For release: Thursday, March 4, 2004
A study in the March 6, 2004, issue of The Lancet ¹ 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 thrombolytics.
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 system.
¹Association 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.
Last Modified March 20, 2013