CDU

It improves outcomes for patients, but for Genentech's (South San Francisco, California) Activase itself, the outcome has not been what it could be.

The only FDA-approved drug to treat ischemic stroke, Activase, also known as tissue plasminogen activator, or tPA, has been on the market for almost 10 years. However, despite its de facto monopoly status, it is not used in the majority of cases for which it is approved only about 20% of eligible patients receive the drug.

The original trial upon which FDA approval was based had an enrollment of slightly more than 600 patients; many physicians worried about whether results from that comparatively small trial would generalize to the general population. Based on those concerns, the National Institutes of Neural Disorders and Stroke (Bethesda, Maryland) commissioned a re-analysis of the trial data; the results of that re-analysis, published in the October 2004 issue of Stroke, reaffirmed the benefits of Activase treatment.

Now, results from a new survey on how likely emergency doctors are to use Activase were published in May in the Annals of Emergency Medicine. Take-home message: many still are not buying.

The survey, which was conducted by researchers at the University of Michigan (Ann Arbor) and the American College of Emergency Physicians (Dallas), asked emergency physicians whether they would use tPA on a stroke patient "under ideal circumstances" basically defined as the availability of CT scanner and neurological support. Use of a CT scanner is necessary to differentiate between ischemic stroke caused by blood clots and benefits from Activase treatment and hemorrhagic stroke, which accounts for about 20% of all stroke cases and can only be made worse by tPA treatment.

Roughly 60% of physicians said they would be very likely or likely to use Activase if they had CT scanner support available, while the remaining 40% said it was unlikely to uncertain that they would use Activase even under optimal circumstances.

More doctors cited safety rather than efficacy as the sticking point. While the drug's reported efficacy of improving outcomes by 30% to 50% is in line with what physicians said they'd want to see to use it, the risk of hemorrhage, which now is about 6% for stroke patients, would have to be reduced by about half to conform to their average expectations.

Activase works by stimulating the body's own clot-dissolving mechanism by activating plasminogen, which is secreted by endothelial cells in response to injury to the artery walls that contributes to clot formation. That mechanism of action also makes it more likely that hemorrhage will occur.

"The greatest risk for bleeding is within 24 hours of tPA administration," Devin Brown, assistant professor of neurology at the University of Michigan and lead author of the study, told CDU's sister publication, BioWorld Today. Patients are watched closely during that time to see whether they show symptoms of brain bleeding, "but really, once bad bleeding has occurred, there is often little that can be done."

Clinical trials are testing both combination therapies of Activase with other medications that might reduce the risk of brain bleeding, and other compounds that may have a lower risk of bleeding. Brown said that university is conducting two clinical trials that fit into those categories.

Marites Cristobal, manager of corporate relations at Genentech, said that the company itself is not planning on conducting any trials to see what the hemorrhage rate would be when using Activase in combination with other agents that might reduce the risk of hemorrhage, but that the company is encouraging physicians to perform a CT scan before treatment to assure that a patient has ischemic rather than hemorrhagic stroke.

"I'm guessing that physicians feel fearful of treating patents and having bleeding occur," Cristobal said, referring to doctors' continued reluctance to use Activase. "So it's a matter of educating physicians on how to prevent that."

Cristobal also stressed the importance of teaching patients to recognize the symptoms of stroke so that they can get treatment quickly; one of the reasons for the low use of Activase is that many patients are not seen by a physician until the three-hour time window in which Activase is effective has passed, a point that Brown also made.

The study was accompanied by an editorial by Robert Wears and David Magid, researchers at the University of Florida Health Science Center (Gainesville, Florida), which also discusses possible reasons for the discrepancy between the evidence that Activase is effective in improving clinical outcomes for stroke victims and its low rate of use. The authors noted that support for Activase use is far from universal. It is endorsed as standard of care by American Heart Association (Dallas) and the American Academy of Neurology (St. Paul, Minnesota), but not by the American Academy of Emergency Medicine (Milwaukee, Wisconsin) or the Society for Academic Emergency Medicine (Lansing, Michigan) and that a survey might only weakly predict what people would actually do when faced with a real stroke patient.

But they also invoked the psychological principles of decision making under complex circumstances to explain why Activase is not more widely used specifically, the concept of "local rationality." As the authors wrote, "clinical problems are so complex that the merely extraordinary humans who must resolve them cannot handle all the potentially relevant information, cannot activate and retain in their minds all the relevant knowledge, and cannot entertain all potentially relevant lines of thought. Thus here again, rationality must be local (or bounded), attending only to a subset of the possible goals, cues and knowledge that could be relevant to the problem."

Wears and Magid argued that because Activase has failed to receive universal support, busy practitioners may be adopting what they term rational agnosticism.

"If the professors in their ivory towers, who have a lot more time and resources to invest, can't figure it out, and since any change requires additional effort (which might turn out to have been wasted), the best strategy might be just to wait and see," they said.

While physicians have sometimes been harangued for failing to adopt new promising therapies (when they are not, as in the case of COX-2 inhibitors, being harangued for overmedicating patients with drugs that the benefit of hindsight proves to be dangerous), Wears and Magid said that "understanding clinician's behavior as locally rational offers an interesting and potentially more productive approach to changing their behavior, if warranted," but by "trying to understand why certain behaviors make sense locally, we might be better positioned to reach our global goals."

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