Lower doses of clot-busting drug safer for stroke patients

A Johns Hopkins study has shown that patients treated for a type of stroke caused by bleeding in the brain, or intracerebral hemorrhage, survived more often if given 1 milligram instead of the previously studied 3 milligram dose of the clot-busting drug tissue plasminogen activator (tPA).

In the study, Daniel Hanley, M.D., a professor and neurologist at The Johns Hopkins University School of Medicine, demonstrated that rates of continued bleeding and subsequent death can be reduced if the tPA dosage is lowered to 1 mg.

"We have good evidence that lower doses of tPA not only worked as well as the higher dose, but also markedly reduced side effects in regard to bleeding," Hanley said. "Ten years ago, the mortality rate for this type of stroke was at 80 percent. One year ago, it was 50 percent. In this study it was 13 percent."

An intracerebral hemorrhage -- bleeding in the brain -- is the only type of stroke without a clearly defined treatment. It occurs in more than 100,000 Americans each year. Up to half of patients die, and those who survive suffer significant disabilities. During such a stroke, blood often extends into the ventricles, small chambers in the brain where cerebrospinal fluid is made, increasing the chances of damage.

In a previous study by Hanley and his group of 26 patients, a 3 milligram dose of tPA could be used safely to treat this type of stroke, reducing the mortality rate to 19 percent. However, continued bleeding was observed in 23 percent of the patients. This new study was designed to find ways to reduce bleeding and further improve patient outcomes.

Researchers studied 16 patients who received either 0.3 milligram or 1 milligram of tPA every 12 hours through a catheter for up to four days or until the ventricles opened. The patient groups were balanced with respect to age, gender, initial stroke severity and demographic characteristics. Results from daily CT scans from this study and the previous study showed that blood clots broke up over the first three days at similar rates for all three doses. Similarly, compared with a placebo, all doses substantially accelerated clot removal. But unlike the patients who received 3 milligram doses, none of the patients who received either 1 or 0.3 milligram doses experienced continued bleeding as a clinically significant side effect. Also, there were fewer deaths in each of the lower-dose groups, suggesting that the lower doses are safer.

Researchers also found that, although both lower-dose levels were equally effective at dissolving clots and reducing mortality rates, a sampling of the cerebral spinal fluid revealed that the 1 milligram dose stayed at therapeutic levels for longer periods of time than the 0.3 milligram dose. They also found that because the 1 milligram dose appears to clear the clot more rapidly from the third and fourth ventricles (sites of critical importance), the catheter can be removed sooner, greatly reducing risk of complications.

Hanley said the next step will be to conduct a randomized controlled phase-III trial where 500 patients will receive a 1 mg. dose of tPA.



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