If you have an ischemic stroke, an artery supplying blood to brain tissue has become blocked. An ischemic stroke is often due to a blood clot that has become affixed to the artery wall. If you are treated within 4.5 hours of the start of symptoms, you may be a good candidate for tissue plasminogen activator (tPA), a drug that helps dissolve blood clots and restores blood flow.
The use of intravenous tPA beyond 4.5 hours raises the risk of excessive bleeding in the brain or other parts of the body. Because of this, a person who wakes up with stroke symptoms, for example, may not be eligible for tPA. There is no way to know when symptoms started during the night. This is also true for any-one with stroke symptoms that can’t be pinpointed to a specific start time.
However, a study led by Massachusetts General Hospital (MGH) researchers may greatly expand the number of stroke patients who can safely be treated with the clot-buster tPA. The study, published online in Annals of Neurology, describes the results of a trial using magnetic resonance imaging (MRI) technologies to identify patients likely to be within 4.5 hours of stroke onset, even though their initial symp-toms had not been witnessed.
“In up to 25 percent of stroke patients, the start of their symptoms is unwitnessed, preventing them from receiving tPA,” says Lee Schwamm, MD, executive vice chairman of MGH’s De-partment of Neurology and director of the MGH Comprehensive Stroke Center. Dr. Schwamm was the co-lead author of the study, which he says may be particularly helpful for people who experience overnight strokes.
“For many of these patients, the first time anything is noticed is when they get up from sleep-ing,” he explains. “Our study showed for the first time that tPA could be given safely to patients with stroke of unwitnessed onset if their imaging suggested the stroke was very early in its progression and they met other treatment criteria. These results pave the way for a large randomized trial of tPA in patients with unwitnessed strokes.”
In the MGH study, researchers at 14 stroke centers around the country were able to use two different types of MRI imaging studies. One is referred to as FLAIR, which usually shows brain changes several hours after blood flow has been reduced. The other is diffusion-weighted imaging (DWI), which is sensitive to brain changes within the first few minutes of a stroke’s onset.
“Brain tissue that is abnormal on DWI but not yet abnormal on FLAIR has been seen in patients who were four hours or less after known symptom onset,” explains study co-lead author Ona Wu, PhD, of the MGH-based Athinoula A. Martinos Center for Biomedical Imaging—the center at which DWI was first applied to stroke patients.
“That discrepancy provides a snapshot of tissue evolution as the stroke progresses in the first few hours, and that is the pattern we used to select patients for treatment, since they were likely to be similar to patients with known symptom onset who have benefited from tPA. Essentially we used an MR Wit-ness—the name of the trial—to identify patients who might be treated with tPA because their strokes had not progressed to the point of irreversible injury.”
First approved by the FDA in 1996, tPA—also called alteplase—is used to treat ischemic strokes, which account for more than 80 percent of all strokes. The safe use of tPA means that doctors must determine that the stroke was not caused by the rupture of a blood vessel (hemorrhagic stroke), in which case tPA would significantly worsen the bleeding complications. Doctors must also establish how much time has gone by since the onset of symptoms, since restoring blood flow to brain tissue that has incurred too much damage may cause additional harm.
The original time limit for tPA administration was three hours from symptom onset. A large clinical trial in 2009 found that the window could be expanded to 4.5 hours. But for patients whose initial symptoms were not witnessed or whose symptoms clearly began more than 4.5 hours prior to being seen by a doctor, tPA is not approved for use by the U.S. Food and Drug Administration (FDA). This restriction can affect the care of 25 to 30 percent of ischemic stroke patients arriving at hospital emergency departments.
A few small studies have reported good outcomes when such patients, (specifically those with so-called “wake-up strokes”) were administered tPA on the basis of MRI studies consistent with the early effects of ischemic stroke.
The outcomes for the MGH study were similar to those previously reported for patients receiving tPA within 4.5 hours of witnessed strokes. The study authors note that more than 70 percent of participants had experienced wake-up strokes, and that the onset of symptoms may have led to the patients’ awakening. On the basis of these results, the researchers hope to conduct a follow-up, placebo-controlled trial that will also compare MRI with computed tomography (CT) imaging for the identification of patients with unwitnessed strokes who could safely and effectively be treated with tPA.
“If that phase 3 study is successful, it would lead to a paradigm shift in the way acute stroke patients are treated,” says Dr. Schwamm, who is also a professor of Neurology at Harvard Medical School. “Rather than treating based on the number of hours since a stroke began, we can treat based on how much damage the stroke has already caused and how much brain can still be saved. Because the imaging methods we will use in our phase 3 study are available on any MRI or CT scanner in use today, if the results of that trial are positive, the approach could be put into practice immediately.”