An independent review of data from a landmark clinical trial has validated the benefit of using the clot-busting drug tissue plasminogen activator (tPA) for ischemic stroke, when given within three hours of symptom onset under a strict treatment protocol.
The reanalysis of the National Institute of Neurological Disorders and Stroke’s (NINDS) tPA for Acute Ischemic Stroke trial is published in Stroke: Journal of the American Heart Association.
The findings of the original NINDS trial on 624 patients were published in 1995. Researchers found that “despite an increase in incidence of symptomatic intracerebral hemorrhage (bleeding in the brain), treatment with intravenous tPA within three hours of the onset of ischemic stroke improved clinical outcome at three months.”
In 1996, after a detailed review of the NINDS data, the U.S. Food and Drug Administration approved tPA use for stroke caused by a blocked blood vessel (ischemic) within three hours of symptom onset. Based on the trial and the FDA approval, several groups, including the American Heart Association and the American Academy of Neurology, recommended tPA for acute ischemic stroke within three hours of symptom onset.
Yet, other medical groups concluded that there was insufficient objective evidence to warrant tPA as a “standard of care.” They were concerned about the risk of intracerebral hemorrhage, about whether an imbalance in baseline stroke severity between the two treatment groups biased the results in favor of tPA treatment, and about whether the trial results could be generalized.
While some subsequent studies found the use of tPA to be safe in the clinical setting, other studies documented bleeding and death rates higher than in the NINDS trial.
Today, fewer than 10 percent of acute ischemic stroke patients are treated with tPA because of the limited time window and these cited concerns about the drug’s safety and efficacy, said Timothy John Ingall, M.D., Ph.D., lead author of the independent reanalysis.
To address the concerns raised about the trial, NINDS commissioned an independent committee of stroke physicians and biostatisticians to reanalyze the data from the 1995 trial. Committee members had no connection with NINDS, the original tPA trial, or companies that manufacture tPA. Committee members reanalyzed the data to assess the tPA treatment effect, the potential effect of a baseline imbalance in stroke severity between the treatment groups, and whether subgroups – such as older people, or those with diabetes – benefit from receiving tPA.
“We found a statistically significant and clinically important benefit of tPA therapy despite the previously reported increased incidence of symptomatic intracerebral hemorrhage in tPA-treated patients and subgroup imbalances in stroke severity,” said Ingall, associate professor of neurology at the Mayo Clinic Scottsdale, in Arizona. “Patients receiving tPA were twice as likely to have a favorable outcome compared to those receiving placebo.”
The committee identified several problems with the blood pressure measurement and management in the trial. However, they concluded that “adjusting for blood pressure would be unlikely to have an impact on the relation between use of tPA and the likelihood of having either a favorable outcome or symptomatic intracerebral hemorrhage.” They said further clinical trials will be needed to assess whether blood pressure management is related to better clinical outcomes in acute ischemic stroke patients treated with tPA.
They also found that the imbalance in baseline stroke severity “did not invalidate the results of the trial.”
No subgroup of patients responded differently to tPA; however, there were not enough patients in the study to adequately assess subgroups. Larger studies are needed to identify groups of patients that might be more likely to either benefit from or be harmed by receiving tPA.
“This review should put to rest the controversy concerning the integrity of the NINDS tPA trial and the analysis and interpretation of the study’s results,” said American Stroke Association spokesperson Larry B. Goldstein, M.D. “The reanalysis further reinforces recommendations that the drug be used in carefully selected patients in strict accord with the NINDS protocol.
“We hope the medical community will support public awareness programs and hospital systems so that stroke patients and their caregivers will be encouraged to call 9-1-1 when symptoms appear, to get to the hospital within the critical time window to receive tPA.”
Ingall said the clinical experience gained since 1996 has shown that the drug is most effective when administered within stroke care systems that adhere to the study protocol.
“Professional organizations representing health professionals who are involved in treating acute stroke patients should work collaboratively to develop guidelines on the resources necessary for institutions to treat all acute stroke patients effectively, administering tPA when appropriate,” he said.
Co-authors are William Michael O’Fallon, Ph.D.; Kjell Asplund, M.D., Ph.D.; Lewis Robert Goldfrank, M.D.; Vicki S. Hertzberg, Ph.D.; Thomas Arthur Louis, Ph.D.; and Teresa J. Hengy Christianson, B.S.