New Study Supports Extended Time for tPA in Ischemic Stroke to 9 Hours
By Ed Susman
March 21, 2019
Article In Brief
An international team of investigators reported that the thrombolysis with tissue plasminogen activator was safe and effective up to nine hours after ischemic stroke. The team, which used automated penumbral imaging, suggest that ischemic penumbra can exist up to 24 hours after onset, and salvaging it can lead to improved outcomes.
HONOLULU—Stroke patients who have viable brain tissue can safely and effectively undergo tissue plasminogen activator (tPA) thrombolysis as long as nine hours after onset of stroke symptoms, researchers reported here at the 2019 International Stroke Conference, sponsored by the American Stroke Association, in February.
In the primary outcome measure, 37 percent of patients treated with tPA in the nine-hour window—including those with so-called ‘wake up’ strokes— achieved a modified Rankin Scale (mRS) score of 0-1 at 90 days compared with 29 percent of patients who were treated with placebo in the so-called EXTEND (Extending the Time for Thrombolysis in Emergency Neurological Deficits) trial (p=0.045), said Henry Ma, MD, PhD, director of physician training at Monash University in Melbourne, Australia.
Fifty-one percent of the patients treated with tPA achieved an mRS score of 0-2 at 90 days—a secondary outcome measure—compared with 43 percent of the patients on placebo therapy (p=0.022), Dr. Ma said in his late-breaker oral presentation.
“EXTEND is the first positive thrombolysis trial in an extended time window using automated penumbral imaging,” he said. “The current guideline for thrombolysis in acute ischemic stroke is less than 4.5 hours from stroke onset. But advanced imaging studies from our group and others suggest that the ischemic penumbra can exist up to 24 hours after onset and its salvage can lead to improved outcome.”
In the trial, the researchers used an automated algorithm using CT scans to determine penumbral mismatch and to select likely candidates for tPA thrombolysis.
Study Methods, Findings
In the study, 113 patients received thrombolysis and 112 patients were assigned to placebo. The patients receiving tPA were older—with a mean age of 74 compared with a mean age of 71.4 for patients receiving placebo patients. Ten percent of the patients were treated in the 4.5–six hour time frame; 25 percent were treated in the six–nine hour time frame; and 65 percent of the patients had wake up strokes. The median time from onset of symptoms to therapy was 7.2 hours; the median time from last known well to therapy was 8.9 hours for placebo patients and 9.9 hours for tPA patients.
Death at 90 days occurred in 9.5 percent of the placebo patients and in 10 percent of the patients who received tPA (p=0.94). Symptomatic intracranial hemorrhage occurred in 1.0 percent of those taking placebo and in 6 percent of the patients who received tPA (p=0.071).
“I think these results will help us push the window out further for the use of thrombolytic drugs as long as it looks like you have patients with salvageable brain.”
—DR. JOSEPH P. BRODERICK
“There was an increase in the rate of symptomatic intracranial hemorrhage consistent with other thrombolytic trials, but this was not associated with increased mortality and did not negate the positive results of the improved rate of excellent functional outcome,” Dr. Ma said.
Commenting on the study, Joseph P. Broderick, MD, FAAN, professor of neurology at the University of Cincinnati said: “It makes sense that anything that can open up the vessel among people who have brain at-risk and not dead brain could benefit these stroke patients. This study did meet its primary endpoint.”
Other smaller studies fell short of that, Dr. Broderick told Neurology Today. He said that new imaging studies can identify brain that has very low blood flow and decreased blood flow and might be salvageable if those areas can be reperfused, and that is what was used in the EXTEND study. He also noted that mechanical removal of clots beyond the time frame for thrombolysis had also indicated that this ‘not dead yet’ brain tissue could be salvaged.
Dr. Broderick said the success of the thrombectomy studies made it necessary to end EXTEND before the full complement of 310 patients had been recruited because doctors were sending the EXTEND candidates to thrombectomy.
“I think these results will help us push the window out further for the use of thrombolytic drugs as long as it looks like you have patients with salvageable brain,” he said. “In general, the longer you wait, the worse you get, but there are people who have enough collateral flow that gives us a longer time window to treat them. But you still want to treat as quickly as possible.”
“We now should be thinking of a physiological clock rather than a chronological clock in assessing these stroke patients,” Dr. Broderick suggested. “But you have to treat as soon as possible after you get that physiological picture because the clock keeps ticking.”
Other researchers said that the EXTEND trial should not be a cue to patients with stroke symptoms to wait around before calling for help.
“Even though we may be able to extend the tPA window to nine hours, obviously getting it in six hours is better and three hours is [even] better.”
—DR. LOUISE D. MCCULLOUGH
“The clinician in the emergency room now knows that there may be a window of opportunity to use tPA. The patient needs to remember to get care as soon as possible.”
—DR. DANIEL T. LACKLAND
“We used to not think that you could use tPA after three hours or 4.5 hours,” Daniel T. Lackland, DrPH, professor of epidemiology at the Medical College of South Carolina in Charleston, told Neurology Today. “I think that time will always be important. The implications of this trial are more important for the clinician that may be administering tPA than for the patient who is receiving it. The clinician in the emergency room now knows that there may be a window of opportunity to use tPA. The patient needs to remember to get care as soon as possible.”
Dr. Lackland said that downside of the EXTEND study is that it could give people who have the early symptoms of stroke—a bad headache or weakness upon getting up from bed—an excuse to think: they have nine hours to get to the hospital. “People with these symptoms should just go to the hospital and get the good news that there is nothing wrong with you.”
Miguel Perez-Pinzon, PhD, chair of the International Stroke Conference 2019 Program Committee, and professor of neurology/neuroscience at the Miller School of Medicine at the University of Miami, agreed. “Patients with symptoms or relatives who see patients with symptoms need to call 911 immediately.”
“Even though we may be able to extend the tPA window to nine hours, obviously getting it in six hours is better and three hours is [even] better,” added Louise D. McCullough, MD, PhD, chair of neurology at McGovern Medical School at the University of Texas Health Science Center in Houston.
Dr. Ma had no relevant disclosures.