CD&D

Tissue plasminogen activator (tPA) has become a key treatment for people who suffer a stroke. Given within a few hours after symptoms begin, this clot-busting drug can decrease the effects of a stroke and reduce the extent of permanent disability. That window of opportunity has been three hours after the onset of symptoms. New studies have proven that the treatment window can now be increased to 4.5 hours for suitable candidates.

The American Heart Association (AHA; Dallas) has issued an advisory to confirm the expanded use. But it remains to be seen what the large-scale effect will be since experts estimate that tPA is used in only about 2% to 5% of all stroke cases.

As the third-leading cause of death in the U.S. each year, strokes will cost $68.9 billion in 2009, primarily because it's the leading cause of disability, according to the AHA

One of the reasons the developers of tPA set the three-hour window is that tPA can actually be harmful after that, causing bleeding in the brain. Few studies have been large enough to address the issue and test the timeline.

"We looked at increased risk and mortality because there was some concern from previous studies that perhaps mortality would be increased in this late time window, but we found this was a chance finding in some of the older studies and there is no effect on mortality," Maarten Lansberg, MD, PhD, assistant professor of neurology and neurological sciences at Stanford University (Stanford, California) told Cardiovascular Devices & Drugs.

Lansberg completed a meta-analysis of four major tPA stroke trials to date to come to this conclusion. The analysis included data from the European Cooperative Acute Stroke Study (ECASS)-3, which provided new data on tPA in the 3-to-4.5-hour window.

"ECASS-3 was the very first study to exclusively enroll patients for the 3-to-4.5-hour window and they demonstrated, with marginal statistical significance, that tPA is beneficial during that window," Lansberg said, adding that study included just 823 patients and his team felt a larger review was in order.

Combining data from ECASS-3 with other tPA studies – for a total of 1,622 patients – provided the needed statistical significance. Of those patients who arrived at the hospital between three and 4.5 hours after their symptoms started, treatment with tPA improved their odds of a favorable outcome by 31%. A favorable outcome was defined as the patient returns to a normal state or has minimal symptoms, such as a slight facial droop or numbness.

"In Europe, this practice was quickly adapted even before the results of our study," Lansberg said.

When tPA was first launched in the mid 1990s, investigators knew that the later you treat a patient, the less effective tPA can be. That fact hasn't changed.

The only FDA-approved tPA is marketed by Genentech (South San Francisco, California) as Activase (alteplase). Lansberg said he is not aware that Genentech has moved to seek an expanded label from the FDA for the broader treatment window.

Genentech reported $275 million in 2008 revenues from its whole portfolio of thrombolytics.

A number of other companies have tried to develop tPA and failed. But some of those failed candidates continue to move forward.

Paion's (Aachen, Germany) clot-buster desmoteplase failed a Phase III stroke trial and got dumped by partner Forest Laboratories (New York) only to be picked up by H. Lundbeck (Copenhagen) which started two new Phase III trials in December 2007.

ImaRx Therapeutics (Redmond, Washington) ran into trouble with intracranial hemorrhage associated with high doses of stroke drug MRX-801, but Phase I/II data showed that lower doses improved recanalization and clinical outcomes without bleeding problems in 2008.