid tandem lesions randomized to IVT plus EVT or EVT alone. METHODS: Individual participant data meta-analysis of 6 randomized clinical trials conducted in Asia, Europe, and Oceania between 2017 and 2021 investigating IVT plus EVT versus EVT alone in patients with carotid tandem lesions presenting directly to EVT-capable centers. The primary outcome was the 90-day modified Rankin Scale score, assessed with mixed-effect ordinal regression models. Safety outcomes were any intracranial hemorrhage and symptomatic intracranial hemorrhage. A secondary analysis used inverse probability of treatment weighting. Treatment effect heterogeneity between IVT plus EVT and EVT alone was assessed in a 2-step meta-analysis. RESULTS: Overall, 340 of 2267 (15%) patients had carotid tandem lesions with 113 of 329 (34%) undergoing acute carotid stenting. Stenting was associated with better 90-day functional outcomes (adjusted common odds ratio, 1.60 [95% CI, 1.03–2.47]), confirmed in inverse probability of treatment weighting analysis (adjusted common odds ratio, 1.66 [95% CI, 1.08–2.54]). Patients undergoing stenting had no statistically significant higher rates of any intracranial hemorrhage (44% versus 35%; adjusted odds ratio, 1.30 [95% CI, 0.79–2.15]) and symptomatic intracranial hemorrhage (6.3% versus 3.7%; adjusted odds ratio, 2.09 [95% CI, 0.78–5.59]). No heterogeneity in treatment effect was observed in patients randomized to IVT plus EVT (adjusted common odds ratio, 2.07 [95% CI, 1.06–4.07]) or EVT alone (1.21 [95% CI, 0.59–2.50]; P interaction=0.81). CONCLUSIONS: In this international individual participant data meta-analysis of patients with carotid tandem lesions randomized to EVT alone or IVT followed by EVT, acute carotid stenting during EVT was associated with better functional outcomes, and this association was not modified by prior treatment with IVT.