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Background: Intracranial hemorrhage (ICH) is a frequent complication after endovascular stroke treatment., Objective: To assess the association of the occurrence and type of ICH after endovascular treatment (EVT) with functional outcome., Methods: We analyzed data from the MR CLEAN-NO IV and MR CLEAN-MED trials. Both trials included adult patients with ischemic stroke with a large vessel occlusion in the anterior circulation, who were eligible for EVT. ICH was classified (1) as asymptomatic or symptomatic (concomitant neurological deterioration of ≥4 points on the NIHSS, or ≥2 points on 1 NIHSS item), and (2) according to the Heidelberg Bleeding Classification. We used multivariable ordinal logistic regression analyses to assess the association of the occurrence and type of ICH with the modified Rankin Scale score at 90 days., Results: Of 1017 included patients, 331 (33%) had an asymptomatic ICH, and 90 (9%) had a symptomatic ICH. Compared with no ICH, both asymptomatic (adjusted common OR (acOR)=0.76; 95% CI 0.58 to 0.98) and symptomatic (acOR=0.07; 95% CI 0.04 to 0.14) ICH were associated with worse functional outcome. In particular, isolated parenchymal hematoma type 2 (acOR=0.37; 95% CI 0.14 to 0.95), combined parenchymal hematoma with hemorrhage outside infarcted brain tissue (acOR=0.17; 95% CI 0.10 to 0.30), and combined hemorrhages outside infarcted brain tissue (acOR=0.14; 95% CI 0.03 to 0.74) were associated with worse functional outcome than no ICH.Strength of the association of ICH with functional outcome depends on the type of ICH. Although the association is stronger for symptomatic ICH, asymptomatic ICH after EVT is also associated with worse functional outcome., Competing Interests: Competing interests: DWJD and AvdL report unrestricted grants from Stryker, Penumbra, Medtronic, Cerenovus, Thrombolytic Science, LLC, Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and Thrombolytic Science, LLC for research, paid to the institution. BR reports funding from the Dutch Heart Foundation and the Netherlands Organisation of Health Research and Development, paid to the institution. BJE reports unrestricted grants from The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and Nicolab b.v. all paid to the institution. CM received funds from, CVON/Dutch Heart Foundation and Stryker, (related to this project, paid to institution) and from the European Commission, Healthcare Evaluation Netherlands TWIN Foundation (unrelated to this project; all paid to the institution) and is a shareholder of Nicolab., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Symptomatic intracranial hemorrhage (sICH) is a severe complication of reperfusion therapy for ischemic stroke. Multiple models have been developed to predict sICH or intracranial hemorrhage (ICH) after reperfusion therapy. We provide an overview of published models and validate their ability to predict sICH in patients treated with endovascular treatment in daily clinical practice., Methods: We conducted a systematic search to identify models either developed or validated to predict sICH or ICH after reperfusion therapy (intravenous thrombolysis and/or endovascular treatment) for ischemic stroke. Models were externally validated in the MR CLEAN Registry (n=3180; Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was sICH according to the Heidelberg Bleeding Classification. Model performance was evaluated with discrimination (c-statistic, ideally 1; a c-statistic below 0.7 is considered poor in discrimination) and calibration (slope, ideally 1, and intercept, ideally 0)., Results: We included 39 studies describing 40 models. The most frequently used predictors were baseline National Institutes of Health Stroke Scale (NIHSS; n=35), age (n=22), and glucose level (n=22). In the MR CLEAN Registry, sICH occurred in 188/3180 (5.9%) patients. Discrimination ranged from 0.51 (SPAN-100 [Stroke Prognostication Using Age and National Institutes of Health Stroke Scale]) to 0.61 (SITS-SICH [Safe Implementation of Treatments in Stroke Symptomatic Intracerebral Hemorrhage] and STARTING-SICH [STARTING Symptomatic Intracerebral Hemorrhage]). Best calibrated models were IST-3 (intercept, -0.15 [95% CI, -0.01 to -0.31]; slope, 0.80 [95% CI, 0.50-1.09]), SITS-SICH (intercept, 0.15 [95% CI, -0.01 to 0.30]; slope, 0.62 [95% CI, 0.38-0.87]), and STARTING-SICH (intercept, -0.03 [95% CI, -0.19 to 0.12]; slope, 0.56 [95% CI, 0.35-0.76])., Conclusions: The investigated models to predict sICH or ICH discriminate poorly between patients with a low and high risk of sICH after endovascular treatment in daily clinical practice and are, therefore, not clinically useful for this patient population.

Introduction: Little is known about the timing of occurrence of symptomatic intracranial hemorrhage (sICH) after endovascular therapy (EVT) for acute ischemic stroke. A better understanding could optimize in-hospital surveillance time points and duration. The aim of this study was to delineate the probability of sICH over time and to identify factors associated with its timing., Patients and Methods: We retrospectively analyzed data from the Dutch MR CLEAN trial and MR CLEAN Registry. We included adult patients who underwent EVT for an anterior circulation large vessel occlusion within 6.5 h of stroke onset. In patients with sICH (defined as ICH causing an increase of ⩾4 points on the National Institutes of Health Stroke Scale [NIHSS]), univariable and multivariable linear regression analysis was used to identify factors associated with the timing of sICH. This was defined as the time between end of EVT and the time of first CT-scan on which ICH was seen as a proxy., Results: SICH occurred in 205 (6%) of 3391 included patients. Median time from end of EVT procedure to sICH detection on NCCT was 9.0 [IQR 2.9-22.5] hours, with a rapidly decreasing incidence after 24 h. None of the analyzed factors, including baseline NIHSS, intravenous alteplase treatment, and poor reperfusion at the end of the procedure were associated with the timing of sICH., Conclusion: SICHs primarily occur in the first hours after EVT, and less frequently beyond 24 h. Guidelines that recommend to perform frequent neurological assessments for at least 24 h after intravenous alteplase treatment can be applied to ischemic stroke patients treated with EVT., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DD and AvdL report funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra Inc., Stryker, Medtronic, Thrombolytic Science, LLC and Cerenovus for research, all paid to institution. CM: received funds from TWIN Foundation (related to this project, paid to institution); and from CVON/Dutch Heart Foundation, Stryker, European Commission, Health Evaluation Netherlands (unrelated; all paid to institution). CM is shareholder of Nicolab, a company that focuses on the use of artificial intelligence for medical imaging analysis. WvZ reports speaker fees from Stryker, Nicolab and Cerenovus, both paid to institution. BR reports funding from the Dutch Heart Foundation, and The Netherlands Organisation for Health Research and Development, all paid to institution., (© European Stroke Organisation 2022.)

Objectives: We aimed to evaluate whether the overall harmful effect of periprocedural treatment with aspirin or heparin during endovascular stroke treatment is different in patients with a successful reperfusion after the procedure., Materials and Methods: We performed a post-hoc analysis of the MR CLEAN-MED trial, including adult patients with a large vessel occlusion in the anterior circulation eligible for endovascular treatment (EVT). In this trial, patients were randomized for periprocedural intravenous treatment with aspirin or no aspirin (1:1 ratio), and for moderate-dose unfractionated heparin, low-dose unfractionated heparin or no unfractionated heparin (1:1:1 ratio). We tested for interaction between the post-EVT extended thrombolysis in cerebral infarction (eTICI) score and treatment with periprocedural medication with multivariable regression analyses. The primary outcome was the modified Rankin Scale score at 90 days. Secondary outcomes were final infarct volume, intracranial hemorrhage, and symptomatic intracranial hemorrhage., Results: Of 534 included patients, 93 (17%) had a post-EVT eTICI score of 0-2a, 115 (22%) a score of 2b, 73 (14%) a score of 2c, and 253 (47%) a score of 3. For both aspirin and heparin, we found no interaction between post-EVT eTICI score and treatment on the modified Rankin Scale score (p=0.76 and p=0.47, respectively). We found an interaction between post-EVT eTICI score and treatment with heparin on the final infarct volume (p=0.01). Of note, this interaction showed a biologically implausible distribution over the subgroups., Conclusions: The overall harmful effect of periprocedural aspirin and unfractionated heparin is not different in patients with a successful reperfusion after EVT., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Symptomatic intracranial hemorrhage (sICH) is a serious complication after endovascular treatment for ischemic stroke. We aimed to identify determinants of its occurrence and location., Methods: We retrospectively analyzed data from the Dutch MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) and MR CLEAN registry. We included adult patients with a large vessel occlusion in the anterior circulation who underwent endovascular treatment within 6.5 hours of stroke onset. We used univariable and multivariable logistic regression analyses to identify determinants of overall sICH occurrence, sICH within infarcted brain tissue, and sICH outside infarcted brain tissue., Results: SICH occurred in 203 (6%) of 3313 included patients and was located within infarcted brain tissue in 50 (25%), outside infarcted brain tissue in 23 (11%), and both within and outside infarcted brain tissue in 116 (57%) patients. In 14 patients (7%), data on location were missing. Prior antiplatelet use, baseline systolic blood pressure, baseline plasma glucose levels, post-endovascular treatment modified treatment in cerebral ischemia score, and duration of procedure were associated with all outcome parameters. In addition, determinants of sICH within infarcted brain tissue included history of myocardial infarction (adjusted odds ratio, 1.65 [95% CI, 1.06-2.56]) and poor collateral score (adjusted odds ratio, 1.42 [95% CI, 1.02-1.95]), whereas determinants of sICH outside infarcted brain tissue included level of occlusion on computed tomography angiography (internal carotid artery or internal carotid artery terminus compared with M1: adjusted odds ratio, 1.79 [95% CI, 1.16-2.78])., Conclusions: Several factors, some potentially modifiable, are associated with sICH occurrence. Further studies should investigate whether modification of baseline systolic blood pressure or plasma glucose level could reduce the risk of sICH. In addition, determinants differ per location of sICH, supporting the hypothesis of varying underlying mechanisms., Registration: URL: https://www.isrctn.com/; Unique identifier: ISRCTN10888758.

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: Optimal blood pressure (BP) management in the acute phase of ischemic stroke remains an unresolved issue. It is uncertain whether guidelines for BP management during and after intravenous alteplase can be extrapolated to endovascular treatment (EVT) for stroke due to large artery occlusion in the anterior circulation. We evaluated the associations between systolic BP (SBP) in the first 6 hours following EVT and functional outcome as well as symptomatic intracranial hemorrhage., Methods: Patients of 8 MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry centers, with available data on SBP in the 6 hours following EVT, were analyzed. We evaluated maximum, minimum, and mean SBP. Study outcomes were functional outcome (modified Rankin Scale) at 90 days and symptomatic intracranial hemorrhage. We used multivariable ordinal and binary regression analysis to adjust for important prognostic factors and studied possible effect modification by successful reperfusion., Results: Post-EVT SBP data were available for 1161/1796 patients. Higher maximum SBP (per 10 mm Hg increments) was associated with worse functional outcome (adjusted common odds ratio, 0.93 [95% CI, 0.88–0.98]) and a higher rate of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.17 [95% CI, 1.02–1.36]). The association between minimum SBP and functional outcome was nonlinear with an inflection point at 124 mm Hg. Minimum SBP lower and higher than the inflection point were associated with worse functional outcomes (adjusted common odds ratio, 0.85 per 10 mm Hg decrements [95% CI, 0.76–0.95] and adjusted common odds ratio, 0.81 per 10 mm Hg increments [95% CI, 0.71–0.92]). No association between mean SBP and functional outcome was observed. Successful reperfusion did not modify the relation of SBP with any of the outcomes., Conclusions: Maximum SBP in the first 6 hours following EVT is positively associated with worse functional outcome and an increased risk of symptomatic intracranial hemorrhage. Both lower and higher minimum SBP are associated with worse outcomes. A randomized trial to evaluate whether modifying post-intervention SBP results in better outcomes after EVT for ischemic stroke seems justified.

Background: There are indications that the use of levodopa/carbidopa can cause symptomatic vitamin B6 deficiency. However, this has only been described for patients who used the product in the form of an intestinal gel., Case Description: We are describing 3 patients who developed vitamin B6 deficiency while using levodopa/carbidopa in tablet form. All 3 patients developed symptoms consistent with peripheral axonal polyneuropathy., Conclusion: The cases of our patients are providing support for the idea that oral use of levodopa/carbidopa can cause symptomatic vitamin B6 deficiency.