Patients suffering from acute ischemic stroke are significantly more likely to achieve recanalization and/or early or dramatic clinical recovery if thrombolytic therapy is combined with continuous transcranial Doppler sonography, according to a study by Andrei V. Alexandrov, M.D., of the University of Texas, Houston, and colleagues.
Of 63 patients receiving ultrasound combined with tissue plasminogen activator (t-PA), 31 (49%) achieved recanalization and/or clinical recovery within 2 hours, compared with 19 of 63 patients (30%) who received t-PA that was combined with sham sonography.
Within 2 hours, 16 (25%) of the patients in the treatment group experienced both recanalization and clinical recovery, compared with 5 (8%) of those in control group. Both of the differences were statistically significant (N. Engl. J. Med. 2004; 351:2170-8).
All patients had occlusions of the middle cerebral artery, and all were treated within 3 hours of the onset of symptoms. The patients were randomly assigned to the treatment or the control group, he said.
Known as the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial, the study was funded in part by the National Institute of Neurological Disorders and Stroke, a unit of the National Institutes of Health.
This phase II study was not sufficiently powered to detect a difference in clinical outcome 3 months after the treatment, but there was a statistical trend in that direction.
Of the 53 patients from the treatment group eligible for follow-up, 22 (42%) had achieved a modified Rankin score of 0 or 1, compared with 4 of the 15 eligible patients (27%) in the control group. Given those rates of recovery, the investigators calculated that a phase III study would need to include just 274 patients in each group to replicate the results with statistical significance.
“If you look at the trials being done in cardiology right now, they enroll thousands and tens of thousands of patients to show a difference of a very few percentage points,” Dr. Alexandrov said in an interview. “Cardiologists would love to have an absolute difference of 10% or more between the groups, and that's what we can shoot for. We can shoot for easily up to a 13% difference between the groups.”
But Dr. Alexandrov is not waiting for the results of that trial, which will likely take 2-3 years, to put the combined treatment into practice.
“At our center, it's the standard of care right now,” he said. “Both [t-PA and transcranial Doppler sonography] are Food and Drug Administration-approved technologies, and the trial was exempt from investigational new drug status by FDA because these results would not change the labels. Right now in our institution, when we give systemic t-PA within 3 hours [after a stroke], we always put a transcranial Doppler probe on the scalp to help the patient pass the clot faster.”
Nevertheless, “I will not stand here and recommend that everybody else should do the same,” Dr. Alexandrov said. “The reason is that to do it right, you have to pass through a very lengthy and labor-intense training that is not a routine part of any neurology residency. To do the protocol, you need 1-6 months of daily practicing of this technique under supervision, and that's something that very few programs can do in the United States.”
Dr. Alexandrov is involved in an effort to design an operator-independent device that would obviate the need for an experienced operator.
With such a device, “an emergency department physician could do it, a neurologist could do it, and a nurse could mount the ultrasound machine on the head,” he said.
The mechanism by which transcranial Doppler sonography improves thrombolysis is still unclear. In a commentary accompanying Dr. Alexandrov's paper, Joseph F. Polak, M.D., of Tufts University, Boston, weighs a number of the possibilities (N. Engl. J. Med. 2004;351:2154-5).
It's clear that the mechanism does not involve cavitation, which ultrasound at high energies can cause. In a cavitational mechanism, the ultrasound energy causes partially dissolved gases to form small bubbles in the blood vessels, which literally explode.
It's also unlikely that the relatively low energies used in transcranial Doppler ultrasound could accelerate thrombolysis by producing heat.
Dr. Alexandrov believes that the combined treatment works because ultrasound is causing a gentle mechanical pressure wave, which delivers more t-PA molecules to and through the clot.
The study was sparked by a clinical observation, Dr. Alexandrov explained. “Patients who were wearing these transducers for diagnostic purposes started to move their paralyzed arms and legs and to talk to us much faster than we ever [would have] expected otherwise.”