Intracranial ultrasound treatment using an operator-independent device together with tissue plasminogen activator (tPA) in stroke patients appears to be safe and produced promising recanalization rates, a new study has shown.
The study, published online in Stroke on October 24, was led by Andrew D. Barreto, MD, University of Texas Health Science Center at Houston.
He explained to Medscape Medical News that ultrasound therapy causes the meshwork of fibrin strands within the clot to disperse, thereby allowing better access of tPA to the clot. “We are particularly targeting patients who have clots that are not likely to lyse completely with tPA — those with moderate to severe strokes,” Dr. Barreto noted.
“Many smaller studies have been performed with transcranial ultrasound and it does seem to have efficacy in helping to dissolve the clot,” he said. The most cited study is the original CLOTBUST(Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic TPA) study published in 2004 in the New England Journal of Medicine, which showed a recanalization rate of 38% with the combination of ultrasound and tPA vs 13% for those given tPA alone.
However, Dr. Barreto noted that delivery of ultrasound via cranial bone windows requires training for both anatomic localization and waveform recognition, which is considered impractical for large-scale use. “As you have to hold the ultrasound device at the same time as identifying the clot, it is too difficult to train enough people to perform the procedure as an emergency bedside therapeutic,” he said.
“Mass expansion of properly trained technicians or clinicians to provide 24/7 stroke coverage to complete a pivotal clinical trial of sonothrombolysis represents a major hurdle,” the researchers write in the Stroke paper.
Operator-independent transcranial stroke treatment device.Source: The investigators
“To that end, the development of an operator-independent device that can target the proximal intracranial arteries without specialized neurovascular ultrasound training would make a large-scale, phase 3 clinical trial feasible,” they add.
Such a “hands-free” device has now been manufactured by Cerevast Therapeutics, and the current study represents the first-ever exposure of patients with acute stroke to a combination of tPA and this hands-free ultrasound device. “This device has been manufactured so that it can be used without special training and be applied to all stroke patients by just placing it on their heads,” Dr. Barreto said.
“It is battery powered and easy to fit. One size fits all, with an adjustable head size and ear position,” he explained. “It has been designed so that the probes are positioned in the areas of thinnest bone of the skull: 6 probes on the left and 6 on the right. The device rotates and sequentially fires each probe, thus targeting all the areas of the brain where a large blood clot would be.”
For the current study, known as CLOTBUST-Hands Free (CLOTBUST-HF), 20 stroke patients with a median National Institutes of Health Stroke Scale score of 15 received standard-dose intravenous tPA, along with 2-MHz pulsed-wave ultrasound therapy delivered by the CLOTBUST-HF device used for 2 hours.
Sites of occlusion were middle cerebral artery in 14 patients, terminal internal carotid artery in 3 patients, and vertebral artery in 3 patients. All patients tolerated the entire 2 hours of ultrasound treatment, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device.
40% Recanalization Rate
At 2 hours, 40% of patients had complete recanalization and 10% had partial recanalization. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate at 57%. At 90 days, 5 patients (25%) had an excellent outcome, defined as a modified Rankin scale score of 0 to 1.
“The recanalization rate of 40% is in line with that shown in the NEJM paper. But we did not have a control group in this study,” Dr. Barreto commented. “At day 90 we had a lower percentage of patients with an excellent outcome than in the previous study, but we only had 20 patients so it is difficult to say much about a clinical outcome.”
“This is just a pilot study looking at safety of delivering ultrasound treatment to different areas of the brain. We didn’t see any safety issues and the results definitely suggest the approach is feasible,” he added.
A phase 3 trial — CLOTBUST-ER — is now underway with the hands-free device. The trial is being conducted in 830 patients from 14 countries, with results expected in 2 to 3 years.
This study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Cerevast Therapeutics provided the study devices and was not involved in the study design, analysis, or manuscript preparation. A coauthor serves as a consultant to Cerevast Therapeutics Inc and holds a US patent on the technology.