Rethinking the six-hour rule for stroke victims

Hospitals reexamine treatment protocols after studies show patients can benefit up to 24 hours after stroke symptoms begin.
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Across the country, hospitals have begun reexamining stroke protocols in the wake of groundbreaking research conducted at academic medical centers that’s upending prior notions about the time window for life-saving stroke treatment.

Two studies published in the New England Journal of Medicine in early 2018 found that physicians have longer than previously thought after the onset of stroke to remove a brain clot and still yield significant health impacts. In fact, the two studies—known as DEFUSE 3 and DAWN—produced such compelling evidence that they were stopped early so control group members and the wider public could benefit. 

In light of the research spearheaded by researchers at Stanford University Medical Center and the University of Pittsburgh Medical Center, the American Heart Association and American Stroke Association released new guidelines on the early management of acute ischemic stroke in January 2018, expanding the eligibility for thrombectomy—mechanically removing a blood vessel clot—to up to 16 hours after stroke for some patients and up to 24 hours for others. Previously, the window of time from stroke onset was just six hours.

“Getting treated in this new time window can have a huge impact on a patient’s survival as well as on quality of life.”

Gregory Albers, MD
Stanford University Medical Center

According to the Centers for Disease Control and Prevention, stroke kills about 140,000 Americans each year and is a leading cause of long-term disability. Around 87% of strokes are ischemic, which means blood flow to the brain is blocked.

“Getting treated in this new time window can have a huge impact on a patient’s survival as well as on quality of life,” says Gregory Albers, MD, professor of neurology at Stanford University Medical Center and director of the Stanford Stroke Center.

“[The six-hour guideline] was helpful for rushing people to the hospital, but it led us to believe that there was no chance for effective treatment after that,” Albers explains, “and that was a huge mistake.”

Rethinking conventional ‘time is brain’ standards

Albers is lead investigator on the DEFUSE 3 study, which found that for certain patients, removing a clot up to 16 hours after initial stroke onset led to better functional outcomes than standard treatment with medication alone.

“You still have to apply the same sense of urgency that you [previously] would within the zero- to six-hour time frame.”

Tudor Jovin, MD
University of Pittsburgh Medical Center Stroke Institute

A key to the research was imaging software known as RAPID, which Albers and colleagues at Stanford developed to quickly generate maps of dead or damaged brain tissue. Using results from a CT scan or a perfusion MRI, which shows blood flow, the software identifies patients likely to benefit from a thrombectomy.

DEFUSE 3 found that employing thrombectomy in stroke patients with a certain amount of salvageable brain tissue is effective up to 16 hours after symptoms begin. In fact, the approach garnered impressive results: 45% of thrombectomy patients achieved independent functioning versus 17% of stroke patients who did not receive the procedure. Within 90 days of the study, 14% of the thrombectomy group died versus 26% of the control group.

“I really cannot overstate the size of this effect,” said Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke, in an agency news release about the findings. 

DEFUSE 3 reinforced findings from the DAWN trial, which also used RAPID but had narrower eligibility criteria for patients and looked at a larger timeframe. To select thrombectomy candidates, both DAWN and DEFUSE 3 trials relied on “mismatch” data—the amount of infarcted, or dead, brain tissue compared to the amount of potentially salvageable tissue. However, the DAWN trial recruited patients with smaller infarcted areas of the brain than DEFUSE 3 and considered a window of 6 to 24 hours.

Among DAWN’s findings was that the measured rate of functional independence 90 days after treatment was 49% among patients who underwent thrombectomy compared with 13% in the control group.

Tudor Jovin, MD, a principal investigator on DAWN and director of the University of Pittsburgh Medical Center Stroke Institute, points to a key takeaway message: “You still have to apply the same sense of urgency that you [previously] would within the zero- to six-hour time frame, but that time frame doesn’t matter anymore in terms of the decision [about how] to treat patients.”

A dramatic shift in stroke care

Nationwide, hospitals are working on how to revise stroke triage protocols in light of the new guidelines as well as to implement the imaging techniques the researchers used to identify slow-growing strokes. In addition, the new guidelines will likely require more coordination between smaller hospitals that assess possible thrombectomy candidates and stroke centers that perform the procedure.

“It’s definitely going to take time,” Albers says. “But for the sake of patients, hospitals should be moving on this as quickly as possible.” Albers’ own institution launched a new 24-hour stroke protocol for thrombectomy eligibility in November—a change that took about four months of planning, he reports.

Many hospitals already have or will easily be able to offer the imaging techniques used in DAWN and DEFUSE 3, but not all will. 

“We’re getting lots of calls from the regional hospitals wondering how to determine who to send to the regional [stroke] center,” says Michael Froehler, MD, PhD, director of the cerebrovascular program at Vanderbilt University Medical Center, which was a DEFUSE 3 research site and has shifted its stroke procedures to meet the new, extended window. “A lot of these smaller hospitals don’t have resources to pay for advanced imaging or the workforce to perform advanced imaging.”

Although the new research shows that the RAPID software may be ideal for finding newly eligible thrombectomy candidates, Froehler says he tells local hospitals that it’s not the only way to determine which patients to transfer for more advanced care. For example, he says if a patient arrives six-plus hours after onset with clinical stroke symptoms but no large infarct on a CT scan, he or she would be eligible for possible intervention.

In addition, Jovin notes that thrombectomy has considerable benefits even when clinicians identify candidates using only the commonly used National Institutes of Health Stroke Scale and plain CT scan results.

“I don’t think you have to have RAPID to make these new decisions,” says Jovin, a professor of neurology and neurosurgery at University of Pittsburgh School of Medicine. “If a patient has a good scan, they very likely have a small infarct and can be further assessed at the endovascular center.”

Rapid transfer still essential

Froehler cautions that the longer treatment windows should not unintentionally encourage complacency in stroke response. He highlights research he copublished in Circulation in 2017 showing that interhospital transfers for stroke were associated with significant treatment delays and lower chances of good outcomes.

“Time is still brain. At some point, the clock runs out.”

Gregory Albers, MD
Stanford University Medical Center

“Earlier treatment is always better,” he notes. “So we can’t afford to be any slower in our workflow process.”

Regarding such concerns, Albers notes that the message of the new guidelines certainly isn’t to change the urgency around stroke response.

“Time is still brain,” he says. “At some point, the clock runs out.”

However, discovering exactly when that clock runs out is the “next frontier,” says Jovin, adding that it’s unlikely that the same time window applies to all patients. “There’s nothing magical,” he says, “about the clock striking 24 hours.”