Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91-180 minutes from onset.
OBJECTIVE
Renewed interest in thrombolytic therapy as potential treatment for patients with acute ischemic stroke prompted a dose-escalation safety study of tissue plasminogen activator in patients with very early (less than or equal to 90 minutes; see Part I) neurological symptoms. To test whether this stringent entry window might be safely lengthened, a second study was organized to test tissue plasminogen activator in patients with symptoms of 91-180 minutes' duration before treatment.


METHODS
An open-label, dose-escalation design was chosen. Eligible patients had pretreatment head computerized tomographic scanning and treatment begun 91-180 minutes from stroke onset. End points examined included the incidence of symptomatic and asymptomatic intracranial hemorrhage, other bleeding, and clinical outcome at 2 hours, 24 hours, and 3 months after treatment.


RESULTS
Twenty patients were treated at three hospitals in 13 months. Three doses were tested: 0.6 mg/kg (n = 8), 0.85 mg/kg (n = 6), and 0.95 mg/kg (n = 6). Two patients, one each at the two highest doses, sustained fatal intracerebral hemorrhages. Three patients (15%) improved by greater than or equal to 4 points on the National Institutes of Health Stroke Scale by 24 hours.


CONCLUSIONS
These observations suggest that tissue plasminogen activator treatment of acute ischemic stroke 91-180 minutes from onset in doses of greater than or equal to 0.85 mg/kg is attended by a risk of intracerebral hemorrhage approximating 17% (range 3-44%, 95% confidence interval). The rate of early neurological improvement observed in this study was small but does not exclude an improvement over the natural history. Future study with placebo control subjects and stratification by time to treatment is indicated.
Haley
E C
EC
Department of Neurology, University of Virginia School of Medicine, Charlottesville 22908.
Levy
D E
DE
Brott
T G
TG
Sheppard
G L
GL
Wong
M C
MC
Kongable
G L
GL
Torner
J C
JC
Marler
J R
JR
D000368:Aged; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000000981:diagnostic imaging; D002561:Cerebrovascular Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016019:Survival Analysis; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed
D006493:Heparin; D010959:Tissue Plasminogen Activator