title: Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.
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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  National Institute of Neurological Disorders and Stroke.
authors.affiliation: Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA. Electronic address: dhanley@jhmi.edu.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hanley
authors.affiliation: Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Lane
authors.affiliation: Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
authors.forename: Nichol
authors.initials: N
authors.lastname: McBee
authors.affiliation: Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Ziai
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Tuhrim
authors.affiliation: University of Glasgow, Glasgow, UK.
authors.forename: Kennedy R
authors.initials: KR
authors.lastname: Lees
authors.affiliation: University of Glasgow, Glasgow, UK.
authors.forename: Jesse
authors.initials: J
authors.lastname: Dawson
authors.affiliation: University of Maryland, Baltimore, MD, USA.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Gandhi
authors.affiliation: Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Ullman
authors.affiliation: Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
authors.forename: W Andrew
authors.initials: WA
authors.lastname: Mould
authors.affiliation: Emissary International LLC, Austin, TX, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Mayo
authors.affiliation: Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A David
authors.initials: AD
authors.lastname: Mendelow
authors.affiliation: Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gregson
authors.affiliation: University of Alberta, Edmonton, AB, Canada.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Butcher
authors.affiliation: University of California, Los Angeles, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Vespa
authors.affiliation: Emory University, Atlanta, GA, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Wright
authors.affiliation: Boston University, Boston, MA, USA.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Kase
authors.affiliation: Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
authors.forename: J Ricardo
authors.initials: JR
authors.lastname: Carhuapoma
authors.affiliation: Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Keyl
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Diener-West
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Muschelli
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Betz
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
authors.forename: Carol B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sugar
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
authors.forename: Gayane
authors.initials: G
authors.lastname: Yenokyan
authors.affiliation: National Institutes of Health, National institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Janis
authors.affiliation: Rush University, Chicago, IL, USA.
authors.forename: Sayona
authors.initials: S
authors.lastname: John
authors.affiliation: Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Harnof
authors.affiliation: University of Texas, Houston, Houston, TX, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Lopez
authors.affiliation: University of Maryland, Baltimore, MD, USA.
authors.forename: E Francois
authors.initials: EF
authors.lastname: Aldrich
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Harrigan
authors.affiliation: University of Utah, Salt Lake City, UT, USA.
authors.forename: Safdar
authors.initials: S
authors.lastname: Ansari
authors.affiliation: Thomas Jefferson University Hospital, Philadelphia, PA, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Jallo
authors.affiliation: University of Texas, San Antonio, San Antonio, TX, USA.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Caron
authors.affiliation: North Shore Long Island Jewish Medical Center, Manhasset, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: LeDoux
authors.affiliation: University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Opeolu
authors.initials: O
authors.lastname: Adeoye
authors.affiliation: University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Zuccarello
authors.affiliation: University of Iowa, Iowa City, IA, USA.
authors.forename: Harold P
authors.initials: HP
authors.lastname: Adams
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenblum
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Thompson
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Issam A
authors.initials: IA
authors.lastname: Awad
mesh_terms: D000368:Aged; D000074042:Cerebral Intraventricular Hemorrhage / Q000000981:diagnostic imaging / Q000628:therapy*; D004322:Drainage / Q000379:methods*; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012720:Severity of Illness Index; D012965:Sodium Chloride / Q000627:therapeutic use*; D020521:Stroke / Q000000981:diagnostic imaging / Q000628:therapy*; D007507:Therapeutic Irrigation / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D012965:Sodium Chloride; D010959:Tissue Plasminogen Activator