Late Thrombectomy Improves Ischemic Stroke Outcomes

LOS ANGELES—When performed between six and 16 hours after stroke onset, thrombectomy plus standard medical management yields better functional outcomes than medical management alone, according to research presented at the International Stroke Conference 2018. Adjunctive thrombectomy also reduces the rates of death and severe disability, compared with medical management alone.

In 2006, Gregory W. Albers, MD, Coyote Foundation Professor of Neurology and Neurological Sciences and Professor, by courtesy, of Neurosurgery at Stanford University Medical Center in California, and colleagues found that MRI could identify patients with stroke who would benefit from IV t-PA as late as six hours after onset. The investigators developed software called RAPID that could determine how much brain tissue was salvageable in a patient with stroke. In a subsequent study, the software allowed researchers to identify patients who would benefit from thrombectomy at a later point after stroke onset than had been considered possible.

Gregory W. Albers, MD

The DEFUSE 3 Trial

Dr. Albers and colleagues conducted the DEFUSE 3 study to analyze whether patients could benefit from thrombectomy if administered between six and 16 hours after stroke onset. Eligible participants in the open-label trial had an occlusion in the middle cerebral artery or the internal carotid artery, an initial infarct size of less than 70 mL, and a ratio of ischemic tissue volume to infarct volume of 1.8 or more on perfusion imaging. The researchers used the RAPID software to determine how much salvageable tissue each patient had.

“We used fairly broad inclusion criteria,” said Dr. Albers. Patients as old as 90 were included, as were patients with moderate to severe strokes. Participants were required to be free of disability at stroke onset.

Patients were randomized to standard medical management alone or thrombectomy plus standard medical management. Medical management included standard stroke prevention therapies, management of blood pressure, and interventions to prevent complications for stroke such as deep venous thrombosis. The primary efficacy end point was modified Rankin scale score at 90 days. The secondary efficacy outcome was modified Rankin scale score of 0 to 2 at 90 days (ie, functional independence). The primary safety outcomes were death within 90 days and symptomatic intracranial hemorrhage within 36 hours.

Study Was Terminated Early

The patients in DEFUSE 3 were similar to those included in trials of thrombectomy administered within six hours, said Dr. Albers. Median age was about 70 in both study arms. About 50% of the study population was female, and median NIH Stroke Scale score was 16.

The researchers conducted an interim analysis when 182 patients had been enrolled at 38 sites, including 92 randomized to thrombectomy. The results of the analysis prompted them to end the study early because of treatment efficacy.

The unadjusted odds ratio (OR) of a favorable outcome on the modified Rankin scale at 90 days was 2.77 in the thrombectomy group, compared with the medical management group. After adjusting for between-group differences, the OR was 3.36. This result “is the largest odds ratio ever reported for a thrombectomy study,” said Dr. Albers. Approximately 45% of participants in the thrombectomy group achieved functional independence, compared with 17% in the medical management group.

The rate of mortality at 90 days was 14% in the thrombectomy arm and 26% in the medical management arm. The combined rate of death or severe disability was 22% in the thrombectomy group and 42% in the medical management group. The rate of symptomatic intracranial hemorrhage did not differ significantly between groups.

The benefit of thrombectomy on the primary and secondary end points was similar for patients with wake-up stroke and patients for whom stroke onset had been witnessed. “This [result] demonstrates that the DEFUSE 3 treatment benefit is not explained by a potentially shorter onset to treatment time in the wake-up group,” said Dr. Albers. The rate of good outcome was also similar in all three prespecified time periods that the investigators examined (ie, treatment at six to nine hours, nine to 12 hours, and 12 to 16 hours after onset).

Results Informed New Stroke Guidelines

The treatment benefits in this study are “even more significant” than when patients receive treatment within six hours of stroke onset, said Dr. Albers. Part of the reason for this difference is that the doctors who performed thrombectomy were successful at reperfusing the brain. About 80% of patients in the thrombectomy arm had excellent reperfusion, but spontaneous reperfusion occurred in less than 20% of the medical arm.

The updated guidelines from the American Heart Association and American Stroke Association for the management of acute ischemic stroke, which were published in the March issue of Stroke, recommend that neurologists use the DEFUSE 3 criteria to select patients for thrombectomy at six to 16 hours after stroke onset.

“Now that we know that we can successfully treat patients in later time windows, it is going to be important for primary stroke centers to be able to do the type of imaging that was done in the DEFUSE 3 and DAWN trials,” said Dr. Albers.

He added that it is still important to rush as quickly as possible to evaluate stroke patients. “Every minute still counts, and there are some unfortunate individuals whose minutes run dry even when they present during the golden hours after symptom onset. But more importantly, we now know that many stroke patients are considerably more fortunate; their hourglass is much kinder and affords medical providers with a golden opportunity to improve outcomes even in time frames that were once thought to be impossible.”

—Erik Greb

Suggested Reading

Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-718.

Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.