ARTICLE IN BRIEF
Two new studies support the use of endovascular treatment plus tissue plasminogen activator for stroke; both suggest the treatment could be effective beyond the four-hour treatment window.
Stroke specialists still say that “time is brain,” but they also now believe that the potential time window to treat strokes caused by a clot is significantly larger than previously thought.
Recently published studies evaluating stent-retriever thrombectomy following intravenous tissue plasminogen activator (tPA) indicate that certain patients with acute ischemic stroke due to a proximal anterior circulation occlusion can benefit from the procedure when it is done up to six or even eight hours after stroke symptoms appear.
Three hours post-symptom onset became the commonly accepted time frame for treatment limit when tPA was approved for use in the US, though doctors will administer the drug up to about 4.5 hours. While experts stress that sooner is always better for treating stroke, they say a recent string of positive results from studies of stent retrievers suggest that the deadline for treatment is not so hard and fast.
“Historically we relied on the clock on the wall,” Anthony J. Furlan, MD, FAAN, a professor and chair of neurology at Case Western University, told Neurology Today. “Now, as we move toward a physiologic approach to patient selection, there certainly are patients who can benefit well beyond three hours.”
A group of researchers are planning to look further at the question of timing by analyzing pooled patient data from the multiple randomized studies that have been conducted to compare stent-retriever thrombectomy following tPA to tPA alone.
“I think the weight of evidence is clearly there to support treatment within six hours,” said Pooja Khatri, MD, a professor of neurology and rehabilitation medicine and director of acute stroke at the University of Cincinnati, who is organizing the research effort. “The question is: Beyond six hours, is there a patient population that would still benefit from endovascular therapy?”
Just a couple of years ago, the usefulness of thrombectomy seemed in doubt because several studies suggested that doing the added endovascular procedure was no more effective than tPA alone. While stent-retriever devices could successfully open up arteries, it wasn't clear that patients went on to have less disability and improved function as a result. [For Neurology Today's coverage of trials on stent-retriever devices, visit http://bit.ly/NT-stentretriever.]
THE STENT-RETRIEVER APPROACH
Now the evidence has turned in favor of thrombectomy, including two studies published June 11 in The New England Journal of Medicine. One study called REVASCAT, conducted in Spain, included patients who underwent thrombectomy following tPA up to eight hours after the onset of stroke. The other study, an international project with the acronym SWIFT PRIME, had a six-hour cutoff.
The Spanish study was conducted at four stroke centers in Catalonia, Spain, and included 206 patients who had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all the study patients, the initial use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome measure was the severity of global disability at 90 days as measured on the modified Rankin scale, ranging from 0 (no symptoms) to 6 (death). The median time from stroke onset to groin puncture for the thrombectomy group was 269 minutes (about 4.5 hours), though the longest time was 340 minutes (almost six hours). The longest time to revascularization with the procedure was 430 minutes, or just over seven hours.
The researchers reported that thrombectomy used in combination with medical therapy reduced the severity of post-stroke disability over the range of the Rankin scale. At 90 days, functional independence (a score of 0 to 2) was achieved in 43.7 percent of patients who received thrombectomy compared to 28.2 percent of those who received tPA alone. There was higher mortality in the thrombectomy group than the medical group at both seven days and 90 days, but the differences were not statistically significant.
Enrollment for the study was ended because of a loss of equipoise after positive results for thrombectomy were reported for other trials.
“Our study contributes evidence to support the efficacy of neurovascular thrombectomy in patients with anterior circulation stroke who could be treated within 8 hours after the onset of symptoms,” the researchers reported.
The second study, conducted at 39 centers in the US and Europe, included a total of 196 patients. The median time from stroke onset to groin puncture was 222 minutes (just under four hours).
At 90 days post-treatment, the group that received thrombectomy had lower scores across the modified Rankin scale. The rate of functional independence was 60 percent for the stent group compared with 35 percent in the group that received tPA alone.
The study's lead author, Jeffrey L. Saver, MD, FAAN, a professor of neurology at the University of California, Los Angeles, and director of the UCLA Comprehensive Stroke Center, told Neurology Today that “we know that ‘time is brain’ and the faster we get the arteries open, the better the patients will be.” But he said he expects that the time window for stroke treatment with stent-retriever thrombectomy will eventually extend to at least eight hours, and maybe as long as 12 or more. His study found that the 90-day outcome was as good for the patients who received the procedure 189 minutes to six hours after stroke onset as they were for those who had the procedure done in less than 189 minutes.
Dr. Furlan, who wrote an editorial that accompanied the two studies in NEJM, said that “many stroke centers were already performing endovascular therapy even before this definitive new data appeared. Now, even skeptics of endovascular therapy will be convinced.”
At press time, the American Heart Association/American Stroke Association has updated its treatment recommendations for stroke to include using a stent retrieval device to remove blood clots from large arteries in select patients. The updated recommendation was published in the June 29 edition of Stroke.
Dr. Furlan said that several key questions still need to be resolved. For instance: “How far can you extend the window? And what kind of imaging do you need to select the right patients?”
The two latest studies used fairly straightforward imaging with computed tomography (CT) or magnetic resonance imaging (MRI). Dr. Furlan said more sophisticated imaging methods (not just MRI) may be required to optimize patient selection, which will “require acute large vessel imaging and also likely involve assessment of core infarct volume and collateral blood flow.”
Another emerging concern is how to organize stroke care systems in communities so that patients who would benefit from thrombectomy are transported to designated comprehensive stroke care centers where it is offered.
“We need to organize our hospital systems so that people get to the right place and so that the right place is not filled with people who don't need to be there,” said Robert J. Adams, MD, a professor of neuroscience at the Medical University of South Carolina. Primary stroke centers, which offer tPA, will remain an essential part of the equation because most people who have stroke do not meet the criteria for thrombectomy, he said, adding: “We need ways to rapidly identify those people who do so that they are routed routinely to the comprehensive center straight away, if feasible.”
Dr. Adams said getting patients quickly to the most suitable center will always be a priority, but we “are heading in the direction of defining time on a physiological rather than chronological basis. Regardless of how time is gauged, we will always want to keep the time from onset to definitive treatment to a dead minimum.”
In an article published June 2 in Stroke, Dr. Khatri and other stroke experts noted that “the recently presented and published trial results allow the field to progress from asking whether cardiovascular therapy is clinically beneficial to asking who will benefit from endovascular therapy.”
Dr. Khatri said that the pooled analysis — called TREAT — should help answer questions about the best tools and criteria for patient selection and the subsets of acute ischemic stroke patients that are most likely to benefit from thrombectomy. With a larger pool of data to consider, the question of timing might also become clearer, she said.
Dr. Khatri said the recent findings that thrombectomy is beneficial will help fuel interest in developing new medical therapies as well, particularly neuroprotective agents.
“Now that we know we can open arteries up, maybe we can find ways for other therapies to be more effective.”
EXPERTS: ON AN EXPANDED TREATMENT WINDOW WITH STENT-RETRIEVAL THERAPY