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

Hanley, D. F. et al. (2017) Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet, 389(10069), pp. 603-611. (doi:10.1016/S0140-6736(16)32410-2) (PMID:28081952)

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Abstract

Background: 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.

Item Type:Articles
Additional Information:Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov NCT00784134.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lees, Professor Kennedy and Thompson, Professor Richard and Dawson, Professor Jesse
Authors: Hanley, D. F., Lane, K., McBee, N., Ziai, W., Tuhrim, S., Lees, K. R., Dawson, J., Gandhi, D., Ullman, N., Mould, W. A., Mayo, S. W., Mendelow, A. D., Gregson, B., Butcher, K., Vespa, P., Wright, D. W., Kase, C. S., Carhuapoma, J. R., Keyl, P. M., Diener-West, M., Muschelli, J., Betz, J. F., Thompson, C. B., Sugar, E. A., Yenokyan, G., Janis, S., John, S., Harnof, S., Lopez, G. A., Aldrich, E. F., Harrigan, M. R., Ansari, S., Jallo, J., Caron, J.-L., LeDoux, D., Adeoye, O., Zuccarello, M., Adams Jr., H. P., Rosenblum, M., Thompson, R. E., and Awad, I. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Lancet
Publisher:The Lancet Publishing Group
ISSN:0140-6736
ISSN (Online):1474-547X
Published Online:10 January 2017
Copyright Holders:Copyright © 2017 Elsevier
First Published:First published in Lancet 389(10069): 603-611
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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