Neuroscientists report they have developed the first effective emergency therapy for stroke, an advance that could prevent as many as 44,000 Americans a year from becoming disabled.
The treatment involves intravenous injection of the clot-dissolving enzyme t-PA--the same enzyme used to treat clots in the heart--into patients within three hours after the onset of stroke symptoms.
In a multicenter study of 624 patients, those who received the enzyme were at least 30% more likely to have minimal or no disabilities than those who received a placebo, the team reports today in the New England Journal of Medicine.
"This is the first unequivocal evidence of an effective treatment of stroke," said neuroscientist Zach W. Hall, director of the National Institute of Neurological Disorders and Stroke, which sponsored the study. The results "signal the beginning of a new era in which stroke will be recognized as an acute illness that can be treated."
"Yesterday, stroke was an untreatable disease," added Dr. James Grotta of the University of Texas in Houston, one of the principal investigators of the study, which also included researchers at UC San Diego. "Today, it is treatable."
Just as important, he noted, the study showed that stroke must be treated as "a dire emergency" in which victims must be taken to the hospital for treatment as quickly as possible.
T-PA's manufacturer, Genentech Inc. of South San Francisco, said Wednesday that it will apply immediately to the Food and Drug Administration for permission to market the drug as a stroke treatment. But because the drug is already approved for use in treating heart attacks, physicians can use it now for stroke if they wish.
The researchers cautioned that t-PA can be hazardous if given to the wrong patients, if used in too high a concentration or if administered after a delay of more than three hours. "We must train physicians how to use this drug," said Dr. Patrick Lyden of UC San Diego.
If too much drug is given or treatment is delayed too long, the drug can cause hemorrhaging into the brain. In fact, 6.4% of the patients who received t-PA in the trial suffered from intracranial bleeding, compared to only 0.6% of those who received a placebo. But that bleeding did not affect mortality: Only 17% of those who received t-PA died within 36 hours, compared to 21% of those who received a placebo.
Stroke is the No. 1 cause of adult disability in the United States and the No. 3 cause of death. An estimated 400,000 Americans have a stroke each year. More than 3 million have suffered lasting impairment from a stroke, with at least a third of those having severe impairment, ranging from loss of speech to paralysis.
The vast majority of strokes, about 84%, are caused by a clot blocking a blood vessel in the brain, cutting off the flow of blood and vital oxygen to brain tissues. These are the targets for t-PA therapy. The remainder are caused by leaky or ruptured blood vessels that allow blood to escape into the brain. T-PA is not an appropriate treatment for these so-called aneurysmal strokes because bleeding is already occurring.
To distinguish between the two types of strokes, physicians use a sophisticated CT scanner to provide three-dimensional X-ray images of the brain. Fortunately, noted Grotta, emergency rooms in virtually every hospital in the country now have CT scanners and are equipped to make such a distinction.
Researchers have long speculated that t-PA, which is so effective at dissolving clots in the heart, could be used to dissolve clots in the brain as well. Pilot studies suggested that it could do so, but three larger trials conducted in Europe were very disappointing.
One of the European t-PA trials showed no significant benefits from the treatment. Two others, using a similar enzyme called streptokinase, had to be halted prematurely because of excessive hemorrhaging in the brain caused by the drug.
But the research team pointed out that, in all three European studies, treatment was not delivered until four to six hours after the onset of symptoms. That is a crucial difference, according to Dr. Thomas Brott of the University of Cincinnati, because significant amounts of brain tissue are dead after four hours. This increases the risk that blood will leak into the brain through the degraded tissue if t-PA or streptokinase dissolves the clot. "The tendency for the brain to bleed appears to depend on time," he said. Among the 624 patients selected for the study, half received a placebo, a quarter receive t-PA within 90 minutes of the first symptoms of a stroke and a quarter received it within 180 minutes. Physicians then assessed the subjects' neurological and functional abilities three months later using four scales. On each scale, 30% to 50% more t-PA recipients scored in the normal range than those on placebos.
On the most comprehensive test, called the NIH scale, 32% of those who received t-PA showed a complete recovery, compared to 20% of those who received the placebo.