Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Daniel F Hanley; Karen Lane; Nichol McBee; Wendy Ziai; Stanley Tuhrim; Kennedy R Lees; Jesse Dawson; Dheeraj Gandhi; Natalie Ullman; W Andrew Mould; Steven W Mayo; A David Mendelow; Barbara Gregson; Kenneth Butcher; Paul Vespa; David W Wright; Carlos S Kase; J Ricardo Carhuapoma; Penelope M Keyl; Marie Diener-West; John Muschelli; Joshua F Betz; Carol B Thompson; Elizabeth A Sugar; Gayane Yenokyan; Scott Janis; Sayona John; Sagi Harnof; George A Lopez; E Francois Aldrich; Mark R Harrigan; Safdar Ansari; Jack Jallo; Jean-Louis Caron; David LeDoux; Opeolu Adeoye; Mario Zuccarello; Harold P Adams Jr; Michael Rosenblum; Richard E Thompson; Issam A Awad

doi:10.1016/S0140-6736(16)32410-2

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Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Journal article

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Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Daniel F Hanley, Karen Lane, Nichol McBee, Wendy Ziai, Stanley Tuhrim, Kennedy R Lees, Jesse Dawson, Dheeraj Gandhi, Natalie Ullman, W Andrew Mould, …

The Lancet (British edition), Vol.389(10069), pp.603-611

02/11/2017

DOI: 10.1016/S0140-6736(16)32410-2

PMCID: PMC6108339

PMID: 28081952

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https://www.ncbi.nlm.nih.gov/pmc/articles/6108339View

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Abstract

Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status.

Severity of Illness Index

Stroke - diagnostic imaging

Humans

Middle Aged

Proportional Hazards Models

Male

Tomography, X-Ray Computed

Treatment Outcome

Tissue Plasminogen Activator - therapeutic use

Sodium Chloride - therapeutic use

Cerebral Intraventricular Hemorrhage - therapy

Cerebral Intraventricular Hemorrhage - diagnostic imaging

Therapeutic Irrigation - methods

Fibrinolytic Agents - therapeutic use

Drainage - methods

Female

Aged

Stroke - therapy

Details

Title: Subtitle: Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial
Creators: Daniel F Hanley - Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA. Electronic address: dhanley@jhmi.edu
Karen Lane - Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA
Nichol McBee - Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA
Wendy Ziai - Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA
Stanley Tuhrim - Icahn School of Medicine at Mount Sinai, New York, NY, USA
Kennedy R Lees - University of Glasgow, Glasgow, UK
Jesse Dawson - University of Glasgow, Glasgow, UK
Dheeraj Gandhi - University of Maryland, Baltimore, MD, USA
Natalie Ullman - Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA
W Andrew Mould - Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA
Steven W Mayo - Emissary International LLC, Austin, TX, USA
A David Mendelow - Newcastle University, Newcastle upon Tyne, UK
Barbara Gregson - Newcastle University, Newcastle upon Tyne, UK
Kenneth Butcher - University of Alberta, Edmonton, AB, Canada
Paul Vespa - University of California, Los Angeles, CA, USA
David W Wright - Emory University, Atlanta, GA, USA
Carlos S Kase - Boston University, Boston, MA, USA
J Ricardo Carhuapoma - Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA
Penelope M Keyl - Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA
Marie Diener-West - Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA
John Muschelli - Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA
Joshua F Betz - Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA
Carol B Thompson - Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA
Elizabeth A Sugar - Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA
Gayane Yenokyan - Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA
Scott Janis - National Institutes of Health, National institute of Neurological Disorders and Stroke, Bethesda, MD, USA
Sayona John - Rush University, Chicago, IL, USA
Sagi Harnof - Chaim Sheba Medical Center, Ramat Gan, Israel
George A Lopez - University of Texas, Houston, Houston, TX, USA
E Francois Aldrich - University of Maryland, Baltimore, MD, USA
Mark R Harrigan - University of Alabama at Birmingham, Birmingham, AL, USA
Safdar Ansari - University of Utah, Salt Lake City, UT, USA
Jack Jallo - Thomas Jefferson University Hospital, Philadelphia, PA, USA
Jean-Louis Caron - University of Texas, San Antonio, San Antonio, TX, USA
David LeDoux - North Shore Long Island Jewish Medical Center, Manhasset, NY, USA
Opeolu Adeoye - University of Cincinnati, Cincinnati, OH, USA
Mario Zuccarello - University of Cincinnati, Cincinnati, OH, USA
Harold P Adams Jr - University of Iowa, Iowa City, IA, USA
Michael Rosenblum - Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA
Richard E Thompson - Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA
Issam A Awad - University of Chicago, Chicago, IL, USA
Resource Type: Journal article
Publication Details: The Lancet (British edition), Vol.389(10069), pp.603-611
DOI: 10.1016/S0140-6736(16)32410-2
PMID: 28081952
PMCID: PMC6108339
NLM abbreviation: Lancet
ISSN: 0140-6736
eISSN: 1474-547X
Publisher: England
Grant note: U01 NS062851 / NINDS NIH HHS UL1 TR001425 / NCATS NIH HHS
Language: English
Date published: 02/11/2017
Academic Unit: Neurology; Iowa Neuroscience Institute
Record Identifier: 9984020989702771

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