Starkweather, B.S. and Asher Kimchi M.D.
Houston, TX – In
experimental models, ultrasound has been shown to facilitate the
activity of fibrinolytic agents within minutes of its exposure
to a thrombus and to blood that contains t-PA. The mechanisms of
ultrasound-enhanced thrombolysis include improved drug
transport, reversible alteration of the fibrin structure, and
increased binding of t-PA to fibrin. A study published by Andrei
V. Alexandrov, M.D., et. al., in the November 18, 2004 issue of
the New England Journal of Medicine, based on a multicenter,
phase 2 randomized clinical trial, suggests that diagnostic
ultrasonography can safely improve the efficacy of systemic
therapy with t-PA in patients with acute ischemic stroke.
The Combined Lysis of Thrombus in Brain Ischemia Using
Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial
sought to determine the safety and biologic activity of
transcranial Doppler ultrasonography when combined with systemic
t-PA treatment in patients with acute ischemic stroke caused by
occlusion of the middle cerebral artery. These results allowed
them to estimate the magnitude of the potential clinical benefit
in order to plan for a subsequent phase 3 efficacy trial.
A total of 126 patients were enrolled in the study, all of whom
suffered from acute ischemic stroke with abnormal flow through
the middle cerebral artery. All patients received systemic t-PA
treatment, and half were randomized to the target group, which
also received continuous ultrasonography. Patients and
physicians were blinded to their group assignment.
Therapy was initiated within three hours of the onset of
symptoms of stroke, either with continuous monitoring with the
use of transcranial Doppler ultrasonography for two hours or
with placebo monitoring. The initiation of monitoring was
immediately followed by administration of a t-PA bolus.
Follow-up measurements were taken at 30, 60, 90 and 120 minutes
following the t-PA bolus.
The treating physicians also assessed neurologic status without
knowledge of patient assignment at the same 30 minute intervals
using the National Institutes of Health Stroke Scale (NIHSS).
Modified Rankin scores were obtained at three months.
The primary activity end point was the occurrence of complete
recanalization according to the TIBI flow-grading system or
early or dramatic clinical recovery from stroke. The primary
safety endpoint was intracerebral hemorrhage with clinical
worsening within 72 hours of the onset of stroke.
Symptomatic intracerebral hemorrhage occurred in two of
sixty-two patients in each of the groups. Within two hours of
the administration of the t-PA bolus, the primary combined end
point was reached by 31 patients in the target group (49
percent) and 19 in the control group (30 percent; P=0.03).
These results show that continuous monitoring of intracranial
occlusion with the use of 2-MHz, single-element pulsed-wave
ultrasonography had a positive effect on the primary activity
end point, with no increase in the rate of intracerebral
hemorrhage. The enhancement of t-PA therapy with ultrasonography
can be achieved safely and noninvasively at the bedside.
Co-authors: Carlos A. Molina, M.D.; James C. Grotta, M.D.; Zsolt
Garami, M.D.; Sheila R. Ford, R.N.; Jose Alvarez-Sabin, M.D.;
Joan Montaner, M.D.; Maher Saqqur, M.D.; Andrew M. Demchuk,
M.D., Lemuel A. Moye, M.D., Ph.D.; Michael D. Hill, M.D., and
Anne W. Wojner, Ph.D.