Medical Device Daily Contributing Writer

NEW ORLEANS — While a festive atmosphere was building outside as annual Mardi Gras events began, inside the huge Ernest Morial Convention Center, the approximately 3,000 attendees at last week's 30th annual International Stroke Conference, sponsored by the American Stroke Association (ASA; Dallas), were hearing the same old refrain from earlier meetings. That is, stroke victims are receiving inadequate treatment and new approaches and therapies are needed to manage the nation's 750,000 annual strokes.

The FDA's 1996 approval of Genentech's (South San Francisco, California) clot-busting drug tissue plasminogen activator (tPA) was hailed as a major breakthrough in the fight against acute ischemic stroke (AIS), which accounts for about 85% of all strokes. The landmark National Institute of Neurological Disorders and Stroke (Bethesda, Maryland) trial demonstrated that tPA fosters an impressive 30% reduction in severe disability in ischemic stroke patients.

However, tPA is hampered with two drawbacks. First, it must be administered within three hours of stroke symptom onset in order to achieve its maximum therapeutic effect. Second, there is a 6% to 7% risk of intracerebral hemorrhage (ICH), which can occasionally be fatal.

Despite tPA's clearcut benefits, the number of patients receiving it is pitifully low. An article in the Oct. 26, 2004, issue of the Journal of the American Medical Association, authored by Peter Heuschmann, et al., noted that only 1.6% to 2.7% of acute ischemic stroke patients treated in community hospitals and 4.1% to 6.3% of AIS patients treated at academic hospitals or specialized stroke centers received thrombolytic therapy.

This depressing data, which is consistent with earlier studies, has numerous explanations, including tPA's highly restrictive three-hour “window of opportunity,“ the oft-subtle symptoms of ischemic stroke (especially compared with an acute heart attack) that cause patients to delay their departure to the hospital, the limitations and lack of availability of current diagnostic technologies, inadequate physician reimbursement and the lack of a written protocol and trained staff.

Several prominent stroke specialists addressed this critical problem and potential means to attack it at an ASA-sponsored press conference titled “Watching the Clock: What's New with Time-Dependent tPA.“

William Barsan, MD, chairman of the emergency department of the University of Michigan Medical Center (Ann Arbor, Michigan), reported that a survey of more than 1000 emergency medicine physicians indicated that tPA's low usage is heavily related to the risks, perceived and real, of ICH. The survey, done in conjunction with the American College of Emergency Physicians (Irving, Texas), concluded that tPA's ICH rate needed to be reduced to approximately 50% of its current levels for emergency room doctors to more fully embraced.

Responding to a question from Medical Device Daily, Barsan said he was “absolutely certain“ that litigation risk was an important factor in the cautious use of tPA by emergency room personnel. “I know of several lawsuits that have been filed against physicians [relative to its use],“ he said.

A second concept, presented by Marc Ribo, MD, PhD, of Hospital Vall d'Hebron (Barcelona, Spain), showed that the limited window of opportunity of tPA can be significantly and safely extended using a multi-modality magnetic resonance imaging (MRI) protocol. Specifically, using a combination of perfusion-weighted MRI, diffusion-weighted MRI and magnetic resonance angiography, Spanish physicians have shown that patients carefully assessed with this advanced diagnostic protocol could be properly identified and successfully treated despite falling well outside the approved window.

This concept is consistent with discussions at last year's stroke conference, when researchers noted that MRI could be used to identify patients outside the therapeutic time window but can still benefit from tPA infusion.

A third concept, presented at the ASA press conference by Carlos Molina, MD, also of Hospital Vall d'Hebron, showed that the addition of microbubbles to tPA administration and ultrasound monitoring improves the rate of ischemic clot lysis.

Molina's relatively small microbubble study builds on the success of ultrasound-based trials demonstrating that galactose-based microbubbles can boost the efficacy of ultrasound. There were three arms of this trial: one tPA with ultrasound, another tPA plus placebo monitoring and the third, tPA with ultrasound and microbubbles. Molina indicated that the latter approach provided the fastest and highest rate of complete recanalization and short-term neurological outcome.

“It appears that these microbubbles explode in combination with tPA and ultrasound,“ he said. Although a larger trial will be required to substantiate these results, Molina said that this is a “very promising concept.“

The use of ultrasound to buoy tPA's effect has become an exciting emerging concept in AIS therapy. At a session on “Use of Ultrasound as Therapy for Acute Stroke,“ several speakers extolled the benefit of ultrasound. George Shaw, MD, PhD, of the University of Cincinnati, said that his models show that ultrasound improves thrombolysis seven-fold. He concluded his talk with the comment that “ultrasound dramatically improves the lysis of clots.“

Another speaker, Andrei Alexandrov, MD, of the University of Texas-Houston Medical School, discussed the results of the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial, which appeared in the Nov. 18, 2004, issue of The New England Journal of Medicine. The article, titled “Ultrasound-Enhanced Systemic Thrombolysis for Acute Stroke,“ authored by Alexandrov, et al., discussed the use of continuous 2 MHz, single-element pulsed-wave transcranial Doppler (TCD) ultrasound monitoring of intracranial occlusion in combination with tPA administration.

This technique achieved a higher rate of complete recanalization and early or dramatic clinical recovery from stroke. The authors noted that a biologic effect of diagnostic ultrasound appears to aid systemic thrombolytic therapy and concluded that there is “potential of diagnostic ultrasonography to improve the efficacy of systemic therapy with tPA in cases of acute ischemic stroke.“

Speaking to a packed room, Alexandrov noted that a larger study, now under way, will be needed to provide further evidence of safety and efficacy. Further, he noted that many centers either do not have TCD available or enough trained operators to provide round-the-clock TCD and tPA therapy.

Other speakers presented different ultrasound approaches to enhanced thrombolysis, and while the best ultrasound and microbubble technology is yet undetermined, it is clear that “sono-thrombolysis“ may become an important new technology in the fight against acute ischemic stroke.

Other positive developments in the quest to improve the treatment of AIS reported at the stroke conference involved solid progress for the lytic agent desmoteplase. Originally found in the saliva of vampire bats, it acts in a similar way to tPA but works almost exclusively by targeting and destroying fibrin, the structural scaffold of blood clots.

Human clinical trials have been under way for more than three years and are very promising. At this year's meeting, the developer, PAION (Aachen, Germany), released the results of the Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke (DEDAS) trial, which used the same study design as the previous trial, Desmoteplase in Acute Ischemic Stroke (DIAS).

Anthony Furlan, MD, the principal investigator of DEDAS and medical director of the Cerebrovascular Center at The Cleveland Clinic (Cleveland), reported that despite a relatively small number of enrollees, DEDAS essentially confirmed the DIAS results. The drug improved reperfusion and resulted in a much better clinical outcome as measured by several widely accepted neurological measures.

Furlan said that he was very encouraged by the “impressively low rate of ICH“ and the fact that safety and efficacy were similar whether patients were treated in three to six hours or six to nine hours from stroke onset.

The larger multi-country DIAS-II trial will begin soon, and if the results cited last week are sustained, Furlan's comments at last year's meeting that this new agent is a “possible blockbuster that would cause a paradigm shift in ischemic stroke therapy“ could reach fruition in a few years.

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