Medical Device Daily

SAN DIEGO — A healthy dose of cloudless skies and warm sunshine was delivered during last week's American Heart Association (Dallas)-sponsored International Stroke Conference here.

The 4,000-plus attendees could use a little cheering – in panel after panel, they were faced with the grim reality that, despite more than 60 failed attempts in the past decade, tissue-plasminogen activator (tPA) remains the only FDA-approved stroke drug.

tPA, marketed by Genentech (South San Francisco, California) as Activase (alteplase), triggers an enzyme cascade that dissolves blood clots. But the drug also increases hemorrhage risks and must be administered within three hours of a stroke. That tight time window and delicate risk-benefit balance severely limit tPA's applicability and use: Genentech reported just $275 million in 2008 revenues from its whole portfolio of thrombolytics.

Peter Sandercock, of the University of Edinburgh's Western General Hospital in Scotland, presented data from an analysis of 600,000 U.S. stroke patients showing that only 2% received tPA within three hours, as recommended, while 30% received the drug within six hours. In his study, 60% of the patients were seen at a specialized stroke unit, and he found that advanced patient age was the primary limiting factor for the use of tPA.

Several studies at the conference focused on how to increase the use of tPA within the three-hour window. New data presented by Jeffery Saver, MD, director of the UCLA Stroke Center (Los Angeles), found that patients who arrived at the hospital within an hour of stroke were twice as likely to receive tPA as those arriving later. Other studies found tPA usage could be optimized by establishing hotlines between rural hospitals and stroke centers, and by starting t-PA prior to transfer to the stroke center.

Another hot topic at the conference was the effectiveness of tPA outside the three-hour window. Werner Hacke of Heidelberg University Hospital (Heidelberg, Germany) presented a summary of the ECASS3 study, in which patients were treated with tPA between 3 and 4.5 hours after stroke.

The study concluded that 52.4% of patients on tPA had a favorable outcome, compared to 45.2% for placebo, although the global analysis missed statistical significance. However, the incidence of intracranial hemorrhage was higher with tPA (27%) than placebo (17.6%), although mortality and other serious adverse events were not significantly different.

The ECASS3 findings were published last year in the New England Journal of Medicine, and Hacke said they are "already changing guidelines." Last month, the European Stroke Organization recommended that tPA be given within 4.5 hours of stroke, even though the drug's European label still includes the 3-hour limit.

In the U.S., Hacke noted that there has been more concern due to the failure of other trials looking at later tPA administration: ECASS1 and ECASS2 missed their primary endpoints, and the ATLANTIS study was halted early due to lack of efficacy and a significant increase in intracerebral hemorrhage. Yet Hacke argued that ECASS1 and ECASS2 "showed the same signal" as ECASS3, and that ATLANTIS was "at least neutral" rather than negative when analyzed to consider labeling differences in Europe versus the U.S.

Sandercock recommended that physicians "set aside" ATLANTIS because it is a "tiny trial – and tiny trials tend to produce very unstable results." He maintained that administration of tPA within six hours "may have quite a useful effect, although we're not quite there yet as far as statistical significance." He said he anticipates that the IST3 trial, which is looking at tPA treatment within six hours in more than 3,000 patients, should put the issue to rest, although data are not expected until 2012.

Another area of focus at the conference was ways to combine tPA with other drugs that might improve its safety or efficacy. Researchers established several years ago that both tPA and the stroke itself activate harmful matrix metalloproteinases (MMPs), and that co-administration of an MMP inhibitor might mitigate that effect.

Yet here too, Eng Lo of Harvard Medical School and Massachusetts General Hospital (both Boston) demonstrated that timing is key. While early administration of an MMP inhibitor can decrease the infarct size in animal models of stroke, administration days later can make the infarct worse, since the drug will interfere with the brain's attempts to heal itself, he said.

Another potential option to improve tPA administration was presented by ImaRx Therapeutics (Redmond, Washington). The company presented data from a Phase I/II trial showing that the combination of tPA with ultrasound and the company's MRX-801 microspheres was twice as likely to cause recanalization (complete clearing of blocked arteries) than tPA alone.

The trial randomized 35 patients to receive tPA alone or in combination with ultrasound and either a high or low dose of MRX-801. Sustained complete recanalization after 36 hours was achieved in 67% of the low dose patients, 46% of the high dose patients, and 33% of the tPA patients. Three months following treatment, improvement in clinical outcomes measured by a Modified Rankin score was reported in 75% of the low dose patients, 50% of the high dose patients, and 36% of the tPA patients.

About a year ago, ImaRx ran into trouble with intracranial hemorrhage associated with high doses of MRX-801. Data from the current study showed no bleeding complications in the low-dose group but three cases in the high-dose group, although the company noted that all three patients also had uncontrolled hypertension and stroke severity tended to be worse in the high-dose group.

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