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BACKGROUND The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODS We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95°/o confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. RESULTS The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). CONCLUSIONS In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.). [ABSTRACT FROM AUTHOR]

Background: Even days after treatment of acute ischemic stroke due to a large vessel occlusion, the infarct lesion continues to grow. This late, subacute growth is associated with unfavorable functional outcome. In this study, we aim to identify patient characteristics that are risk factors of late, subacute lesion growth., Methods: Patients from the MR CLEAN trial cohort with good quality 24 h and 1-week follow up non-contrast CT scans were included. Late Lesion growth was defined as the difference between the ischemic lesion volume assessed after 1-week and 24-h. To identify risk factors, patient characteristics associated with lesion growth (categorized in quartiles) in univariable ordinal analysis ( p < 0.1) were included in a multivariable ordinal regression model., Results: In the 226 patients that were included, the median lesion growth was 22 (IQR 10-45) ml. In the multivariable model, lower collateral capacity [aOR: 0.62 (95% CI: 0.44-0.87); p = 0.01], longer time to treatment [aOR: 1.04 (1-1.08); p = 0.04], unsuccessful recanalization [aOR: 0.57 (95% CI: 0.34-0.97); p = 0.04], and larger midline shift [aOR: 1.18 (95% CI: 1.02-1.36); p = 0.02] were associated with late lesion growth., Conclusion: Late, subacute, lesion growth occurring between 1 day and 1 week after ischemic stroke treatment is influenced by lower collateral capacity, longer time to treatment, unsuccessful recanalization, and larger midline shift. Notably, these risk factors are similar to the risk factors of acute lesion growth, suggesting that understanding and minimizing the effects of the predictors for late lesion growth could be beneficial to mitigate the effects of ischemia., Competing Interests: PK is funded by INSIST (www.insist-h2020.eu): a European Union's Horizon 2020 research and innovation program (grant agreement number: 777072). ABo is a shareholder of Nico.Lab. AY reports grants from Cerenovus Neurovascular, Medtronic, Stryker, Penumbra, and Genentech for investigator-initiated studies; funds from Stryker, Cerenovus Neurovascular and Penumbra (core imaging lab activities) and Genentech (consultation); and declares to have equity ownership from Insera Therapeutics. WZ reports speaker fees from Stryker and Cerenovus (paid to the institution). AL and DD report funds from the Cerenovus Neurovascular, Dutch Heart Foundation, Brain Foundation Netherlands, Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants paid to the institution from AngioCare BV, Covidien/EV3, MEDAC Gmbh/LAMEPRO, PenumbraInc., Top Medical/Concentric, Stryker, Stryker European Operations BV, Medtronic, Thrombolytic Science and LLC for research. AL further reports grants paid to the institution from the Siemens Healthineers, GE Healthcare and Philips Healthcare. YR is a shareholder at Nico-Lab. CM reports grants from European Commission, during the conduct of the study; grants from CVON/Dutch Heart Foundation, grants from TWIN Foundation, grants from Stryker, outside the submitted work; and owns stock in Nico.lab. HM is a Co-founder and shareholder of Nico.lab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Konduri, Bucker, Boers, Dutra, Samuels, Treurniet, Berkhemer, Yoo, van Zwam, van Oostenbrugge, van der Lugt, Dippel, Roos, Bot, Majoie, Marquering and the MR CLEAN Trial Investigators (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands).)

Introduction: Hyperglycemia is highly prevalent in patients with acute ischemic stroke and is associated with increased risk of symptomatic intracranial hemorrhage, larger infarct size and unfavorable outcome. Furthermore, glucose may modify the effect of endovascular treatment (EVT) in patients with ischemic stroke. Hyperglycemia might lead to accelerated conversion of penumbra into infarct core. However, it remains uncertain whether hyperglycemia on admission is associated with the size of penumbra or infarct core in acute ischemic stroke. In this study, we aimed to assess the association between hyperglycemia and Computed Tomographic Perfusion (CTP) derived parameters in patients who underwent EVT for acute ischemic stroke., Methods: We used data from the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Hyperglycemia was defined as admission serum glucose of >7.8 mmol/L. Dichotomized and quantiles of glucose levels were related to size of core, penumbra and core penumbra ratio. Hypoperfused area is mean transient time 45% higher than that of the contralateral hemisphere. Core is the area with cerebral blood volume of <2 mL/100 g and penumbra is the area with cerebral blood volume > 2 mL/100 g. Core-penumbra ratio is the ischemic core divided by the total volume of hypoperfused tissue (core plus penumbra) multiplied by 100. Adjustments were made for age, sex, NIHSS on admission, onset-imaging time and diabetes mellitus., Results: Hundred seventy-three patients were included. Median glucose level on admission was 6.5 mmol/L (IQR 5.8-7.5 mmol/L) and thirty-five patients (20%) were hyperglycemic. Median core volume was 33.3 mL (IQR 13.6-62.4 mL), median penumbra volume was 80.2 mL (IQR 36.3-123.5 mL) and median core-penumbra ratio was 28.5% (IQR 18.6-45.8%). Patients with hyperglycemia on admission had larger core volumes and core penumbra ratio than normoglycemic patients with a regression coefficient of 15.1 (95% confidence interval (CI), 1.8 to 28.3) and 11.5 (95% confidence interval (CI), 3.4 to 19.7) respectively., Conclusion: Hyperglycemia on admission was associated with larger ischemic core volume and larger core-penumbra ratio in patients with acute ischemic stroke who underwent endovascular treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke., Methods: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621., Findings: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13-3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14-3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69-1·21]) and unfractionated heparin (0·81 [0·61-1·08]) led to a non-significant shift towards worse modified Rankin Scale scores., Interpretation: Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome., Funding: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation., Competing Interests: Declaration of interests BR and DWJD report financial support for the current manuscript from the CONTRAST consortium, all paid to their institution. AvdL, BR, HBvdW, CBLMM, DWJD, and MU report funding from the Dutch Heart Foundation, all paid to their institution. AvdL and DWJD report funding from the Dutch Brain foundation paid to their institution. AvdL, BJE, DWJD, and MU report funding from Health Holland Top Sector Life Sciences & Health, all paid to their institution. AvdH, BJE, BR, DWJD, JAV, JMC, and RvdB report grants from the Netherlands Organisation for Health Research and Development, all paid to their institution. AvdL, AJY, HBvdW, CBLMM, and DWJD report funding from Stryker, all paid to their institution. AvdL, AJY, DWJD, and RPHB report funding from Cerenovus, all paid to their institution. AvdL, AJY, DWJD, and JMC report funding from Medtronic, all paid to their institution. AvdL, AJY, and DWJD report funding from Penumbra, all paid to their institution. AvdL and DWJD report funding from Thrombolytic Science paid to their institution. AJY, CBLMM and YBWEMR are minor shareholders of Nicolab. AJY reports funding from Genentech paid to his institution; consulting fees from Penumbra, Cerenovus, Philips, and Vesalio paid to himself; participates in an advisory board of Philips, Nicolab, XCath, and HCA; is part of the endovascular safety monitor of the NIH MOST trial; is an associate editor of the Stroke: Vascular and Interventional Neurology journal; and is a stock owner of Insera. AAP reports institutional grants from Siemens Healthineers and Bayer Healthcare. FJAM reports reimbursements for lectures for Speaker Bureau and Canon Medical Systems. AMT reports being a junior staff member of the Dutch Heart Foundation. BJE reports being a delegate of the Netherlands in the European Union of Medical Specialists Neuroradiology. HBvdW reports grants from the European Union, and participation in an advisory board of Bayer Healthcare and LivaNova, all paid to their institution. CBLMM received funds from the European Commission, TWIN foundation, and Health Evaluation Netherlands, all paid to their institution. JMC reports funding from the Dutch Thrombosis Society and the Dr CJ Vaillant Foundation; consulting fees from Bayer Healthcare, Boehringer, and Portola, all paid to their institution; a fellowship from the European Stroke Organisation; and is a member of the writing committee of the European Stroke Organisation guideline on cerebral venous thrombosis, both unpaid. WvZ reports consulting and speaker fees from Philips, Stryker, Cerenovus, and NicoLab, all paid to their institution; and participation in advisory boards of WeTrust (Philips), Solonda (Anaconda), and InExtremis (CHU Montpellier). All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Purpose: Ischemic lesion volume can increase even 24 hours after onset of an acute ischemic stroke. In this study, we investigated the association of lesion evolution with functional outcome and the influence of successful recanalization on this association., Methods: We included patients from the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) who received good quality noncontrast CT images 24 hours and 1 week after stroke onset. The ischemic lesion delineations included infarct, edema, and hemorrhagic transformation. Lesion evolution was defined as the difference between the volumes measured on the 1-week and 24-hour noncontrast CTs. The association of lesion evolution with functional outcome was evaluated using unadjusted and adjusted logistic regression. Adjustments were made for baseline, clinical, and imaging parameters that were associated P<0.10) in univariate analysis with favorable functional outcome, defined as modified Rankin Scale score of ≤2. Interaction analysis was performed to evaluate the influence of successful recanalization, defined as modified Arterial Occlusion Lesion score of 3 points, on this association., Results: Of the 226 patients who were included, 69 (31%) patients achieved the favorable functional outcome. Median lesion evolution was 22 (interquartile range, 10–45) mL. Lesion evolution was significantly inversely correlated with favourable functional outcome: unadjusted odds ratio, 0.76 (95% CI, 0.66–0.86; per 10 mL of lesion evolution; P<0.01) and adjusted odds ratio: 0.85 (95% CI, 0.72–0.97; per 10 mL of lesion evolution; P=0.03). There was no significant interaction of successful recanalization on the association of lesion evolution and favorable functional outcome (odds ratio, 1.01 [95% CI, 0.77–1.36]; P=0.94)., Conclusions: In our population, subacute ischemic lesion evolution is associated with unfavorable functional outcome. This study suggests that even 24 hours after onset of stroke, deterioration of the brain continues, which has a negative effect on functional outcome. This finding may warrant additional treatment in the subacute phase.