LOS ANGELES — Time is brain has been a hard-fought mantra in acute stroke care. Decades after introduction of IV thrombolysis, the still-slow climb in rates of use show just how difficult.
The time-focused message is butting up against the DEFUSE 3 and DAWN trials, showing that a mechanical thrombectomy treatment window out to 16 and even 24 hours still can benefit imaging-selected patients, and newly-released American Heart Association/American Stroke Association guidelines officially promoting that extended window.
A subanalysis of DEFUSE 3 presented after the main results at the International Stroke Conference (ISC) here showed just how unimportant time was for thrombectomy outcomes when patients presented beyond 6 hours were selected with perfusion imaging.
Whereas the likelihood of good functional outcome (modified Rankin Scale score 0-2) dropped precipitously as time at presentation increased from 6 hours to 16 in that trial among patients in the medical treatment-only arm, the mechanical thrombectomy arm saw exactly the same likelihood of functional independence at hour 6 as at 16.
The discussion immediately turned to how to manage the interpretation.
“How do we as practitioners manage the messaging around it? Because it could foster some complacency a little bit. You don’t want any complacency,” said Bruce Ovbiagle, MD, of the Medical University of South Carolina in Charleston, who chaired a press conference where the findings were presented. “We’ve been pushing that for a long time. We don’t want to dilute our message in any way.”
“We certainly don’t want to give the message that it’s okay to delay treatment, that it’s okay to delay coming to the hospital,” agreed Maarten Lansberg, MD, of Stanford University in Stanford, California, who presented the substudy. “The message here is time is still important; it is not too late when it’s 6 hours. Even at 16 hours and probably up to 24 hours, there is still a subset of the population that’s going to benefit.”
Gregory Albers, MD, also of Stanford, presented the main DEFUSE 3 results at ISC, and said that the extended-window thrombectomy studies provide the next evolution in stroke beyond a simple time is brain mantra.
That mantra gained urgency with the approval of tissue plasminogen activator (tPA) in 1996 with just a 3-hour window. But as imaging developed in the 1990s, it also became clear that strokes developed uniquely — some patients who came in immediately after symptom onset had massive infarcts whereas others remained small hours after onset.
In 2006, the first DEFUSE trial tested tPA out to 6 hours with MRI to predict response. Albers’ group developed the RAPID software to see how much brain tissue is salvageable, which has been used in thrombectomy trials to select patients for that treatment.
“With DAWN and DEFUSE , the world is moving from a time clock to a tissue clock,” commented Jeffrey Saver, MD, of the University of California Los Angeles But, he clarified, “it’s no longer just a time clock, it’s also a tissue clock.”
Although imaging can find patients all along the time spectrum who still have salvageable tissue that would stand to benefit, it’s still important to rush at every point along the line.
“The time is still critical because a smaller percentage of the people you check with that perfusion imaging will have that good brain,” J Mocco, MD, of Mount Sinai Hospital in New York City, said in panel discussion at the DEFUSE 3 press conference. “But once you use the imaging to select the patient, it’s completely reasonable that they would have a consistent treatment effect, because you’ve selected the ones that are going to have that benefit.”
After the imaging, “we still want everyone, even at 12 hours, to move as fast as they can,” Ralph Sacco, MD, of the University of Miami and president of the American Academy of Neurology, told MedPage Today. “In other studies, it is clearly shown that the longer it takes to open the vessel, the worse the outcome. So we need to keep that message going that time is brain, and that minutes count, and we need to get these vessels open pretty quickly.”
“The only good thing I think for the public is, when you wake up with a stroke and you’re out of that 6-hour time window, because last known well was when you went to bed, there is now hope,” he added.
The changing maxim also opens up more opportunities for research, noted Ovbiagele. “What is it about these patients who, for whatever reason, their strokes are developing more slowly as opposed to the people who are developing rather quickly? People tend to say it’s collaterals; we continue to study that. But I think you have 50% [of patients] with this who come in not eligible … others somehow are going slowly. I think it will be important for us to think about this.”
DEFUSE 3 was funded by the National Institute of Neurological Disorders and Stroke.
Lansberg disclosed no relevant relationships with industry.
Albers disclosed relevant relationships with iSchemaView, Medtronic outside DEFUSE 3, and a patent licensed to Stanford University for automated detection of arterial input function and venous output function voxels in medical imaging.
Mocco disclosed a relevant relationships with Penumbra.