For release: Wednesday, December 13, 1995
A 5-year clinical trial has shown that treatment with the clot-dissolving drug t-PA* is an effective emergency treatment for acute ischemic stroke despite some risk from bleeding. The trial found that carefully selected stroke patients who received t-PA treatment within 3 hours of their initial stroke symptoms were at least 30 percent more likely than untreated patients to recover from their stroke with little or no disability after 3 months. The nationwide study of more than 600 stroke patients was organized and funded by the National Institute of Neurological Disorders and Stroke (NINDS). Results appear in the December 14, 1995, issue of The New England Journal of Medicine.**
"Stroke, which leaves millions of adults disabled, is one of the most devastating and costly health problems that we face," said Zach W. Hall, Ph.D., director of the NINDS. "The positive result of this trial should be encouraging to all Americans at risk of stroke who hope to live to a healthy, independent old age. A notable feature of this study is that its quality sets a very high standard for future clinical trials."
Each year, about 500,000 Americans suffer a stroke. Of these strokes, 400,000 are ischemic, caused by a blood clot that reduces blood flow to the brain. The remaining 20 percent are hemorrhagic strokes, caused by bleeding into the brain. Stroke ranks as the third leading cause of death in the country after heart disease and cancer, killing about 150,000 Americans each year. The overall cost of stroke to the nation is estimated to be $30 billion each year.
In the two-part NINDS trial conducted at nine centers across the country, 624 patients received either intravenous t-PA or a placebo within 3 hours of the initial symptoms of a stroke. Before treatment could start, a medical team performed a CT scan to be sure the stroke was not caused by bleeding, administered a variety of blood tests, and obtained informed consent. Part 1 of the trial was designed to look for marked improvement in the patients' conditions 24 hours after treatment and, secondarily, to examine efficacy of the treatment at 3 months. Part 2 was designed to confirm the long-term benefit of the drug. In both parts, there was a dramatic 3-month improvement in those who received t-PA. The investigators demonstrated that the number of patients with complete or almost complete recovery was increased by 30 percent or more as measured by four different medical outcome scales. For every 100 patients receiving t-PA, at least 11 more had an excellent recovery as measured by the four scales. A powerful statistical approach, the global test statistic, combined information from all four outcome scales in order to compare the odds of an excellent outcome between treatments. The overall odds in favor of the t-PA treated group were 1.7 times greater than the placebo group.
The drug t-PA works by dissolving the blood clots that block brain arteries and cause over 80 percent of all strokes. Although it has been proven effective in the treatment of heart attack, t-PA's potential as a treatment for stroke has been unclear because of an increased risk of brain hemorrhage. In the NINDS trial, bleeding into the brain within 36 hours of treatment worsened strokes in 6.4 percent of those patients who received t-PA compared to 0.6 percent of those who received placebo. Overall, however, there were greater numbers of stroke survivors who were able to live normal lives in the t-PA treated group, leading the investigators to conclude that the use of t-PA for stroke is beneficial. Furthermore, the NINDS trial showed lower levels of brain hemorrhage than previously published stroke trials involving clot-dissolving drugs.
According to the investigators, timing is a critical factor. Over the past 12 years basic and clinical scientists have been working to discover the window of opportunity for emergency treatment of stroke. Based on research in animal models and clinical observations, the NINDS t-PA clinical investigators designed their highly coordinated emergency treatment program to work within the narrow time window of 3 hours.
"One of the keys to the success of this study was treating stroke as the true emergency that it is. The concept that stroke is every bit as serious as heart attack is one that physicians must recognize in order for this new treatment to have widespread benefit," said Thomas Brott, M.D., clinical investigator at the University of Cincinnati Medical Center in Ohio, the study site that treated the most patients.
Because of the risks involved, investigators urge physicians to take a cautious approach before introducing the use of this new stroke treatment. "It would be a mistake for physicians with limited experience in treating stroke to rush in and begin treatment with t-PA," said Patrick D. Lyden, M.D., clinical investigator at the University of California at San Diego School of Medicine. "Starting t-PA treatment more than three hours after stroke could easily result in a much higher rate of bleeding into the brain." He also emphasized that t-PA should be given only after a complete evaluation of the patient including a careful examination of a brain CT scan.
The investigators agree that substantial efforts by the health care community will be necessary before t-PA can be used on a widespread basis. These efforts include intensive public education about the signs of stroke and the importance of immediate treatment; the organization and training of medical personnel to evaluate and treat stroke patients; as well as planning for the rapid transport of patients to treatment centers through emergency medical services.
"This is a major breakthrough that will forever change the way stroke is treated. After years of discouraging results, the positive results of this trial will lead to renewed efforts to make even more progress in treating and preventing the devastating consequences of stroke," said John R. Marler, M.D., NINDS neurologist and project officer for the trial.
Principal investigators participating in the trial were: Thomas Brott, M.D., University of Cincinnati Medical Center, OH; Patrick D. Lyden, M.D., University of California, San Diego; James C. Grotta, M.D., University of Texas Medical Center, Houston; Thomas Kwiatkowski, M.D., Long Island Jewish Medical Center, New Hyde Park, NY; Steven R. Levine, M.D., Henry Ford Hospital, Detroit, MI; Michael R. Frankel, M.D., Emory University, Atlanta, GA; E. Clarke Haley, Jr., M.D., University of Virginia Medical Center, Charlottesville; Michael Meyer, M.D., University of Tennessee Medical Center, Knoxville and Memphis. Barbara C. Tilley, Ph.D., headed the Coordinating Center at Henry Ford Health Science Center, Detroit, MI. K.M.A. Welch, M.D., Henry Ford Health Science Center, Detroit, MI, was the medical monitor and chairman of the steering committee. John R. Marler, M.D., was the NINDS project officer for the trial.
The NINDS is the nation's principal supporter of research on the brain and nervous system and a lead agency for the Congressionally designed Decade of the Brain. The Institute supports and conducts a broad program of basic and clinical neurological investigations and is part of the National Institutes of Health, located in Bethesda, MD.
*t-PA = tissue plasminogen activator.
**The National Institute of Neurological Disorders and Stroke t-PA Stroke Study Group. "Tissue Plasminogen Activator for Acute Ischemic Stroke." The New England Journal of Medicine, Vol. 333, No. 24, pp. 1581-1587.
Originally prepared by Margo Warren and Norman Oliver, NINDS Office of Communications and Public Liaison.
Last Modified August 7, 2009