Issue of
March 1, 2000

Clot-buster proves safe, effective given during first three hours after a stroke  

BY KRISTA CONGER

A clot-busting drug to treat stroke patients can be safely administered by properly trained neurologists and emergency room physicians throughout the United States, according to a nationwide trial headed by a Stanford physician. Previous studies have shown that patients who receive the drug within three hours after the onset of stroke symptoms have substantially better recoveries than untreated patients. The results of the new trial relieve concern about a possible increase in the rate of dangerous side-effects when the drug moved out of clinical trials and into real-world use.

Although administering the drug, tissue plasminogen activator, or t-PA, is both effective and relatively simple, a 1995 study by the National Institute of Neurological Disorders and Stroke (NINDS) pinpointed a troubling problem: Its ability to dissolve blood clots throughout the body can cause potentially fatal bleeding in the brain of a small percentage of stroke patients. However, the new multicenter study found the risk of intracranial hemorrhage after t-PA treatment does not outweigh the clear benefits of the drug for most patients.

"The rate of bleeding in the brain was actually lower than we had expected," said Gregory Albers, MD, lead author on the paper, appearing in the March 1 issue of the Journal of the American Medical Association.

According to Albers, a professor of neurology and director of the Stanford Stroke Center, the FDA was concerned that the tightly controlled atmosphere of the clinical trial demonstrating t-PA's effectiveness may have underestimated the true rate of brain hemorrhage. But the incidence of symptomatic brain hemorrhage within three days after t-PA treatment actually decreased slightly, from 6.4 percent in the NINDS study to 3.3 percent in the new study, which tracked the clinical outcomes of nearly 400 stroke patients who were treated with t-PA at 57 medical centers nationwide.

Prompt t-PA treatment can make a significant difference in long-term outcomes, even for older patients with large strokes. While a complete recovery may still be out of reach, rapid t-PA treatment can reduce the severity of the patient's long-term disability and possibly make the difference between entering a nursing facility or returning to independent living.

"One message to physicians is that they should at least consider treating these patients with t-PA," said Albers.

t-PA is effective for treating acute ischemic stroke, which occurs when a clot lodges in a blood vessel in the brain and blocks the normal flow of blood. The oxygen-starved brain cells downstream of the obstruction quickly begin to die, and the patient experiences sudden onset of symptoms that can include muscle weakness or numbness (often isolated on one side of the body), impaired speech, visual loss, poor balance and loss of coordination, a sharp headache or mental confusion. t-PA can help to dissolve the clot and minimize the amount of permanent neurological damage ­ but only if it is administered within three hours of symptom onset. After this time, t-PA treatment is no longer effective for most patients and the risk of hemorrhage may outweigh the potential benefits.

Many physicians are aware that time is precious when diagnosing a stroke, but few realize that the patient's prognosis directly corresponds to the timing of t-PA administration, Albers said.

"It's more effective the sooner you administer it," said Albers. But in the new study, only half of the patients were treated prior to the last 15 minutes of the three-hour treatment window. "We need to educate physicians to begin treatment as soon as possible," he said.

But the responsibility for rapid treatment doesn't rest solely with the patient's doctor. "Most people are not very aware of stroke symptoms and the fact that they should call 911 if they think they might be having a stroke," said Albers. Watchful waiting makes it difficult for a stroke sufferer to receive treatment in time to prevent brain damage.

The challenge of treating stroke patients within such a narrow time window is compounded by the fact that t-PA treatment is not warranted in every situation. In a hemorrhagic stroke, caused when a blood vessel in the brain ruptures and blood pools in the surrounding tissue, t-PA treatment would be very dangerous as it could cause additional bleeding in the brain. This difference in cause and treatment makes a correct yet speedy diagnosis particularly essential, said Albers. Emergency room physicians use a computerized tomography (CT) scan to quickly visualize the brain and determine which type of stroke is affecting the patient before deciding on a course of treatment.

Albers' collaborators on the study include Vernice Bates, MD, from the Dent Neurological Institute, Millard Fillmore Hospital, Buffalo, N.Y.; Wayne Clark, MD, Oregon Stroke Center, Oregon Health Sciences Center, Portland, Ore.; Rodney Bell, MD, Thomas Jefferson University, Philadelphia, Pa.; Piero Verro, MD, Seton Hall University, Edison, N.J.; and Scott Hamilton, PhD, Genentech, Inc., South San Francisco, Calif. The study was funded by Genentech, Inc. which markets t-PA under the trade name Alteplase. Albers, Bates, Clark, Bell and Verro have all been members of Genentech's speakers bureau. SR