Publications by authors named "Peter D Schellinger"

168 Publications

Off-label use of intravenous thrombolysis for acute ischemic stroke: a critical appraisal of randomized and real-world evidence.

Ther Adv Neurol Disord 2021 26;14:1756286421997368. Epub 2021 Feb 26.

Department of Neurology, The University of Tennessee Health Science Center, Memphis, TN, USA.

Intravenous thrombolysis (IVT) represents the only systemic reperfusion therapy able to reverse neurological deficit in patients with acute ischemic stroke (AIS). Despite its effectiveness in patients with or without large vessel occlusion, it can be offered only to a minority of them, because of the short therapeutic window and additional contraindications derived from stringent but arbitrary inclusion and exclusion criteria used in landmark randomized controlled clinical trials. Many absolute or relative contraindications lead to disparities between the official drug label and guidelines or expert recommendations. Based on recent advances in neuroimaging and evidence from cohort studies, off-label use of IVT is increasingly incorporated into the daily practice of many stroke centers. They relate to extension of therapeutic time windows, and expansion of indications in co-existing conditions originally listed in exclusion criteria, such as use of alternative thrombolytic agents, pre-treatment with antiplatelets, anticoagulants or low molecular weight heparins. In this narrative review, we summarize recent randomized and real-world data on the safety and efficacy of off-label use of IVT for AIS. We also make some practical recommendations to stroke physicians regarding the off-label use of thrombolytic agents in complex and uncommon presentations of AIS or other conditions mimicking acute cerebral ischemia. Finally, we provide guidance on the risks and benefits of IVT in numerous AIS subgroups, where equipoise exists and guidelines and treatment practices vary.
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http://dx.doi.org/10.1177/1756286421997368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934037PMC
February 2021

The impact of the DWI-FLAIR-mismatch in the ECASS-4 trial - A post hoc analysis.

Eur Stroke J 2020 Dec 23;5(4):370-373. Epub 2020 Apr 23.

Heidelberg University Hospital, Department of Neurology, Heidelberg, Germany.

Introduction: To investigate the impact of a mismatch between diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) on functional outcome in patients with acute stroke in a prolonged time window or unknown time of symptom onset randomized to intravenous thrombolysis or placebo.

Patients And Methods: We performed a post-hoc analysis of the European Cooperative Acute Stroke Study-4 (ECASS-4) trial. ECASS-4 was an investigator driven, phase 3, multi-center, double-blind, placebo-controlled study which randomized ischemic stroke patients presenting within 4.5 and 9h of stroke onset or unknown time-window to either rt-PA or placebo after MR-imaging. Two subgroups "no mismatch" (nMM) and "any mismatch" (aMM) were created by applying a DWI-FLAIR-mismatch criterion. We calculated frequency of nMM and aMM and performed a univariate analysis (Fisher's Test) for excellent clinical outcome (mRS 0-1) and mortality (mRS=6).

Results: MR-Imaging of n=111/119 (93.2%) patients was suitable for this analysis. DWI-FLAIR mismatch was found in 49 patients (44.1%). Proportions of mismatch nMM and aMM were comparable in treatment-groups (aMM: Placebo 46.3%, Alteplase 42.1%; p=0.70). Patients with nMM showed no benefit of rt-PA-treatment (OR (95%CI) mRS 0-1: 0.95 (0.29-3.17)). Patients with aMM showed a point estimate of the odds ratio in favour of a treatment benefit of rt-PA (mRS 0-1: OR (95%CI) 2.62 (0.68-11.1)). Mortality within 90 days was not different in patients treated with rt-PA if nMM (15.2%) or aMM (12.5%) was present.

Discussion: In this analysis no significant evidence, but subtle indication towards patients treated with rt-PA in a prolonged time window reaching an excellent clinical outcome if a DWI-FLAIR-mismatch is present on initial stroke MR-imaging.

Conclusion: A DWI-FLAIR mismatch in the region of ischemia as imaging based surrogate parameter for patient selection for i.v. rt-PA should be strongly pursued.
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http://dx.doi.org/10.1177/2396987320920114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856579PMC
December 2020

Detection of Atrial Fibrillation on Stroke Units: Comparison of Manual versus Automatic Analysis of Continuous Telemetry.

Cerebrovasc Dis 2020 18;49(6):647-655. Epub 2020 Nov 18.

Department of Neurology, Evangelisches Klinikum Bethel, EvKB, Bielefeld, Bielefeld, Germany.

Background: Detection of atrial fibrillation (AF) is one of the primary diagnostic goals for patients on a stroke unit. Physician-based manual analysis of continuous ECG monitoring is regarded as the gold standard for AF detection but requires considerable resources. Recently, automated computer-based analysis of RR intervals was established to simplify AF detection. The present prospective study analyzes both methods head to head regarding AF detection specificity, sensitivity, and overall effectiveness.

Methods: Consecutive stroke patients without history of AF or proof of AF in the admission ECG were enrolled over the period of 7 months. All patients received continuous ECG telemetry during the complete stay on the stroke unit. All ECGs underwent automated analysis by a commercially available program. Blinded to these results, all ECG tracings were also assessed manually. Sensitivity, specificity, time consumption, costs per day, and cost-effectiveness were compared.

Results: 216 consecutive patients were enrolled (70.7 ± 14.1 years, 56% male) and 555 analysis days compared. AF was detected by manual ECG analysis on 37 days (6.7%) and automatically on 57 days (10.3%). Specificity of the automated algorithm was 94.6% and sensitivity 78.4% (28 [5.0%] false positive and 8 [1.4%] false negative). Patients with AF were older and had more often arterial hypertension, higher NIHSS at admission, more often left atrial dilatation, and a higher CHA2DS2-VASc score. Automation significantly reduced human resources but was more expensive compared to manual analysis alone.

Conclusion: Automatic AF detection is highly specific, but sensitivity is relatively low. Results of this study suggest that automated computer-based AF detection should be rather complementary to manual ECG analysis than replacing it.
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http://dx.doi.org/10.1159/000511563DOI Listing
March 2021

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

Lancet 2020 11 8;396(10262):1574-1584. Epub 2020 Nov 8.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.

Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.

Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024).

Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734592PMC
November 2020

Maintaining stroke care in Europe during the COVID-19 pandemic: Results from an international survey of stroke professionals and practice recommendations from the European Stroke Organisation.

Eur Stroke J 2020 Sep 10;5(3):230-236. Epub 2020 Jun 10.

Stroke Unit, Department of Neurology, Oslo University Hospital, Oslo, Norway.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has been placing an overwhelming burden on health systems, thus threatening their ability to operate effectively for acute conditions in which treatments are highly time sensitive, such as cerebrovascular disorders and myocardial infarction. As part of an effort to reduce the consequences of this outbreak on health service delivery to stroke patients, the European Stroke Organisation has undertaken a survey aimed at collecting information on the provision of stroke care during the pandemic.

Methods: Cross-sectional, web-based survey, conducted from 26 March through 1 April 2020 among stroke care providers, focused on reorganisation of health services, the delivery of acute and post-acute stroke care and the availability of personal protective equipment.

Results: A total of 426 stroke care providers from 55 countries completed the survey, most of whom worked in Europe (n = 375, 88%) and were stroke physicians/neurologists (n = 334, 78%). Among European respondents, 289 (77%) reported that not all stroke patients were receiving the usual care in their centres and 266 (71%) estimated that functional outcomes and recurrence rates of stroke patients would be negatively affected by the organisational changes caused by the pandemic. The areas considered as being most affected were acute care and rehabilitation. Most professionals had to adapt their activities and schedules and more than half reported shortage of protective equipment.

Discussion: Strategies to maintain availability of stroke care during the COVID-19 outbreak are crucial to prevent indirect mortality and disability due to suboptimal care.

Conclusion: European Stroke Organisation proposes a set of targeted actions for decision makers facing this exceptional situation.
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http://dx.doi.org/10.1177/2396987320933746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538757PMC
September 2020

Case Report: Adult Still's Disease in an Alemtuzumab-Treated Multiple Sclerosis Patient.

Front Immunol 2020 28;11:2099. Epub 2020 Aug 28.

Department of Neurology and Neurogeriatrics, Johannes-Wesling-Hospital Minden, University Hospital Ruhr University of Bochum, Minden, Germany.

Background: Autoimmune adverse events are the most relevant risks of alemtuzumab therapy. We present a patient with relapsing-remitting multiple sclerosis, who developed adult-onset Still's disease (AOSD) following alemtuzumab treatment.

Case Presentation: The patient suffered from sore throat, swallowing difficulties, high spiking quotidian fever, generalized skin rash, arthritis, and myalgia 2 months after the second course of alemtuzumab. Laboratory tests revealed elevated acute-phase reactants, anemia, neutrophilic leukocytosis, and thrombocytosis. Serum calprotectin, interleukin-2, and interleukin-6 levels were strongly increased. Autoimmune, rheumatic, neoplastic, infectious, and granulomatous disorders were excluded. The NLRP1 and NLRP3 gene test, which was performed under the presumption of a cryopyrin-associated autoinflammatory syndrome, was negative. Based on the Yamaguchi and Fautrel criteria, and supported by the histological findings from a skin biopsy of the rash, the diagnosis of AOSD was established. Therapy with the anti-IL-1 agent (anakinra) led to a significant improvement of symptoms and blood parameters. However, anakinra had to be converted to rituximab due to generalized drug eruption. Following therapy with rituximab, the patient has fully recovered.

Conclusion: The current case highlights AOSD as another rare and potentially life-threatening secondary autoinflammatory/autoimmune event following alemtuzumab treatment.
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http://dx.doi.org/10.3389/fimmu.2020.02099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493652PMC
April 2021

Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.

J Hypertens 2021 Feb;39(2):266-272

Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Objective: To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA).

Methods: We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER.

Results: The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53).

Conclusion: BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.
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http://dx.doi.org/10.1097/HJH.0000000000002628DOI Listing
February 2021

Recurrent and Drastic Increase in Dabigatran Levels May Be Induced by Therapeutic Plasma Exchange.

J Stroke 2020 May 31;22(2):266-267. Epub 2020 May 31.

Department of Neurology and Neurogeriatrics, Johannes Wesling Medical Center Minden, University Clinic RUB, Minden, Germany.

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http://dx.doi.org/10.5853/jos.2019.03601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341013PMC
May 2020

Neurological manifestations and implications of COVID-19 pandemic.

Ther Adv Neurol Disord 2020 9;13:1756286420932036. Epub 2020 Jun 9.

4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China and rapidly spread worldwide, with a vast majority of confirmed cases presenting with respiratory symptoms. Potential neurological manifestations and their pathophysiological mechanisms have not been thoroughly established. In this narrative review, we sought to present the neurological manifestations associated with coronavirus disease 2019 (COVID-19). Case reports, case series, editorials, reviews, case-control and cohort studies were evaluated, and relevant information was abstracted. Various reports of neurological manifestations of previous coronavirus epidemics provide a roadmap regarding potential neurological complications of COVID-19, due to many shared characteristics between these viruses and SARS-CoV-2. Studies from the current pandemic are accumulating and report COVID-19 patients presenting with dizziness, headache, myalgias, hypogeusia and hyposmia, but also with more serious manifestations including polyneuropathy, myositis, cerebrovascular diseases, encephalitis and encephalopathy. However, discrimination between causal relationship and incidental comorbidity is often difficult. Severe COVID-19 shares common risk factors with cerebrovascular diseases, and it is currently unclear whether the infection represents an independent stroke risk factor. Regardless of any direct or indirect neurological manifestations, the COVID-19 pandemic has a huge impact on the management of neurological patients, whether infected or not. In particular, the majority of stroke services worldwide have been negatively influenced in terms of care delivery and fear to access healthcare services. The effect on healthcare quality in the field of other neurological diseases is additionally evaluated.
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http://dx.doi.org/10.1177/1756286420932036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284455PMC
June 2020

Cross-sectional area in median and ulnar nerve ultrasound correlates with hand volume.

Muscle Nerve 2020 07 27;62(1):83-88. Epub 2020 Apr 27.

Department of Neurology and Neurogeriatrics, Ruhr-University Bochum, Johannes-Wesling-Klinikum Minden, UK RUB, Minden, Germany.

Background: The influence of demographic and anthropometric factors on nerve cross-sectional area (CSA) reference values in high-resolution ultrasound was evaluated in a prospective observational study.

Methods: We measured CSA of median, ulnar, radial, and sural nerves in 80 healthy adults from 18 to 98 years of age. Pearson's correlation and multiple linear regression with age, gender, body mass index, and hand volume were calculated.

Results: Ulnar and median nerve CSA showed a significant positive correlation with ipsilateral hand volume. Median nerve CSA in the left forearm (mean, 6.2 mm ; SD, 1.2) increased by 0.006 mm (SE = 0.002; P < .001) per cm of hand volume, resulting in a difference of 1.9 mm predictable by hand volume (mean, 326 cm ; SD, 81; range, 180-500).

Conclusions: The observed correlation of CSA and hand volume may influence the interpretation of CSA values in patients with very large or small hands.
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http://dx.doi.org/10.1002/mus.26881DOI Listing
July 2020

Embolic Stroke of Undetermined Source: Gateway to a New Stroke Entity?

Am J Med 2020 07 2;133(7):795-801. Epub 2020 Apr 2.

Department of Neurology, Harvard Medical School, Boston, Mass.

Embolic stroke of unknown source (ESUS) is currently thought to represent a subpopulation of cryptogenic strokes defined by its embolic stroke pattern on imaging, and if after a carefully performed diagnostic evaluation, a specific, well-recognized cause of stroke has not been identified. The concept was primarily established to justify and enable the conduct of the ESUS trials, such as Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RESPECT-ESUS) and New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS). With both studies having neutral results, the question arises if the ESUS concept is misleading or rather a gateway for a modern understanding of stroke etiology. This review will analyze the background of the ESUS concept, overview the results and the impact of the recent multicenter trials and cohort studies, and discuss the definition, etiology, and diagnosis of ESUS.
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http://dx.doi.org/10.1016/j.amjmed.2020.03.005DOI Listing
July 2020

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

Int J Stroke 2020 Aug 19;15(6):609-618. Epub 2020 Jan 19.

Department of Neurology, University Hospital, Essen, Germany.

Background: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth.

Aims: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage.

Methods: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used.

Results: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in  = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay.

Conclusion: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.
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http://dx.doi.org/10.1177/1747493019895654DOI Listing
August 2020

Thrombolysis for acute ischemic stroke in the unwitnessed or extended therapeutic time window.

Neurology 2020 03 31;94(12):e1241-e1248. Epub 2019 Dec 31.

From the Second Department of Neurology (G.T., A.H.K.), "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Greece; Department of Neurology (G.T., A.V.A.), University of Tennessee Health Science Center, Memphis; Department of Neurology (A.H.K., C.K.), St. Josef Hospital, Ruhr University Bochum, Germany; Department of Neurology (K.M.), Allegheny Health Network, Pittsburgh, Pennsylvania; Department of Neurology (A.S., A.D.B.), University of Texas Health Science Center, Houston; Department of Neurology (M.K.), Universitaetsklinikum Essen, Germany; Department of Neurology (N.A.), Karolinska University Hospital; Department of Clinical Neuroscience (N.A.), Karolinska Institute, Stockholm, Sweden; Stroke Unit and Division of Cardiovascular Medicine (V.C.), University of Perugia, Italy; and Departments of Neurology and Neurogeriatry (P.D.S.), Johannes Wesling Medical Center, Ruhr University Bochum, Minden, Germany.

Objective: To assess the utility of IV thrombolysis (IVT) treatment in patients with acute ischemic stroke (AIS) with unclear symptom onset time or outside the 4.5-hour time window selected by advanced neuroimaging.

Methods: We performed random-effects meta-analyses on the unadjusted and adjusted for potential confounders associations of IVT (alteplase 0.9 mg/kg) with the following outcomes: 3-month favorable functional outcome (FFO; modified Rankin Scale [mRS] scores 0-1), 3-month functional independence (FI; mRS scores 0-2), 3-month mortality, 3-month functional improvement (assessed with ordinal analysis on the mRS scores), symptomatic intracranial hemorrhage (sICH), and complete recanalization (CR).

Results: We identified 4 eligible randomized clinical trials (859 total patients). In unadjusted analyses, IVT was associated with a higher likelihood of 3-month FFO (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.12-1.96), FI (OR 1.42, 95% CI 1.07-1.90), sICH (OR 5.28, 95% CI 1.35-20.68), and CR (OR 3.29, 95% CI 1.90-5.69), with no significant difference in the odds of all-cause mortality risk at 3 months (OR 1.75, 95% CI 0.93-3.29). In the adjusted analyses, IVT was also associated with higher odds of 3-month FFO (adjusted OR [OR] 1.62, 95% CI 1.20-2.20), functional improvement (OR 1.42, 95% CI 1.11-1.81), and sICH (OR 6.22, 95% CI 1.37-28.26). There was no association between IVT and FI (OR 1.61, 95% CI 0.94-2.75) or all-cause mortality (OR 1.75, 95% CI 0.93-3.29) at 3 months. No evidence of heterogeneity was evident in any of the analyses ( = 0).

Conclusion: IVT in patients with AIS with unknown symptom onset time or elapsed time from symptom onset >4.5 hours selected with advanced neuroimaging results in a higher likelihood of CR and functional improvement at 3 months despite the increased risk of sICH.
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http://dx.doi.org/10.1212/WNL.0000000000008904DOI Listing
March 2020

Mortality Risk in Acute Ischemic Stroke Patients With Large Vessel Occlusion Treated With Mechanical Thrombectomy.

J Am Heart Assoc 2019 11 28;8(21):e014425. Epub 2019 Oct 28.

Second Department of Neurology "Attikon" Hospital School of Medicine National and Kapodistrian University of Athens Greece.

Background Recent randomized controlled clinical trials have provided solid evidence that mechanical thrombectomy (MT) coupled with best medical therapy (BMT) improve functional outcomes of acute ischemic stroke patients with large vessel occlusion compared with BMT alone. However, they provided inconclusive evidence on the benefit of MT on mortality. Methods and Results We evaluated the association of MT+BMT compared with BMT with the risk of 3-month mortality using aggregate data from all available randomized controlled clinical trials. We also sought to identify potential predictors on the mortality risk and performed univariate meta-regression analyses. Our literature search identified 11 eligible randomized controlled clinical trials, including a total of 2460 patients. The pooled rates of 3-month mortality were 15% (95% CI:12%-19%) and 19% (95% CI:16%-23%), respectively, in the MT+BMT and BMT groups. In the overall analysis MT+BMT was associated with a significantly lower risk for 3-month mortality compared with BMT (risk ratio=0.83, 95% CI:0.69-0.99; =0.04), without heterogeneity across included studies (I=3%, for Cochran Q=0.41). No evidence of publication bias was present in funnel plot inspection and Egger statistical test (=0.762). In meta-regression analyses no moderating effect on the aforementioned association was detected with patient age (=0.254), sex (=0.702), admission systolic blood pressure (=0.601), admission glucose (=0.277), onset-to-groin puncture time (=0.985), administration of intravenous alteplase before MT (=0.804), MT under general anesthesia (=0.735), and successful reperfusion following MT (=0.663). Conclusions Our meta-analysis provides evidence that MT+BMT reduces the risk of 3-month mortality compared with BMT alone. This association appears not to be moderated by individual patient or procedural characteristics.
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http://dx.doi.org/10.1161/JAHA.119.014425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898819PMC
November 2019

Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage.

JAMA 2019 10;322(14):1392-1403

Department of Neurology, University of Cologne, Cologne, Germany.

Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established.

Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH.

Design, Setting, And Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015).

Exposure: Surgical hematoma evacuation vs conservative treatment.

Main Outcomes And Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH.

Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02).

Conclusions And Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.
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http://dx.doi.org/10.1001/jama.2019.13014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784768PMC
October 2019

Duration of Implantable Cardiac Monitoring and Detection of Atrial Fibrillation in Ischemic Stroke Patients: A Systematic Review and Meta-Analysis.

J Stroke 2019 Sep 30;21(3):302-311. Epub 2019 Sep 30.

Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.

Background And Purpose: Current guidelines do not provide firm directions on atrial fibrillation (AF) screening after ischemic stroke (IS). We sought to investigate the association of implantable cardiac monitoring (ICM) duration with the yield of AF detection in IS patients.

Methods: We included studies reporting AF detection rates by ICM in IS patients with negative initial AF screening. We excluded studies reporting prolonged cardiac monitoring with devices other than ICM, not providing AF detection rates or monitoring duration, and reporting overlapping data for the same population. The random-effects model was used for all pooled estimates and meta-regression analyses.

Results: We included 28 studies (4,531 patients, mean age 65 years). In meta-regression analyses, the proportion of AF detection by ICM was independently associated with monitoring duration (coefficient=0.015; 95% confidence interval [CI], 0.005 to 0.024) and mean patient age (coefficient=0.009; 95% CI, 0.003 to 0.015). No associations were detected with other patient characteristics, including IS subtype (cryptogenic vs. embolic stroke of undetermined source) or time from IS onset to CM implantation. In subgroup analyses, significant differences (P<0.001) in the AF detection rates were found for ICM duration (<6 months: 5% [95% CI, 3% to 6%]; ≥6 and ≤12 months: 21% [95% CI, 16% to 25%]; >12 and ≤24 months: 26% [95% CI, 22% to 31%]; >24 months: 34% [95% CI, 29% to 39%]).

Conclusion: s Extended duration of ICM monitoring and increased patient age are factors that substantially increase AF detection in IS patients with initial negative AF screening.
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http://dx.doi.org/10.5853/jos.2019.01067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780018PMC
September 2019

Medical Management vs Mechanical Thrombectomy for Mild Strokes: An International Multicenter Study and Systematic Review and Meta-analysis.

JAMA Neurol 2020 01;77(1):16-24

Department of Neurosurgery, Mount Sinai Medical Center, New York, New York.

Importance: The benefit of mechanical thrombectomy (MT) in patients with stroke presenting with mild deficits (National Institutes of Health Stroke Scale [NIHSS] score <6) owing to emergency large-vessel occlusion (ELVO) remains uncertain.

Objective: To assess the outcomes of patients with mild-deficits ELVO (mELVO) treated with MT vs best medical management (bMM).

Data Sources: We retrospectively pooled patients with mELVO during a 5-year period from 16 centers. A meta-analysis of studies reporting efficacy and safety outcomes with MT or bMM among patients with mELVO was also conducted. Data were analyzed between 2013 and 2017.

Study Selection: We identified studies that enrolled patients with stroke (within 24 hours of symptom onset) with mELVO treated with MT or bMM.

Main Outcomes And Measures: Efficacy outcomes included 3-month favorable functional outcome and 3-month functional independence that were defined as modified Rankin Scale scores of 0 to 1 and 0 to 2, respectively. Safety outcomes included 3-month mortality and symptomatic and asymptomatic intracranial hemorrhage (ICH).

Results: We evaluated a total of 251 patients with mELVO who were treated with MT (n = 138; 65 women; mean age, 65.2 years; median NIHSS score, 4; interquartile range [IQR], 3-5) or bMM (n = 113; 51 women; mean age, 64.8; median NIHSS score, 3; interquartile range [IQR], 2-4). The rate of asymptomatic ICH was lower in bMM (4.6% vs 17.5%; P = .002), while the rate of 3-month FI (after imputation of missing follow-up evaluations) was lower in MT (77.4% vs 88.5%; P = .02). The 2 groups did not differ in any other efficacy or safety outcomes. In multivariable analyses, MT was associated with higher odds of asymptomatic ICH (odds ratio [OR], 11.07; 95% CI, 1.31-93.53; P = .03). In the meta-analysis of 4 studies (843 patients), MT was associated with higher odds of symptomatic ICH in unadjusted analyses (OR, 5.52; 95% CI, 1.91-15.49; P = .002; I2 = 0%). This association did not retain its significance in adjusted analyses including 2 studies (OR, 2.06; 95% CI, 0.49-8.63; P = .32; I2 = 0%). The meta-analysis did not document any other independent associations between treatment groups and safety or efficacy outcomes.

Conclusions And Relevance: Our multicenter study coupled with the meta-analysis suggests similar outcomes of MT and bMM in patients with stroke with mELVO, but no conclusions about treatment effect can be made. The clinical equipoise can further be resolved by a randomized clinical trial.
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http://dx.doi.org/10.1001/jamaneurol.2019.3112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763987PMC
January 2020

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke.

Ther Adv Neurol Disord 2019 12;12:1756286419860652. Epub 2019 Jul 12.

Departments of Neurology and Neurogeriatry, John Wesling Medical Center Minden, Ruhr University Bochum, Minden, Germany.

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers.

Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials.

Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06-0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89-1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0-2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01-2.31; p = 0.04).

Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.
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http://dx.doi.org/10.1177/1756286419860652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628520PMC
July 2019

Intravenous thrombolysis prior to mechanical thrombectomy in large vessel occlusions.

Ann Neurol 2019 09 22;86(3):395-406. Epub 2019 Jul 22.

Second Department of Neurology, Attikon Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Objective: The substantial clinical improvement in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT), combined with the poor response of proximal intracranial occlusions to intravenous thrombolysis (IVT), led to questions regarding the utility of bridging therapy (BT; IVT followed by MT) compared to direct mechanical thrombectomy (dMT) for AIS patients with large vessel occlusion (LVO).

Methods: We aimed to investigate the comparative safety and efficacy of BT and dMT in AIS patients. We included all observational studies and post hoc analyses from randomized controlled clinical trials that provided data on the outcomes of AIS patients with LVO stratified by IVT treatment status prior to MT.

Results: We identified 38 eligible observational studies (11,798 LVO patients, mean age = 68 years, 56% treated with BT). In unadjusted analyses, BT was associated with a higher likelihood of 3-month functional independence (odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.32-1.76), 3-month functional improvement (common OR [cOR] for 1-point decrease in modified Rankin Scale score = 1.52, 95% CI = 1.18-1.97), early neurological improvement (OR = 1.21, 95% CI = 1.83-1.76), successful recanalization (OR = 1.22, 95% CI = 1.02-1.46), and successful recanalization with ≤2 device passes (OR = 2.28, 95% CI = 1.43-3.64) compared to dMT. BT was also related to a lower likelihood of 3-month mortality (OR = 0.64, 95% CI = 0.57-0.73). In the adjusted analyses, BT was independently associated with a higher likelihood of 3-month functional independence (adjusted OR = 1.55, 95% CI = 1.26-1.91) and lower odds of 3-month mortality (adjusted OR = 0.80, 95% CI = 0.66-0.97) compared to dMT. The two groups did not differ in functional improvement (adjusted cOR = 1.24, 95% CI = 0.89-1.74) or symptomatic intracranial hemorrhage (adjusted OR = 0.87, 95% CI = 0.61-1.25).

Interpretation: BT appears to be associated with improved functional independence without evidence for safety concerns, compared to dMT, for AIS patients with LVO. ANN NEUROL 2019;86:395-406.
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http://dx.doi.org/10.1002/ana.25544DOI Listing
September 2019

Prolonged Cardiac Rhythm Monitoring and Secondary Stroke Prevention in Patients With Cryptogenic Cerebral Ischemia.

Stroke 2019 08 20;50(8):2175-2180. Epub 2019 Jun 20.

Department of Neurology, Alpert Medical School, Brown University, Providence, RI (B.M.G., B.A.R., S.C., K.F., S.Y.).

Background and Purpose- Although prolonged cardiac rhythm monitoring (PCM) can reveal a substantial proportion of ischemic stroke (IS) patients with atrial fibrillation not detected by conventional short-term monitoring, current guidelines indicate an uncertain clinical benefit for PCM. We evaluated the impact of PCM on secondary stroke prevention using data from available to date randomized clinical trials and observational studies. Methods- We performed a comprehensive literature search in MEDLINE, SCOPUS, CENTRAL (Cochrane Central Register of Controlled Trial), and conference proceedings to identify studies reporting stroke recurrence rates in patients with history of cryptogenic IS or transient ischemic attack (TIA) receiving PCM compared with patients receiving conventional (non-PCM) cardiac monitoring. Results- We included 4 studies (2 randomized clinical trials and 2 observational studies), including a total of 1102 patients (mean age: 68 years, 41% women). We documented an increased incidence of atrial fibrillation detection (risk ratio=2.46; 95% CI, 1.61-3.76) and anticoagulant initiation (risk ratio=2.07; 95% CI, 1.36-3.17) and decreased risk of recurrent stroke (risk ratio=0.45; 95% CI, 0.21-0.97) and recurrent stroke/TIA (risk ratio=0.49; 95% CI, 0.30-0.81) during follow-up for IS/TIA patients who underwent PCM compared with IS/TIA patients receiving conventional cardiac monitoring. In the subgroup analysis, according to study type, atrial fibrillation detection, anticoagulant initiation, and IS/TIA recurrence rates were comparable between PCM and non-PCM in randomized clinical trials and observational studies. No evidence of heterogeneity (I<12%) was documented across all the aforementioned subgroups. Conclusions- We provide preliminary evidence for a potential impact of PCM on secondary stroke prevention, as patients with cryptogenic IS/TIA undergoing PCM had higher rates of atrial fibrillation detection, anticoagulant initiation, and lower stroke recurrence.
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http://dx.doi.org/10.1161/STROKEAHA.119.025169DOI Listing
August 2019

Embolic strokes of undetermined source: theoretical construct or useful clinical tool?

Ther Adv Neurol Disord 2019 24;12:1756286419851381. Epub 2019 May 24.

Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, Gudrunstr.56, Bochum, 44791, Germany.

In 2014, the definition of embolic strokes of undetermined source (ESUS) emerged as a new clinical construct to characterize cryptogenic stroke (CS) patients with complete vascular workup to determine nonlacunar, nonatherosclerotic strokes of presumable embolic origin. NAVIGATE ESUS, the first phase III randomized-controlled, clinical trial (RCT) comparing rivaroxaban (15 mg daily) with aspirin (100 mg daily), was prematurely terminated for lack of efficacy after enrollment of 7213 patients. Except for the lack of efficacy in the primary outcome, rivaroxaban was associated with increased risk of major bleeding and hemorrhagic stroke compared with aspirin. RE-SPECT ESUS was the second phase III RCT that compared the efficacy and safety of dabigatran (110 or 150 mg, twice daily) to aspirin (100 mg daily). The results of this trial have been recently presented and showed similar efficacy and safety outcomes between dabigatran and aspirin. Indirect analyses of these trials suggest similar efficacy on the risk of ischemic stroke (IS) prevention, but higher intracranial hemorrhage risk in ESUS patients receiving rivaroxaban compared to those receiving dabigatran (indirect HR = 6.63, 95% CI: 1.38-31.76). ESUS constitute a heterogeneous group of patients with embolic cerebral infarction. Occult AF represents the underlying mechanism of cerebral ischemia in the minority of ESUS patients. Other embolic mechanisms (paradoxical embolism via patent foramen ovale, aortic plaque, nonstenosing unstable carotid plaque, etc.) may represent alternative mechanisms of cerebral embolism in ESUS, and may mandate different management than oral anticoagulation. The potential clinical utility of ESUS may be challenged since the concept failed to identify patients who would benefit from anticoagulation therapy. Compared with the former diagnosis of CS, ESUS patients required thorough investigations; more comprehensive diagnostic work-up than is requested in current ESUS diagnostic criteria may assist clinicians in uncovering the source of brain embolism in CS patients and individualize treatment approaches.
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http://dx.doi.org/10.1177/1756286419851381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535711PMC
May 2019

European Stroke Organisation (ESO) - European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischaemic StrokeEndorsed by Stroke Alliance for Europe (SAFE).

Eur Stroke J 2019 Mar 26;4(1):6-12. Epub 2019 Feb 26.

Klinik und Poliklinik für Neuroradiologische Diagnostik und Intervention, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background: Mechanical thrombectomy (MT) has become the cornerstone of acute ischaemic stroke management in patients with large vessel occlusion (LVO). The aim of this guideline document is to assist physicians in their clinical decisions with regard to MT.

Methods: These Guidelines were developed based on the standard operating procedure of the European Stroke Organisation and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. An interdisciplinary working group identified 15 relevant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote evidence based recommendations. Expert opinion was provided if not enough evidence was available to provide recommendations based on the GRADE approach.

Results: We found high quality evidence to recommend MT plus best medical management (BMM, including intravenous thrombolysis whenever indicated) to improve functional outcome in patients with LVO-related acute ischaemic stroke within 6 hours after symptom onset. We found moderate quality of evidence to recommend MT plus BMM in the 6-24h time window in patients meeting the eligibility criteria of published randomized trials. These guidelines further detail aspects of prehospital management, patient selection based on clinical and imaging characteristics, and treatment modalities.

Conclusions: MT is the standard of care in patients with LVO-related acute stroke. Appropriate patient selection and timely reperfusion are crucial. Further randomized trials are needed to inform clinical decision making with regard to the mothership and drip-and-ship approaches, anesthaesia modalities during MT, and to determine whether MT is beneficial in patients with low stroke severity or large infarct volume.
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http://dx.doi.org/10.1177/2396987319832140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533858PMC
March 2019

European Stroke Organisation (ESO)- European Society for Minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischemic stroke.

J Neurointerv Surg 2019 Jun;11(6):535-538

Klinik und Poliklinik für Neuroradiologische Diagnostik und Intervention, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background: Mechanical thrombectomy (MT) has become the cornerstone of acute ischemic stroke management in patients with large vessel occlusion (LVO). The aim of this guideline document is to assist physicians in their clinical decisions with regard to MT.

Methods: These guidelines were developed based on the standard operating procedure of the European Stroke Organisation, and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. An interdisciplinary working group identified 15 relevant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote evidence based recommendations. Expert opinion was provided if not enough evidence was available to provide recommendations based on the GRADE approach.

Results: We found high quality evidence to recommend MT plus best medical management (BMM, including intravenous thrombolysis whenever indicated) to improve functional outcome in patients with LVO related acute ischemic stroke within 6 hours after symptom onset. We found moderate quality of evidence to recommend MT plus BMM in the 6-24 hour time window in patients meeting the eligibility criteria of published randomized trials. These guidelines further detail aspects of prehospital management, patient selection based on clinical and imaging characteristics, and treatment modalities.

Conclusions: MT is the standard of care in patients with LVO related acute stroke. Appropriate patient selection and timely reperfusion are crucial. Further randomized trials are needed to inform clinical decision making with regard to the mothership and drip-and-ship approaches, anesthaesia modalities during MT, and to determine whether MT is beneficial in patients with low stroke severity or large infarct volume.
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http://dx.doi.org/10.1136/neurintsurg-2018-014568DOI Listing
June 2019

Extending thrombolysis to 4·5-9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data.

Lancet 2019 07 22;394(10193):139-147. Epub 2019 May 22.

Department of Neurology, Sapienza University of Roma, Rome, Italy.

Background: Stroke thrombolysis with alteplase is currently recommended 0-4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.

Methods: In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036.

Findings: We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96, p=0·66).

Interpretation: Patients with ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(19)31053-0DOI Listing
July 2019

Characteristics in Non-Vitamin K Antagonist Oral Anticoagulant-Related Intracerebral Hemorrhage.

Stroke 2019 06 16;50(6):1392-1402. Epub 2019 May 16.

Department of Neurology, University of Münster, Germany (A.L.F., J.M.).

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.
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http://dx.doi.org/10.1161/STROKEAHA.118.023492DOI Listing
June 2019

Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source.

N Engl J Med 2019 05;380(20):1906-1917

From the University Duisburg-Essen and University Hospital Essen, Essen (H.-C.D.), Boehringer Ingelheim Pharma GmbH K.G., Biberach (C.G.), Boehringer Ingelheim International GmbH, Ingelheim, Faculty of Medicine Mannheim of the University of Heidelberg, Mannheim (M.B.), Kreisklinikum Siegen, Siegen, and the University of Marburg, Marburg (M.G.), University Hospital Erlangen, Erlangen (B.K.), and Johannes Wesling Klinikum Minden and Ruhr University Bochum, Minden (P.D.S.) - all in Germany; Miller School of Medicine, University of Miami, Miami (R.L.S.); University of California at San Francisco, San Francisco (J.D.E.), and the Department of Neurology and Comprehensive Stroke Center, University of California at Los Angeles, Los Angeles (J.L.S.) - both in California; Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (C.B.G.); Feinberg School of Medicine of Northwestern University, Chicago (R.A.B.); International University of Health and Welfare, Center for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Center, Tokyo (S.U.), and the National Cerebral and Cardiovascular Center, Osaka (K.T.) - both in Japan; Boehringer Ingelheim, Singapore, Singapore (J. Kreuzer); Boehringer Ingelheim, Burlington, ON, Canada (L.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.C.); City Clinical Emergency Care Hospital, Kursk (M.C.), and the Military Medical Academy, St. Petersburg (M.O.) - both in Russia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia (G.D.); Serviço de Neurologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal (J.M.F.); F. Ass. Mutua Terrassa, Terrassa (J. Krupinski), and Servicio de Neurología, Hospital Universitario Ramón y Cajal (IRYCIS), Departamento de Medicina, Universidad de Alcalá, Madrid (J.M.) - both in Spain; Hallym University Sacred Heart Hospital, Seoul, South Korea (B.-C.L.); KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology, VIB Center for Brain & Disease Research, University Hospitals Leuven, Department of Neurology, Leuven, Belgium (R.L.); and Hospital Policlinico Umberto I, Sapienza University, Rome (D.T.).

Background: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear.

Methods: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding.

Results: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively.

Conclusions: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).
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http://dx.doi.org/10.1056/NEJMoa1813959DOI Listing
May 2019

Intravenous thrombolysis in patients with acute ischaemic stroke with history of prior ischaemic stroke within 3 months.

J Neurol Neurosurg Psychiatry 2019 12 17;90(12):1383-1385. Epub 2019 Apr 17.

Neurology, Institute for Stroke and Cerebrovascular Disease, The University of Texas Health Science Center, Houston, Texas, USA.

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http://dx.doi.org/10.1136/jnnp-2019-320422DOI Listing
December 2019

Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage.

J Neurol Neurosurg Psychiatry 2019 07 16;90(7):783-791. Epub 2019 Apr 16.

Neurology, University of Münster, Münster, Germany.

Objective: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH.

Methods: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC.

Results: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC.

Conclusions: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.
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http://dx.doi.org/10.1136/jnnp-2018-319786DOI Listing
July 2019

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial.

Lancet Neurol 2019 04;18(4):338-347

Departments of Neurology and Neurogeriatry, John Wesling Medical Center Minden, Ruhr University Bochum, Minden, Germany.

Background: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke.

Methods: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility.

Findings: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53).

Interpretation: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care.

Funding: Cerevast Therapeutics.
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http://dx.doi.org/10.1016/S1474-4422(19)30026-2DOI Listing
April 2019

European Stroke Organisation (ESO) - European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischemic Stroke.

J Neurointerv Surg 2019 Feb 26. Epub 2019 Feb 26.

Klinik und Poliklinik für Neuroradiologische Diagnostik und Intervention, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background: Mechanical thrombectomy (MT) has become the cornerstone of acute ischemic stroke management in patients with large vessel occlusion (LVO).

Objective: To assist physicians in their clinical decisions with regard toMT.

Methods: These guidelines were developed based on the standard operating procedure of the European Stroke Organisation and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. An interdisciplinary working group identified 15 relevant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert opinion was provided if not enough evidence was available to provide recommendations based on the GRADE approach.

Results: We found high-quality evidence to recommend MT plus best medical management (BMM, including intravenous thrombolysis whenever indicated) to improve functional outcome in patients with LVO-related acute ischemic stroke within 6 hours after symptom onset. We found moderate quality of evidence to recommend MT plus BMM in the 6-24h time window in patients meeting the eligibility criteria of published randomized trials. These guidelinesdetails aspects of prehospital management, patient selection based on clinical and imaging characteristics, and treatment modalities.

Conclusions: MT is the standard of care in patients with LVO-related acute stroke. Appropriate patient selection and timely reperfusion are crucial. Further randomized trials are needed to inform clinical decision-making with regard tothe mothership and drip-and-ship approaches, anesthaesia modalities during MT, and to determine whether MT is beneficial in patients with low stroke severity or large infarct volume.
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http://dx.doi.org/10.1136/neurintsurg-2018-014569DOI Listing
February 2019