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Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial

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Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke : A Randomized Placebo-Controlled Trial. / Modrau, Boris; Andersen, Grethe; Mikkelsen, Irene Klærke; Nielsen, Anne; Hansen, Mikkel Bo; Johansen, Martin Berg; Eskildsen, Helle Wulf; Povlsen, Jan Plougmann; Yavarian, Yousef; Mouridsen, Kim; Østergaard, Leif; Bach, Flemming Winther; Hjort, Niels.

In: Stroke, Vol. 51, No. 7, 2020, p. 1983-1990.

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Modrau, Boris ; Andersen, Grethe ; Mikkelsen, Irene Klærke ; Nielsen, Anne ; Hansen, Mikkel Bo ; Johansen, Martin Berg ; Eskildsen, Helle Wulf ; Povlsen, Jan Plougmann ; Yavarian, Yousef ; Mouridsen, Kim ; Østergaard, Leif ; Bach, Flemming Winther ; Hjort, Niels. / Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke : A Randomized Placebo-Controlled Trial. In: Stroke. 2020 ; Vol. 51, No. 7. pp. 1983-1990.

Bibtex

@article{5384ca5ac62949c4a48fdf16b7b23b50,
title = "Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial",
abstract = "Background and Purpose: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. Methods: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. Results: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). Conclusions: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.",
keywords = "clinical trial, neuroprotective drugs, reperfusion, stroke, theophylline, thrombolytic therapy, tissue-type plasminogen activator",
author = "Boris Modrau and Grethe Andersen and Mikkelsen, {Irene Kl{\ae}rke} and Anne Nielsen and Hansen, {Mikkel Bo} and Johansen, {Martin Berg} and Eskildsen, {Helle Wulf} and Povlsen, {Jan Plougmann} and Yousef Yavarian and Kim Mouridsen and Leif {\O}stergaard and Bach, {Flemming Winther} and Niels Hjort",
year = "2020",
doi = "10.1161/STROKEAHA.119.027446",
language = "English",
volume = "51",
pages = "1983--1990",
journal = "Stroke",
issn = "0039-2499",
publisher = "LIPPINCOTT WILLIAMS & WILKINS",
number = "7",

}

RIS

TY - JOUR

T1 - Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke

T2 - A Randomized Placebo-Controlled Trial

AU - Modrau, Boris

AU - Andersen, Grethe

AU - Mikkelsen, Irene Klærke

AU - Nielsen, Anne

AU - Hansen, Mikkel Bo

AU - Johansen, Martin Berg

AU - Eskildsen, Helle Wulf

AU - Povlsen, Jan Plougmann

AU - Yavarian, Yousef

AU - Mouridsen, Kim

AU - Østergaard, Leif

AU - Bach, Flemming Winther

AU - Hjort, Niels

PY - 2020

Y1 - 2020

N2 - Background and Purpose: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. Methods: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. Results: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). Conclusions: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

AB - Background and Purpose: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. Methods: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. Results: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). Conclusions: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

KW - clinical trial

KW - neuroprotective drugs

KW - reperfusion

KW - stroke

KW - theophylline

KW - thrombolytic therapy

KW - tissue-type plasminogen activator

UR - http://www.scopus.com/inward/record.url?scp=85086938156&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.119.027446

DO - 10.1161/STROKEAHA.119.027446

M3 - Journal article

C2 - 32568651

AN - SCOPUS:85086938156

VL - 51

SP - 1983

EP - 1990

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 7

ER -