NEW ORLEANS—Ever since tissue plasminogen activator (t-PA) was introduced nearly 10 years ago as the first FDA-approved treatment for acute ischemic stroke, researchers and clinicians have been grappling with ways to increase the drug’s effectiveness and administer it to more patients. Now, investigators in Spain and at the University of Texas in Houston have hit on a novel method that promises to help accomplish both aims—microbubbles.

At last year’s American Stroke Association’s International Stroke Conference, Andrei V. Alexandrov, MD, and colleagues, including Carlos A. Molina, MD, reported the phase II results of the CLOTBUST (Combined Lysis Of Thrombus in Brain ischemia using 2 MHz transcranial Ultrasound and Systemic T-PA) trial. The study demonstrated that the use of transcranial Doppler ultrasound with t-PA safely augmented the effectiveness of t-PA to completely break up clots in the brain vessels. A combination of t-PA and ultrasound yielded higher rates of complete recanalization and dramatic clinical recovery within two hours after initiation of drug therapy, compared with t-PA given alone as the standard of care.

At the 2005 International Stroke Conference, Dr. Molina reported the results of a trial showing an even bigger boost in recanalization rates. In a study involving 103 consecutive stroke patients with middle cerebral artery occlusion, he and his colleagues at Vall d’Hebrón Hospital in Barcelona found that the rate of early recanalization with the combination of t-PA, ultrasound monitoring, and injection of microbubbles into the blocked vessel was even higher than that obtained with t-PA plus ultrasound. The rate of complete recanalization within two hours of t-PA bolus was significantly higher in the patients receiving microbubbles (54.5%) than in either the t-PA/ ultrasound group (40.8%) or the t-PA group (23.9%), he reported.

Microbubbles are safe IV contrast agents for ultrasound imaging and make transcranial insonation possible in more than 98% of stroke patients, said Dr. Alexandrov, who assessed the utility of microbubble administration in extracranial ultrasound monitoring. “Ultrasound-enhanced thrombolysis may be further improved with the addition of microbubbles.” Microbubbles are coated with lipid shells and circulate in the bloodstream without interaction until they encounter an ultrasound beam. Ultrasound pressure opens the lipid shell, releasing microbubbles with transient cavitation, fluid motions, and stronger echoes, he elaborated.

A phase IIa CLOTBUST study is now under way in which 30 stroke patients treated with t-PA, transcranial Doppler ultrasound, and microbubbles (using the ImaRx Nanobubble Platform Definity‘ and MRX-815) will be compared with patients treated with only t-PA and transcranial Doppler ultrasound. Dr. Alexandrov, who is Associate Professor and Director of Cerebrovascular Ultrasound at the University of Texas in Houston, also reported that the design of the phase III trial will be based on the “signal of efficacy” in phase IIa-b. Ultimately, he envisions conducting studies that examine whether use of microbubbles, ultrasound, and additional drugs can extend the window of treatment into the three-to-nine-hour range.

CONTINUING CONTROVERSY

Currently, t-PA is FDA-approved in the United States only for use within three hours from the onset of acute stroke. The inability of many stroke victims to reach the hospital within that time window continues to be the number one reason why less than 5% of acute stroke patients are treated with t-PA.

Wider application of t-PA is further complicated by the continued reluctance of some emergency physicians and neurologists to use it—largely out of concern that the drug will lead to hemorrhaging, particularly if patients are not appropriately selected for the therapy. In a survey of more than 1,100 emergency physicians, reported at the Stroke Conference by Devin L. Brown, MD, and colleagues from the University of Michigan and elsewhere, 41% of the 922 respondents indicated they were not likely to use t-PA for stroke even in the ideal setting. More than half of the 41% cited the risk of hemorrhage as the reason, Dr. Brown noted.

Despite such limitations and the continuing controversy they generate, thrombolytic therapy has become an established treatment for acute stroke patients in an increasing number of stroke centers and community hospitals in the US and around the world, and recent years have seen a burgeoning of studies aimed at such aspects as getting patients to the hospital more quickly so they can receive t-PA, improving the selection process to enable more patients to be eligible for t-PA when they do arrive on time, and extending the time window beyond three hours.

Dr. Molina’s group alone was responsible for several t-PA presentations at the Stroke Conference. In a study of 135 consecutive patients with acute middle cerebral artery occlusion, Marc Ribo, MD, and colleagues found that patients treated with t-PA between three and six hours of symptom onset after undergoing a multimodal MRI selection protocol had similar recanalization and bleeding rates to those of patients treated within three hours. In terms of the number of patients who benefited from treatment, however, the three-to-six-hour group had a slightly higher number than the zero-to-three-hour group. The results suggest that use of MRI selection criteria may be able to extend the window for safe and effective t-PA treatment beyond three hours and that a high number of patients could benefit from the extension.

In another study, Joan Montaner, MD, PhD, and colleagues from Vall d’Hebrón Hospital and other institutions in Spain did genotyping of blood samples obtained from stroke patients who received t-PA within three hours of symptom onset. The investigators found a correlation between several gene variants on the one hand and decreased recanalization rates and increased bleeding and mortality on the other, suggesting that the genetic makeup of stroke patients may help condition their individual response to thrombolytic therapy. It is therefore conceivable that the safety and efficacy of t-PA could be improved in the future by the advent of pharmacogenomic testing, the researchers concluded.

Taken together, the three studies from the Barcelona group build on the results of the CLOTBUST study and point to a promising future for thrombolytic therapy, said Mark Alberts, MD, Professor of Neurology at Northwestern University Medical School in Chicago. In his view, the phase II results of the CLOTBUST trial showing the use of transcranial Doppler ultrasound to be safe and effective were generally well received by the medical community; but because the study was relatively small and the larger, phase III segment of the trial is just getting under way, it remains to be seen how quickly this approach will become part of the standard clinical protocol.

“It’s too soon to say how well this use of transcranial Doppler will be adopted by physicians treating stroke patients acutely with thrombolytic therapy,” he said. “It’s certainly a very promising, effective treatment … and we need further studies to expand that database.”

Dr. Alberts cited the technology’s lack of immediate availability at most hospitals and the need for specially trained technicians to operate it. “It’s not in any guidelines at this point, and I suspect it will be some time before it appears in any guidelines,” he said. “But [all these studies] represent a very exciting line of research, and the general theme ... from all the presenters is that we need better ways to increase the efficacy, safety, and utilization of thrombolytic therapy.”

THE LAZARUS EFFECT

In discussing the phase II results of CLOTBUST after presenting them at the 2004 International Stroke Conference (the study was published in the New England Journal of Medicine later in 2004), Dr. Alexandrov described a “Lazarus effect” of ultrasound-enhanced t-PA infusion. “If [practicing neurologists] give t-PA under continuous ultrasound monitoring and monitor the patients clinically, within two hours of bolus they will see nearly half of the patients … either open up their vessels or recover dramatically in front of [the neurologists’] eyes,” he said in an interview with Neurology Reviews. “That is the kind of Lazarus response that has been previously documented in treatment of heart attacks but was lacking with clot-busting therapy for stroke.”

In the trial, investigators found that three times more patients in the ultrasound (or target) group experienced complete recanalization coupled with dramatic clinical recovery within two hours after t-PA bolus than did control patients receiving t-PA alone. Furthermore, a subgroup analysis that has yet to be published revealed that all five patients experiencing this Lazarus-like recovery who had a baseline National Institutes of Health Stroke Scale (NIHSS) score of 20 or greater were in the target group, suggesting that there may be a benefit of ultrasound-enhanced thrombolysis for patients with the most severe form of disease.

The phase II results of the CLOTBUST study also demonstrated significant differences favoring the target arm for several other outcomes measured, including the primary end point of complete recanalization or total NIHSS score of 3 or less or recovery by 10 or more NIHSS points, any early recanalization on transcranial Doppler, and sustained complete middle cerebral artery recanalization.

Overall, the trial demonstrated that continuous monitoring of intracranial occlusion with transcranial Doppler is safe and enhances t-PA–associated recanalization, Dr. Alexandrov reiterated to the 2005 Stroke Conference audience. “The ultrasound-monitoring group showed a trend to more patients responding clinically to t-PA therapy … with a 13% difference over the control response,” he said, referring to outcomes at three months (42% versus 29%, respectively).

OPERATIVE LIMITATIONS

Despite the overall success of the trial, however, the phase II results had some limitations. First, the sample size was not powered to detect a difference in clinical outcomes; the 13% difference observed in phase II will require recruitment of about 600 patients for the phase III trial. Then there is the obstacle posed by the technology itself. Transcranial Doppler ultrasound is an extremely operator-dependent device: Only four centers in the study had experienced transcranial Doppler technicians available at all times on a 24/7 basis.

There is a great need for operator independence, Dr. Alexandrov maintained, adding that current transcranial Doppler technology is not suitable for a pivotal phase III trial. “An operator-independent device will standardize exposure to ultrasound across participating centers,” he said. “[In the future] I would like to see one person, one clinician, who is in the emergency room be able to administer ultrasound-enhanced thrombolysis regardless of skills and knowledge in diagnostic sonography.”

Thus, in addition to examining whether ultrasound plus microbubbles enhances t-PA therapy, the phase III trial will also explore whether the operator-independent ultrasound device that Dr. Alexandrov and colleagues are developing is suitable for clinical use. But a larger question—whether such innovations will lead to more patients being successfully treated with thrombolytic therapy—may ultimately depend on how the trial results are interpreted by those directly responsible for administering t-PA: emergency department physicians and attending neurologists, including those who remain skeptical of the drug’s safety and efficacy.

NR

—Fred Balzac

Suggested Reading
Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004;351:2170-2178.
Molina CA, Montaner J, Arenillas JF, et al. Differential pattern of tissue plasminogen activator–induced proximal middle cerebral artery recanalization among stroke subtypes. Stroke. 2004;35:486-490.
Ribo M, Molina CA, Rovira A, et al. Safety and efficacy of intravenous tissue plasminogen activator stroke treatment in the 3- to 6-hour window using multimodal transcranial Doppler/MRI selection protocol. Stroke. 2005; Epub ahead of print.
Tissue plasminogen activator for acute ischemic stroke: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.

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