ARTICLE IN BRIEF:
A secondary analysis of data from the large phase 3 DEFUSE 3 trial found that endovascular therapy can be beneficial, regardless of age, mild symptoms, or late presentation in patients with large-vessel strokes and salvageable tissue on CT and MRI.
Patients with strokes caused by large vessel occlusions benefitted universally from receiving endovascular thrombectomy, according to a new paper published in the online January 28 edition of JAMA Neurology.
“This finding simplifies the clinical decision-making regarding candidates for endovascular thrombectomy. Patients up to the age of 90 with imaging evidence of large occlusions and substantial salvageable brain tissue should be considered,” lead investigator Maarten Lansberg, MD, PhD, associate professor of neurology at Stanford University School of Medicine, told Neurology Today.
This secondary analysis of the DEFUSE 3 randomized, controlled trial adds to the previous findings that late window (six to 16 hours) endovascular thrombectomy plus medical therapy significantly improved functional outcomes and reduced mortality compared with medical therapy alone.
The positive results from DEFUSE 3 and DAWN, both studies of endovascular therapy initiated beyond six hours after stroke onset, led the American Heart Association to adopt a later time window for administering endovascular thrombectomy in its 2018 guidelines.
The DEFUSE 3 trial was conducted between May 2016 and May 2017 and funded by the National Institutes of Health. The researchers analyzed the data of 182 patients who had acute ischemic strokes due to an occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA) and evidence of salvageable tissue on perfusion CT or MRI.
Fifty-one percent (92) of the 182 patients were women, the median age was 70 [interquartile range 59-80], and the median score on the NIH Stroke Scale (NIHSS) was 16 (11-21), according to the paper.
Ninety-two patients were randomized to the endovascular treatment arm and 90 patients were randomized to the control arm (medical therapy alone). The study was stopped early for efficacy.
The primary outcome was a 90-day assessment of functional outcomes based on the modified Rankin Scale (mRS). The secondary outcome was the percentage of patients who were functionally independent (mRS score of 2 or less) at 90-days after randomization.
The common odds ratio for improved functional outcome with endovascular therapy, adjusted for age, NIHSS score, and serum glucose was 3.1 (95%CI, 1.8-5.4). The probability of being functionally independent (with an mRS of 0-2) at day 90, declined with older age and higher NIHSS scores in the endovascular and medical treatment arms. However, 20 percent of very elderly persons achieved functional independence following thrombectomy compared to nearly zero in the medical control group.
The researchers concluded that endovascular therapy was universally beneficial among trial participants based on no significant interaction with the independent variables analyzed: age (range 23-90 years), baseline stroke severity (NIHSS range 6-38), time to randomization (range 6-16 hours), arterial occlusive lesion location (ICA or MCA) or imaging modality used to qualify patients (CT or MRI).
“We were surprised by the overall results, particularly by the findings that older patients and patients who were treated towards the end of our 16-hour time-window experienced similar benefits from thrombectomy compared to younger patients and patients treated earlier,” said Dr. Lansberg.
The major study limitation was the small sample size, which limited the power to demonstrate significant differences in treatment effects between these subgroups.
Whether thrombectomy is effective in patient subgroups excluded from DEFUSE 3, such as patients older than 90 and with very large infarcts on their baseline imaging scans, remains to be answered by future randomized controlled trials, said Dr. Lansberg.
In the meantime, Dr. Lansberg and his colleagues are currently trying to improve stroke outcomes for patients transferred from peripheral hospitals to tertiary care centers with comprehensive stroke centers.
“The transfer can take up to four hours and meanwhile patients' strokes worsen and the amount of viable brain tissue shrinks,” he said. “To prevent that, we are very interested in studying neuroprotective drugs that could slow down or temporarily stop the expansion of the ischemic infarct so that patients remain good candidates for thrombectomy when they arrive.”
The findings support previous overall trial data involving endovascular thrombectomy showing that the treatment was robust across different ages, stroke severities, time to treatment, imaging modality used, and MCA versus ICA occlusion site, independent experts said.
“This should reassure clinicians that as long as they meet the imaging criteria, they should be less concerned about these specifics,” said Andrew Demchuk, MD, professor of neurology in the department of clinical neurosciences and radiology at the University of Calgary Cumming School of Medicine.
The DEFUSE and DAWN studies also highlighted how poorly patients with large vessel occlusion and small ischemic core do without endovascular treatment intervention. “The number of patients who achieve independent outcomes in the control arm falls off dramatically to very low levels if randomized close to 16 hours from onset. We had expected greater improvement in these patients with medical management because their infarcts were initially so small with good collateral flow,” said Dr. Demchuk.
He noted that due to the relatively small sample sizes in the individual late window trials, a pooling together of all trial data in a large database (AURORA) is underway to explore other subgroups in this late window.
Dr. Demchuk and his colleagues plan to start a randomized control trial this year called ENDOLOW to focus on whether thrombectomy will benefit people with large vessel occlusions but milder stroke severity than what was included in the DEFUSE 3 trial.
“We have very little information from early- or late-window trials in mild stroke when the NIHSS scores are below 6, which has been the stroke severity cutoff for enrollment in most prior endovascular trials.”
Bruce Ovbiagele, MD, MSc, FAAN, professor of neurology and associate dean at the University of California, San Francisco School of Medicine, was not surprised that the timing of treatment initiation was not critical in this sample. “This underscores what we know about the pathophysiology of slowly evolving strokes—that they tend to occur in people with a large amount of salvageable brain tissue and good collateral flow compared to people with rapidly evolving strokes.”
The research also underscored the benefits of having a longer therapeutic window and using imaging (CT/MRI) to measure patients' salvageable brain tissue to select patients for endovascular thrombectomy.
“These windows into the brain tissue status have radically changed what neurologists do with stroke treatment. In clinical practice, the uncertainty involving when the stroke occurred has been a major barrier to initiating thrombectomy,” said Dr. Ovbiagele. For example, in the DEFUSE 3 study, only one-third of the 182 patients had witnesses to their strokes compared with two-thirds without witnesses, he said.
Besides the small sample, the study was limited by a lack of data on the magnitude of the treatment benefits for the three main variables analyzed: age, stroke severity, and time to treatment, according to Dr. Ovbiagele. “When we discuss the benefits of thrombectomy treatment with patients, it would be helpful to know the magnitude of the treatment effects.”
Because the elderly will continue to have more severe strokes and a poorer prognosis than younger people, Dr. Ovbiagele suggested that future studies focus on the interaction between treatment, older age, and stroke severity. “I would like to know if an 88-year-old comes to me with a very devastating stroke what his quality of life will be after thrombectomy.”
Dr. Lansberg has received consulting fees from Novo Nordisk Genentech, Biogen, and Moeach, Inc.