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March 24, 2020; 94 (12) Article

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

Georgios Tsivgoulis, Aristeidis H. Katsanos, Konark Malhotra, Amrou Sarraj, Andrew D. Barreto, Martin Köhrmann, View ORCID ProfileChristos Krogias, Niaz Ahmed, Valeria Caso, Peter D. Schellinger, Andrei V. Alexandrov
First published December 31, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008904
Georgios Tsivgoulis
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.
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Aristeidis H. Katsanos
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.
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Konark Malhotra
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.
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Amrou Sarraj
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.
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Andrew D. Barreto
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.
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Martin Köhrmann
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.
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Christos Krogias
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.
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  • ORCID record for Christos Krogias
Niaz Ahmed
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.
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Valeria Caso
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.
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Peter D. Schellinger
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.
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Andrei V. Alexandrov
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.
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Citation
Thrombolysis for acute ischemic stroke in the unwitnessed or extended therapeutic time window
Georgios Tsivgoulis, Aristeidis H. Katsanos, Konark Malhotra, Amrou Sarraj, Andrew D. Barreto, Martin Köhrmann, Christos Krogias, Niaz Ahmed, Valeria Caso, Peter D. Schellinger, Andrei V. Alexandrov
Neurology Mar 2020, 94 (12) e1241-e1248; DOI: 10.1212/WNL.0000000000008904

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Abstract

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 [ORadj] 1.62, 95% CI 1.20–2.20), functional improvement (ORadj 1.42, 95% CI 1.11–1.81), and sICH (ORadj 6.22, 95% CI 1.37–28.26). There was no association between IVT and FI (ORadj 1.61, 95% CI 0.94–2.75) or all-cause mortality (ORadj 1.75, 95% CI 0.93–3.29) at 3 months. No evidence of heterogeneity was evident in any of the analyses (I2 = 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.

Glossary

AIS=
acute ischemic stroke;
CI=
confidence interval;
DWI=
diffusion-weighted imaging;
ECASS=
European Cooperative Acute Stroke Study;
EPITHET=
Echoplanar Imaging Thrombolytic Evaluation Trial;
EXTEND=
Extending the Time for Thrombolysis in Emergency Neurological Deficits;
FLAIR=
fluid-attenuated inversion recovery;
FFO=
favorable functional outcome;
FI=
functional independence;
IVT=
IV thrombolysis;
mRS=
modified Rankin Scale;
OR=
odds ratio;
RCT=
randomized clinical trial;
sICH=
symptomatic intracranial hemorrhage

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received June 3, 2019.
  • Accepted in final form September 30, 2019.
  • © 2019 American Academy of Neurology
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  • Reader Response: Thrombolysis for acute ischemic stroke in the unwitnessed or extended therapeutic time window
    • Koto Ishida, Neurologist, Associate Professor of Neurology, New York University (New York, NY)
    Submitted January 02, 2020
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