|Early Treatment Confirmed as Key to Stroke Recovery
A study in the March 6, 2004, issue of The Lancet*
confirms the benefits of getting stroke patients to the hospital
quickly for rapid thrombolytic treatment. The study provides the
results of an extensive analysis of more than 2,700 stroke patients
in six controlled clinical trials who were randomized for treatment
with thrombolytic t-PA or a placebo.
While physicians have known since a breakthrough study in 1995
that early treatment with thrombolytics can improve a stroke patient's
chance of a full recovery, only an estimated 2 to 5 percent of all
eligible acute stroke patients in the U.S. are being treated with
Stroke patients who were treated within 90 minutes of the onset
of their symptoms showed the most improvement. The study suggests
that t-PA given up to 4 hours after the onset of symptoms may be
of benefit, but the authors caution that as time goes on there is
a diminishing effect of treatment, and there is estimated to be
almost no benefit when treatment is at 6 hours.
"Once again we learn that time is brain," said John R.
Marler, M.D., one of the study authors and associate director for
clinical trials at the National Institute of Neurological Disorders
and Stroke (NINDS), a part of the National Institutes of Health
(NIH). "Although rapid stroke treatment presents a great challenge
to physicians and may require substantial change in many health
care systems, we now have stronger evidence that rapid early treatment
offers the best chance of recovery for acute ischemic stroke patients."
Thrombolytics work as "clot busters," breaking up the
clot that appears in the brain during an ischemic stroke, and allowing
blood to flow freely again in the occluded or blocked artery. Patients
must have computerized tomography (CT) scans of the brain taken
before treatment begins to confirm that the stroke is caused by
a clot. Seventy-five percent of patients who were treated within
60 minutes of stroke onset had the best chance of having a complete
or partial reopening of the occluded artery.
Another significant finding reported by the authors is that severe
stroke patients tend to present to the hospital earlier than patients
with milder strokes, and those who were treated had much better
recoveries than patients who were given a placebo. This means that
the greatest effect of early treatment was seen in the group with
the most to gain in terms of reducing long-term disability.
"This study confirms that door-to-needle time is just as critical
in stroke as it is in heart attack. We need to work on breaking
down the current barriers to rapid stroke treatment," said
Story C. Landis, Ph.D., NINDS director.
The pooled data from the trials two of which were sponsored
by pharmaceutical companies and one that was by the NIH represent
the work of 16 teams of researchers and several statisticians around
the world. "This scientific work is a good example of a cooperative
effort between the Federal Government and the pharmaceutical industry,"
said NIH Director Elias A. Zerhouni, M.D. "By sharing these
important data, the scientists have advanced our understanding of
stroke treatment, which we hope will lead to significant improvements
in treating this major disease."
In 1995, the NINDS t-PA Study Group published the results of two
randomized clinical trials with more than 600 patients that showed
a clear benefit of t-PA in stroke patients treated within 3 hours
of onset and a diminishing effect for patients treated later than
that. [The U.S. Food and Drug Administration (FDA) approved t-PA
as a treatment for acute stroke in June of 1996, with the restriction
that treatment begin within 3 hours of the stroke onset.]
Two other groups have conducted large randomized trials of t-PA
for stroke, using longer windows of treatment. The European Cooperative
Acute Stroke Study (ECASS) conducted two trials using a 6-hour window
and the Alteplase ThromboLysis for Acute Noninterventional Therapy
in Ischemic Stroke (ATLANTIS) investigators conducted two trials
with treatment windows of 5 and 6 hours each. The investigators
from the three studies collaborated to test the hypothesis that
pooling their patient data would show the importance of time to
treatment, and their results appear in The Lancet.
To measure favorable outcome at 3 months, investigators used various
neurological scales to measure post-stroke disability. They also
looked at the occurrence of hemorrhage, the primary risk of t-PA
use. The final analysis included 2,775 patients treated at 300 hospitals
from 18 countries. The median age was 68 years and the median time
of "onset to treatment" was 243 minutes. Substantial intracerebral
hemorrhage occurred in 5.9% of the treated patients as compared
to 1.1% of placebo patients.
Although the data in The Lancet paper suggest that the beneficial
effect of t-PA may extend beyond 3 hours (from 181 to 270 minutes),
the authors caution that large prospective randomized trials would
be required to confirm this finding and that this does not justify
any delays in treatment. The ATLANTIS trial enrolled 79% of patients
in the 4-5 hour window and failed to demonstrate efficacy.
"The most appropriate interval for beginning thrombolytic
treatment remains to be clarified," the authors write in The
Lancet; however they urge those in the health care system, from
paramedics to physicians, to set a target of 1 hour after arrival
in the emergency room to begin intravenous thrombolytic treatment
for patients with acute ischemic stroke.
The ATLANTIS trial was funded by Genentech, Inc., the makers of
t-PA. The ECASS trial was funded by Boehringer Ingelheim Pharmaceuticals,
which markets t-PA in Europe. The NINDS trials were funded by the
NIH. Genentech provided the study drug and additional study monitoring
as required by the FDA.
The NINDS is a component of the National Institutes of Health
within the Department of Health and Human Services and is the nation's
primary supporter of biomedical research on the brain and nervous
This release will be posted on EurekAlert! at http://www.eurekalert.org
and on the NINDS website at http://www.ninds.nih.gov/news_and_events/index.htm.
*"Association of outcome with early stroke treatment:
pooled analysis of ATLANTIS, ECASS, and NINDS
rt-PA stroke trials." Authors: The ATLANTIS, ECASS and NINDS r-t-PA Study Group Investigators. The Lancet, March 6, 2004, Vol. 363, pp. 768-774.