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Use of Ultrasound Safely Enhances t-PA Thrombolysis for Acute Ischemic Stroke

November 24, 2004

By Ashley 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.

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