Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: The intraventricular hemorrhage thrombolysis trial

Neal Naff, Michael A. Williams, Penelope M. Keyl, Stanley Tuhrim, Ross Bullock, Stephan A. Mayer, William Coplin, Raj Narayan, Stephen Haines, Salvador Cruz-Flores, Mario Zuccarello, David Brock, Issam Awad, Wendy C. Ziai, Anthony Marmarou, Denise Rhoney, Nichol McBee, Karen Lane, Daniel F. Hanley

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE-: 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.

Original languageEnglish
Pages (from-to)3009-3016
Number of pages8
JournalStroke
Volume42
Issue number11
DOIs
StatePublished - Nov 1 2011

Fingerprint

Intracranial Hemorrhages
Tissue Plasminogen Activator
Placebos
Hemorrhage
Cerebral Hemorrhage
Mortality
Safety
Cerebrovascular Circulation
Therapeutics
Phase III Clinical Trials
Glasgow Coma Scale
Intracranial Pressure
Infection
Respiratory System
Demography
Blood Pressure
Equipment and Supplies

Keywords

  • intracerebral hemorrhage
  • intraventricular hemorrhage
  • thrombolysis
  • tissue-type plasminogen activator

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage : The intraventricular hemorrhage thrombolysis trial. / Naff, Neal; Williams, Michael A.; Keyl, Penelope M.; Tuhrim, Stanley; Bullock, Ross; Mayer, Stephan A.; Coplin, William; Narayan, Raj; Haines, Stephen; Cruz-Flores, Salvador; Zuccarello, Mario; Brock, David; Awad, Issam; Ziai, Wendy C.; Marmarou, Anthony; Rhoney, Denise; McBee, Nichol; Lane, Karen; Hanley, Daniel F.

In: Stroke, Vol. 42, No. 11, 01.11.2011, p. 3009-3016.

Research output: Contribution to journalArticle

Naff, N, Williams, MA, Keyl, PM, Tuhrim, S, Bullock, R, Mayer, SA, Coplin, W, Narayan, R, Haines, S, Cruz-Flores, S, Zuccarello, M, Brock, D, Awad, I, Ziai, WC, Marmarou, A, Rhoney, D, McBee, N, Lane, K & Hanley, DF 2011, 'Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: The intraventricular hemorrhage thrombolysis trial', Stroke, vol. 42, no. 11, pp. 3009-3016. https://doi.org/10.1161/STROKEAHA.110.610949
Naff, Neal ; Williams, Michael A. ; Keyl, Penelope M. ; Tuhrim, Stanley ; Bullock, Ross ; Mayer, Stephan A. ; Coplin, William ; Narayan, Raj ; Haines, Stephen ; Cruz-Flores, Salvador ; Zuccarello, Mario ; Brock, David ; Awad, Issam ; Ziai, Wendy C. ; Marmarou, Anthony ; Rhoney, Denise ; McBee, Nichol ; Lane, Karen ; Hanley, Daniel F. / Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage : The intraventricular hemorrhage thrombolysis trial. In: Stroke. 2011 ; Vol. 42, No. 11. pp. 3009-3016.
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AU - Williams, Michael A.

AU - Keyl, Penelope M.

AU - Tuhrim, Stanley

AU - Bullock, Ross

AU - Mayer, Stephan A.

AU - Coplin, William

AU - Narayan, Raj

AU - Haines, Stephen

AU - Cruz-Flores, Salvador

AU - Zuccarello, Mario

AU - Brock, David

AU - Awad, Issam

AU - Ziai, Wendy C.

AU - Marmarou, Anthony

AU - Rhoney, Denise

AU - McBee, Nichol

AU - Lane, Karen

AU - Hanley, Daniel F.

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N2 - BACKGROUND AND PURPOSE-: 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.

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