ISC 2009: Combination of Ultrasound, Microspheres, and tPA Shows Promise in Ischemic Stroke

Caroline Cassels

February 27, 2009

February 27, 2009 (San Diego, California) — Combining transcranial Doppler ultrasound (TCD) with microspheres (µS) and tissue plasminogen activator (tPA) is more effective than tPA alone in treating ischemic stroke.

Presented here at the American Stroke Association International Stroke Conference 2009, results from the phase 1/2 investigational Transcranial Ultrasound in Clinical Sonothrombolysis (TUCSON) trial shows a low-dose of µS combined with tPA promoted faster clearing of blood vessels and improved patient outcomes 3 months later.

In addition, sustained rates of complete recanalization at 36 hours in those treated with low-dose or high-dose µS were 67% and 46%, respectively, compared with 33% in those treated with tPA alone.

Further, the median time to any recanalization tended to be faster in patients who received low-dose µS therapy, compared with 60 minutes in controls.

"We now have a safe dose of ultrasound and microspheres, combined with tPA, or possibly in future trials given without tPA, to help induce a very early recanalization effect.

"We were able to bust more clots with this technology compared with tPA and most important, we were able to achieve this goal on average 30 minutes earlier [than with tPA]. This is very important, because as we all know time is brain," said study investigator Andrei Alexandrov, MD, from the University of Alabama, in Birmingham.

According to Dr. Alexandrov, tPA dissolves clots relatively slowly, inducing partial recanalization and leading to patient improvement over 1 day to 3 months. Five years ago, he said, research by his group demonstrated that the addition of externally applied ultrasound amplified the action of tPA.

Tempest in a Teacup

Adding µS to the treatment leverages the energy from ultrasound waves to propel these tiny "bubbles" to accelerate and enhance the clot-busting effect.

The tiny gas-filled bubbles, which are 1 to 2 µm in size, are coated in a lipid shell and propelled by external ultrasound to the clot, where they augment the chemical effect of tPA by mechanically "eroding" or "sanding" the clot.

Dr. Alexandrov likened the process to sweetening a cup of tea. "If you simply add the sugar, it sinks to the bottom of the cup. In order to sweeten the tea, you have to stir it. The same thing happens when you give intravenous tPA. It goes into the [bloodstream] but doesn't reach its destination as effectively as it does if you zap the area with a mechanical pressure wave. The blood shakes up better, and the tPA reaches its target destination more effectively," he said.

The study involved 35 patients and evaluated 2 separate doses of intravenous µS infusion over 90 minutes — 1.4 mL or 2.8 mL — and compared them with tPA treatment alone.

There were 12 patients in the low-dose treatment group, 11 patients in the high-dose group, and 12 in the tPA monotherapy cohort.

Bleeding Complications in High-Dose Group

At 90 days, improvement in clinical outcomes, measured by modified Rankin Scale, was reported in 75% of the low-dose group compared with 50% and 36% in the high-dose and monotherapy groups, respectively.

In addition, overall levels of neurological deficit as measured by the National Institutes of Health Stroke Scale were lower at 90 minutes, 120 minutes, 24 to 36 hours, and 90 days in each of the µS-treated groups. This improvement was most notable for subjects in the low-dose group, and the difference from control subjects was most evident at the 90-minute time point.

No bleeding complications occurred in the low-dose group or controls. However, 3 of patients (27%) in the high-dose group experienced bleeding. Poststudy analysis revealed that the overall stroke severity was significantly higher in the high-dose group, with a medianNIHSS score of 16, vs 10 for the low-dose group. In addition, the researchers report that all 3 patients who experienced bleeding complications also had uncontrolled hypertension.

However, Dr. Alexandrov added that his team will conduct further research into the safety concerns associated with the use of the high-dose treatment.

One of the current issues with this technique that potentially limits its widespread use is the need for a highly trained sonographer to target the clot. However, he said, his group has just received funding from the National Institutes of Health to test an operator-independent device that would allow the treatment to be more widely available.

Commenting on this research, Cheryl Busnell, MD, a neurologist from Wake Forest University Health Sciences, in Winston-Salem, North Carolina, said the findings are encouraging and offer hope for a treatment that has the potential to significantly augment the effect clot-busting effect of tPA.

"I think it this technique has wonderful potential. If you understand clot formation and clot resolution, this new technique makes a lot of sense," she told Medscape Neurology & Neurosurgery.

TUCSON was supported by ImaRx Therapeutics. Several of the researchers work for ImaRx Therapeutics.

International Stroke Conference: Abstract 145. Presented February 19, 2009.


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