Evidence map›Paper›PMID 33176180›Full record

SynthesisLancet (London, England)2020

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

Götz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell and 36 more

4 registry-linked trialsOpen access · bronzeAbstract readMeta-AnalysisSystematic Review
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Lancet (London, England), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 4 registered trials, which are not on this map. Cited by 92 papers, 12 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
92citing papers in PubMed, 12 pooled it
15.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT05983757 narecruitingnot on this mapstarted 2024, after this paper: background citation

A Phase III, Randomized, Multicenter, Investigational, Open Label Clinical Trial That Will Examine Whether Treatment With Endovascular Thrombectomy is Superior to Standard Medical Therapy Alone in Patients Who Suffer a Distal Medium Vessel Occlusion Ischemic Strokes.

TypeinterventionalSponsorRaul NogueiraRan2024 to 2027Enrolled584ConditionsIschemic StrokeArmsExperimental: endovascular thrombectomy in patients who suffer a distal medium vessel occlusion, Standard medical management
NCT06121336 recruitingnot on this mapstarted 2023, after this paper: background citation

PRecisiOn Medicine In StrokE Study on the Evolution of Plasma Brain-Derived Tau in 100 Patients With Acute Ischemic Stroke

TypeobservationalSponsorLudwig-Maximilians - University of MunichRan2023 to 2027Enrolled100ConditionsStroke, Stroke, Acute, Stroke, Ischemic, Cerebrovascular DisordersArmsPlasma levels of BD-tau
NCT07553650 not yet recruitingnot on this mapstarted 2026, after this paper: background citation

Master Study Protocol for the Cohort of the Specialist Network Stroke (SN Stroke) (Stroke-CORE)

Typeobservational_patient_registrySponsorCharite University, Berlin, GermanyRan2026 to 2030Enrolled12,750ConditionsIntracerebral Haemorrhage, Paediatric Stroke, Stroke Acute, Stroke
NCT07740018 narecruitingnot on this mapstarted 2026, after this paper: background citation

Factors Affecting Clinical and Radiological Outcome in Endovascular Management of Acute Ischemic Stroke Due to Large Vessel Occlusion

TypeinterventionalSponsorSohag UniversityRan2026 to 2028Enrolled40ConditionsEndovascular ThrombectomyArmsendovascular thrombectomy
3 · Its place in the literature

Who cites it

92 citing papers in PubMed, 12 syntheses or guidelines pooled it, 175 citations in OpenAlex.

  1. Pooled it
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  4. Guideline
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  6. Early antiplatelet therapy after intravenous thrombolysis for acute ischemic stroke: a systematic review and meta-analysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025
    Pooled it
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  12. Efficacy and Safety of Intravenous Thrombolytics in Ischemic Stroke Beyond the 4.5-Hour Time Window: A Systematic Review and Meta-Analysis.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
    Pooled it
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  20. [Risk of stroke during left atrial catheter ablation for atrial fibrillation].Herzschrittmachertherapie & Elektrophysiologie · 2026
    Review

32 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

46 authors at 20 institutions in 12 countries.

Götz ThomallaKlinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. Electronic address: thomalla@uke.de.
Florent BoutitieHospices Civils de Lyon, Service de Biostatistique, Lyon, France; Université Lyon 1, Villeurbanne, France; Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France.
Henry MaDepartment of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.
Masatoshi KogaDepartment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
Peter RinglebDepartment of Neurology, University of Heidelberg, Heidelberg, Germany.
Lee H SchwammDepartment of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Ona WuAthinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
Martin BendszusDepartment of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
Christopher F BladinDepartment of Neurosciences, Eastern Health and Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia.
Bruce C V CampbellDepartments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.
Bastian ChengKlinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Leonid ChurilovDepartments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.
Martin EbingerCentrum für Schlaganfallforschung Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Klinik für Neurologie Medical Park Berlin Humboldtmühle, Berlin, Germany.
Matthias EndresCentrum für Schlaganfallforschung Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany; German Centre of Cardiovascular Research, Berlin, Germany; German Center of Neurodegenerative Diseases, Berlin, Germany.
Jochen B FiebachCentrum für Schlaganfallforschung Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Mayumi Fukuda-DoiDepartment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan.
Manabu InoueDepartment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
Timothy J KleinigDepartment of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia.
Lawrence L LatourAcute Cerebrovascular Diagnostics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Robin LemmensDepartment of Neurosciences, Experimental Neurology, KU Leuven, University of Leuven, Leuven, Belgium; VIB Center for Brain and Disease Research Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
Christopher R LeviThe Department of Neurology, Priority Research Centre for Brain and Mental Health Research, John Hunter Hospital, University of Newcastle, Newcastle, NSW, Australia.
Didier LeysUniversité de Lille, Inserm U1171, Lille, France.
Kaori MiwaDepartment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
Carlos A MolinaStroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Keith W MuirInstitute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
Norbert NighoghossianDepartment of Stroke Medicine, Université Claude Bernard Lyon 1, CarMeN Laboratory, INSERM U1060/INRA 1397, Lyon, France.
Mark W ParsonsDepartments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.
Salvador PedrazaDepartment of Radiology, Institut de Diagnòstic per la Imatge, Hospital Dr Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona, Spain.
Peter D SchellingerUniversitätsklinik für Neurologie, Mühlenkreiskliniken, Johannes Wesling Klinikum Minden, Universitätsklinikum der Ruhr-Universität Bochum, Minden, Germany.
Stefan SchwabDepartment of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.
Claus Z SimonsenDepartment of Neurology, Aarhus University Hospital, Aarhus, Denmark.
Shlee S SongDepartment of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Vincent ThijsFlorey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia; Department of Neurology, Austin Health, Heidelberg, VIC, Australia.
Danilo ToniDepartment of Human Neurosciences, University of Rome "La Sapienza", Rome, Italy.
Chung Y HsuGraduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Nils WahlgrenDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Haruko YamamotoCenter for Advancing Clinical and Translational Sciences, National Cerebral and Cardiovascular Center, Suita, Japan.
Nawaf YassiDepartments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Sohei YoshimuraDepartment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
Steven WarachDell Medical School, University of Texas at Austin, Austin, TX, USA.
Werner HackeDepartment of Neurology, University of Heidelberg, Heidelberg, Germany.
Kazunori ToyodaDepartment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
Geoffrey A DonnanDepartments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.
Stephen M DavisDepartments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.
Christian GerloffKlinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators
Universität Hamburg · DECedars-Sinai Medical Center · USNational Cerebral and Cardiovascular Center · JPThe Royal Melbourne Hospital · AUFlorey Institute of Neuroscience and Mental Health · AUJohannes Wesling Klinikum Minden · DECharité - Universitätsmedizin Berlin · DEChina Medical University · TWJohn Hunter Hospital · AUAarhus University Hospital · DKHeidelberg University · DEHumboldt-Universität zu Berlin · DEFriedrich-Alexander-Universität Erlangen-Nürnberg · DEGerman Center for Neurodegenerative Diseases · DEMassachusetts General Hospital · USUniversité Claude Bernard Lyon 1 · FRKarolinska Institutet · SERoyal Adelaide Hospital · AUVall d'Hebron Hospital Universitari · ESSapienza University of Rome · IT

Funding

Specialized Programs of Translational Research in Acute Stroke at the PartnersP50NS051343 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI FURIE, KAREN L · 2006 to 2013
$17.5M
Project 4P41EB015896 · NIBIB · MASSACHUSETTS GENERAL HOSPITAL · PI ROSEN, BRUCE R · 2012 to 2018
$9.8M
Quantitative MRI-based metrics for multi-center stroke treatment assessmentR01NS059775 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI WU, ONA · 2008 to 2012
$2.0M
NIBIB NIH HHS P41 EB015896NINDS NIH HHS P50 NS051343NINDS NIH HHS R01 NS059775
6 · The paper itself

Abstract

backgroundPatients 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.

methodsWe 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.

findingsOf 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

interpretationIn 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.

fundingNone.

Indexed as

Time-to-TreatmentDiffusion Magnetic Resonance ImagingFibrinolytic AgentsHumansInfusions, IntravenousIschemic StrokeRecovery of FunctionTissue Plasminogen ActivatorTomography, X-Ray ComputedTreatment OutcomeFibrinolytic AgentsTissue Plasminogen Activator

Identifiers

PMID33176180
PMCPMC7734592
OpenAlexW3102589670

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.