title: Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial.
abstract: OBJECTIVE
  Patients with intracerebral hemorrhage and intraventricular hemorrhage have a reported mortality of 50% to 80%. We evaluated a clot lytic treatment strategy for these patients in terms of mortality, ventricular infection, and bleeding safety events, and for its effect on the rate of intraventricular clot lysis.
  
  
  METHODS
  Forty-eight patients were enrolled at 14 centers and randomized to treatment with 3 mg recombinant tissue-type plasminogen activator (rtPA) or placebo. Demographic characteristics, severity factors, safety outcomes (mortality, infection, bleeding), and clot resolution rates were compared in the 2 groups.
  
  
  RESULTS
  Severity factors, including admission Glasgow Coma Scale, intracerebral hemorrhage volume, intraventricular hemorrhage volume, and blood pressure were evenly distributed, as were adverse events, except for an increased frequency of respiratory system events in the placebo-treated group. Neither intracranial pressure nor cerebral perfusion pressure differed substantially between treatment groups on presentation, with external ventricular device closure, or during the active treatment phase. Frequency of death and ventriculitis was substantially lower than expected and bleeding events remained below the prespecified threshold for mortality (18% rtPA; 23% placebo), ventriculitis (8% rtPA; 9% placebo), symptomatic bleeding (23% rtPA; 5% placebo, which approached statistical significance; P=0.1). The median duration of dosing was 7.5 days for rtPA and 12 days for placebo. There was a significant beneficial effect of rtPA on rate of clot resolution.
  
  
  CONCLUSIONS
  Low-dose rtPA for the treatment of intracerebral hemorrhage with intraventricular hemorrhage has an acceptable safety profile compared to placebo and historical controls. Data from a well-designed phase III clinical trial, such as CLEAR III, will be needed to fully evaluate this treatment.
authors.affiliation: Sandra and Malcolm Berman Brain & Spine Institute, Department of Neurology, Sinai Hospital of Baltimore, MD, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Naff
authors.forename: Michael A
authors.initials: MA
authors.lastname: Williams
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Keyl
authors.forename: Stanley
authors.initials: S
authors.lastname: Tuhrim
authors.forename: M Ross
authors.initials: MR
authors.lastname: Bullock
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Mayer
authors.forename: William
authors.initials: W
authors.lastname: Coplin
authors.forename: Raj
authors.initials: R
authors.lastname: Narayan
authors.forename: Stephen
authors.initials: S
authors.lastname: Haines
authors.forename: Salvador
authors.initials: S
authors.lastname: Cruz-Flores
authors.forename: Mario
authors.initials: M
authors.lastname: Zuccarello
authors.forename: David
authors.initials: D
authors.lastname: Brock
authors.forename: Issam
authors.initials: I
authors.lastname: Awad
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Ziai
authors.forename: Anthony
authors.initials: A
authors.lastname: Marmarou
authors.forename: Denise
authors.initials: D
authors.lastname: Rhoney
authors.forename: Nichol
authors.initials: N
authors.lastname: McBee
authors.forename: Karen
authors.initials: K
authors.lastname: Lane
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hanley
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012120:Respiration Disorders / Q000139:chemically induced; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D015854:Up-Regulation / Q000502:physiology
chemical_list: D010919:Placebos; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator