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In the Clinic-Stroke
Thrombectomy Window Extended Up to 16 Hours

ARTICLE IN BRIEF

About 45 percent of patients who underwent endovascular therapy plus medical therapy had a favorable outcome at 90 days — a score of zero to two on the modified Rankin Scale — compared with 17 percent of the patients receiving medical therapy alone, according to findings from the DEFUSE trial.

LOS ANGELES–Patients diagnosed with major strokes who miss the tight time window for intravenous thrombolytic therapy appear to have dramatic positive outcomes if they are subsequently treated with mechanical thrombectomy within an extended six-hour to 16-hour period after stroke symptoms are discovered, researchers said here at the International Stroke Conference. The findings were simultaneously published online January 24 in The New England Journal of Medicine.

About 45 percent of patients who underwent endovascular therapy plus medical therapy had a favorable outcome at 90 days — a score of zero to two on the modified Rankin Scale (mRS) — compared with 17 percent of the patients receiving medical therapy alone (p<0.001), said Gregory W. Albers, MD, the Coyote Foundation Professor and professor of neurosurgery at the Stanford University School of Medicine in California.

In his presentation of the DEFUSE 3 study, Dr. Albers also reported that the 90-day mortality rate was 14 percent in the endovascular-therapy group and 26 percent in the medical-therapy group (p=0.05); there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage — 7 percent among the patients undergoing thrombectomy compared with 4 percent of patients just getting medical treatment (p=0.75); and no significant difference in overall serious adverse events — 43 percent among patients undergoing thrombectomy compared with 53 percent of patients assigned to medical treatment only (p=0.18).

Patients were assigned to either thrombectomy or medical therapy alone after undergoing computed tomography (CT) or magnetic resonance imaging (MRI) screening using a software program known as RAPID, which could determine if there was more compromised brain tissue than tissue that had already been destroyed by the stroke. If the volume of the at-risk tissue was 1.8 times that of the dead tissue, then patients were eligible for entry into the study.

At the conference, Dr. Albers said about half the patients with stroke in which disability was measured at a score six or greater on the National Institutes of Health Stroke Scale showed evidence using the RAPID test that viable brain tissue could be salvaged despite the patients last known status of being well six to 16 hours earlier.

Of the 92 patients assigned to endovascular therapy, at 90 days 10 percent had a mRS of 0;16 percent had a score of one, and 18 percent had a score of two. There was 14 percent mortality in this group.

Of the 90 patients assigned to medical therapy only, 8 percent had a mRS of zero at 90 days, 4 percent had a score of one, and 4 percent had a score of two. The mortality in this group at 90 days was 26 percent.

EXPERT COMMENTARY

“You have to remember that the patients in the DEFUSE 3 study are very carefully selected. All of them had large vessel intracranial occlusions,” said Jose Biller, MD, chairman and professor of neurology and director of the Stroke Center at Loyola University, who was not involved in the study.

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DR. GREGORY W. ALBERS said about half the patients with stroke in which disability was measured at a score six or greater on the National Institutes of Health Stroke Scale showed evidence using the RAPID test that viable brain tissue could be salvaged despite the patients last known being well was six to 16 hours earlier.

He told Neurology Today that the six- to 16-hour window for use for mechanical thrombectomy in the DEFUSE 3 trial enables patients with so-called wake-up strokes to be eligible for assessment in anticipation of mechanical thrombectomy. “There is no question there will be a new structure for stroke treatment, including making sure there are people available to perform these procedures 24/7,” he said.

Dr. Biller suggested that the concept of “tissue is brain” rather than “time is brain” may be advancing, but that treatment as soon as possible is still the standard of care. “The sooner you treat a patient with stroke, the better. Even though we have now expanded the window, you can't relax and say, ‘We can wait another hour.’

“We have robust data now for use of thrombolytics within three hours of stroke onset, and within 4.5 to six hours there is an expansion of use with caution,” Dr. Biller said. “Now there an expansion of use for mechanical thrombectomy between six and 24 hours,” he said, referring to findings of the DAWN trial (published online in November in The New England Journal of Medicine).

“What I suspect is going to happen is that this numerical severity of the stroke as measured by the NIH Stroke Scale will be blurred,” he said. “DAWN [the trial that extends the treatment window to 24 hours] finds patients had to have a score of 10; with DEFUSE, it was six. But patients may have aphasia, a very disabling symptom, and the maximum score for aphasia is three points. So, if a patient has aphasia and limb weakness that would be a score of five, and it is a bad stroke. So, doctors have to use judgment in cases like this,” he said.

Clinicians do not have to use the RAPID algorithm on imaging to decide on whether the patients are eligible for mechanical thrombectomy, Dr. Biller said. Local institutional imaging assessments can be made that would be as accurate — if a bit more time-consuming — to configure.

The inclusion of patients who had longer times from the patients' last known normal status add more patients to the mix of those eligible for treatment, he said, but it still leaves the medical world short of treatments for patients with other strokes such as “the basilar artery, posterior circulation strokes that have not been part of these studies.”

“DEFUSE 3 really is a big deal,” said Bruce Ovbiagele, MD, MSc, FAAN, the Admiral Paul E. Pihl Endowed Professor of Neuroscience and chairman of neurology at the Medical University of South Carolina in Charleston. “This is a big population that has devastating outcomes and many of these patients are having very good outcomes with mechanical thrombectomy in this trial.”

In addition, said Dr. Ovbiagele, “We are gaining an understanding of the pathophysiology of these types of strokes. For a long time were have considered that ‘time is brain.’ But this issue of tissue can be very, very important. We are trying to understand why in some patients the tissue dies very quickly and not so in others. By performing this intervention in the eligible patients, we are going to prevent a large number of people from having devastating effects of stroke.”

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DR. JOSE BILLER said the six- to 16-hour window for use for mechanical thrombectomy in the DEFUSE 3 trial enables patients with so-called wake-up strokes to be eligible for assessment in anticipation of mechanical thrombectomy. “There is no question there will be a new structure for stroke treatment, including making sure there are people available to perform these procedures 24/7.”

DISCLOSURES

Dr. Albers disclosed a relevant relationship with iSchemaView, the company that owns the RAPID software that was used in the trial.

LINK UP FOR MORE INFORMATION:

• Albers GW, Marks MP, Kemp S, et al; for the DEFUSE 3 Investigators. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging http://www.nejm.org/doi/full/10.1056/NEJMoa1713973. N Engl J Med 2018; Epub Jan 24.
    • Nogueria RG, Jadhav AP, Haussen DC, et al; for the DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct http://www.nejm.org/doi/full/10.1056/NEJMoa1706442. N Engl J Med 2018; 378:11–21.