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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.
Hanley, Daniel F; Lane, Karen; McBee, Nichol; Ziai, Wendy; Tuhrim, Stanley; Lees, Kennedy R; Dawson, Jesse; Gandhi, Dheeraj; Ullman, Natalie; Mould, W Andrew; Mayo, Steven W; Mendelow, A David; Gregson, Barbara; Butcher, Kenneth; Vespa, Paul; Wright, David W; Kase, Carlos S; Carhuapoma, J Ricardo; Keyl, Penelope M; Diener-West, Marie; Muschelli, John; Betz, Joshua F; Thompson, Carol B; Sugar, Elizabeth A; Yenokyan, Gayane; Janis, Scott; John, Sayona; Harnof, Sagi; Lopez, George A; Aldrich, E Francois; Harrigan, Mark R; Ansari, Safdar; Jallo, Jack; Caron, Jean-Louis; LeDoux, David; Adeoye, Opeolu; Zuccarello, Mario; Adams, Harold P; Rosenblum, Michael; Thompson, Richard E; Awad, Issam A.
Affiliation
  • Hanley DF; Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA. Electronic address: dhanley@jhmi.edu.
  • Lane K; Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
  • McBee N; Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
  • Ziai W; Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
  • Tuhrim S; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Lees KR; University of Glasgow, Glasgow, UK.
  • Dawson J; University of Glasgow, Glasgow, UK.
  • Gandhi D; University of Maryland, Baltimore, MD, USA.
  • Ullman N; Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
  • Mould WA; Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
  • Mayo SW; Emissary International LLC, Austin, TX, USA.
  • Mendelow AD; Newcastle University, Newcastle upon Tyne, UK.
  • Gregson B; Newcastle University, Newcastle upon Tyne, UK.
  • Butcher K; University of Alberta, Edmonton, AB, Canada.
  • Vespa P; University of California, Los Angeles, CA, USA.
  • Wright DW; Emory University, Atlanta, GA, USA.
  • Kase CS; Boston University, Boston, MA, USA.
  • Carhuapoma JR; Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
  • Keyl PM; Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
  • Diener-West M; Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
  • Muschelli J; Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
  • Betz JF; Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
  • Thompson CB; Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
  • Sugar EA; Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
  • Yenokyan G; Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
  • Janis S; National Institutes of Health, National institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • John S; Rush University, Chicago, IL, USA.
  • Harnof S; Chaim Sheba Medical Center, Ramat Gan, Israel.
  • Lopez GA; University of Texas, Houston, Houston, TX, USA.
  • Aldrich EF; University of Maryland, Baltimore, MD, USA.
  • Harrigan MR; University of Alabama at Birmingham, Birmingham, AL, USA.
  • Ansari S; University of Utah, Salt Lake City, UT, USA.
  • Jallo J; Thomas Jefferson University Hospital, Philadelphia, PA, USA.
  • Caron JL; University of Texas, San Antonio, San Antonio, TX, USA.
  • LeDoux D; North Shore Long Island Jewish Medical Center, Manhasset, NY, USA.
  • Adeoye O; University of Cincinnati, Cincinnati, OH, USA.
  • Zuccarello M; University of Cincinnati, Cincinnati, OH, USA.
  • Adams HP; University of Iowa, Iowa City, IA, USA.
  • Rosenblum M; Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
  • Thompson RE; Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
  • Awad IA; University of Chicago, Chicago, IL, USA.
Lancet ; 389(10069): 603-611, 2017 02 11.
Article in En | MEDLINE | ID: mdl-28081952
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 (11), 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.

FUNDING:

National Institute of Neurological Disorders and Stroke.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sodium Chloride / Drainage / Tissue Plasminogen Activator / Stroke / Fibrinolytic Agents / Cerebral Intraventricular Hemorrhage / Therapeutic Irrigation Type of study: Clinical_trials / Guideline / Prognostic_studies Limits: Aged / Female / Humans / Male / Middle aged Language: En Journal: Lancet Year: 2017 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sodium Chloride / Drainage / Tissue Plasminogen Activator / Stroke / Fibrinolytic Agents / Cerebral Intraventricular Hemorrhage / Therapeutic Irrigation Type of study: Clinical_trials / Guideline / Prognostic_studies Limits: Aged / Female / Humans / Male / Middle aged Language: En Journal: Lancet Year: 2017 Type: Article