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
In the study, Daniel Hanley, a professor of
neurology at the
School of Medicine, demonstrated that rates of continued
bleeding and subsequent death can be reduced if the tPA
dosage is lowered to 1 milligram.
"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."
Hanley presented the study Feb. 18 at the
International Stroke Conference, held in Kissimmee, Fla.
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
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
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 milligram dose of tPA.
The Orphan Drug Programs of the FDA was a primary
sponsor of this study. Support for the research program
also came from the National Institute of Neurological
Disease and Stroke.