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DALLAS -- Large ischemic strokes benefited from mechanical thrombectomy in two trials, supporting an expanded use beyond the currently recommended use only for smaller ischemic cores.

In the from China that treated patients with anterior circulation infarcts in the 70-100 mL range or an Alberta Stroke Program Early CT Score (ASPECTS) of 3 to 5, scores on the modified Rankin scale (mRS) shifted toward better outcomes with endovascular therapy compared with medical management alone (generalized OR 1.37, 95% CI 1.11-1.69, P=0.004).

In the international that treated cases with an ASPECTS value of 3 to 5 or a core volume of at least 50 mL, mRS scores likewise moved toward functionally independent survival, with a generalized odds ratio for a shift in the distribution favoring thrombectomy of 1.51 (95% CI 1.20-1.89, P<0.001), yielding a number needed to treat of about 5 for one patient to achieve better functional outcome.

The findings of these two trials, presented at the American Stroke Association's International Stroke Conference (ISC) and simultaneously published online in the New England Journal of Medicine, covered a population largely excluded from trials that laid the groundwork for thrombectomy becoming the standard of care for smaller-core ischemic strokes.

Trial Implications

Stroke guidelines recommend mechanical thrombectomy for only the populations studied in those positive trials -- largely those with ischemic-core volumes of less than 50 mL.

"The concerns that have limited the use of thrombectomy to smaller strokes arise from potential reperfusion injury in necrotic brain tissue, resulting in an increased risk of hemorrhage, edema, disability, and death," noted Pierre Fayad, MD, of the University of Nebraska Medical Center in Omaha, in an the papers.

"Together, the trials provide reassuring information from more than a thousand patients with large ischemic strokes in different medical systems that will probably lead to changes in patterns of care delivery," he wrote. "It is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes (which represent about 20% of all ischemic strokes due to proximal occlusion of a cerebral vessel) if they arrive in a timely fashion at a center that is capable of performing the procedure and if the patients have an ASPECTS value of 3 to 5 or an ischemic-core volume of 50 mL or greater."

ISC chair and session moderator Tudor Jovin, MD, of Cooper Neurological Institute in Camden, New Jersey, agreed that the findings should be rapidly implemented in practice and suggested a shift in triage as well.

"I think we are paying too much attention on selection and building our systems of care and transfer pathways along trying to find out how large the exact size of the core of the infarct, and what these two studies are telling me is that it may not matter that much," he said in an interview with MedPage Today.

While infarct size is prognostically important, a CT scan might be sufficient without advanced perfusion imaging or MRI, Jovin suggested. "Why should we spend all that precious time before reperfusion in finding out what the size of the infarct is for prognostic purposes? ... I hope that these trials will open the door to such radical changes in systems of care."

There were increased risks with thrombectomy in ANGEL-ASPECT and SELECT2 that need to be communicated to patients and their families, but these risks were exceeded by the benefits and will be "welcome news for the patients and for the field of stroke treatment," Fayad noted.

Both trials had been stopped early at interim analyses after the positive results of a similar Japanese randomized trial became known, albeit with questions of wider applicability based on its exclusively Japanese cohort, use of a lower alteplase dose before thrombectomy than is typical in some other countries, and the selection of patients on the basis of MRI, which is more sensitive than CT, as Fayad noted.

ANGEL-ASPECT

The ANGEL-ASPECT trial, presented at the meeting by Zhongrong Miao, MD, of Beijing Tiantan Hospital, enrolled 456 patients at 46 comprehensive stroke centers in China from Oct. 2, 2020 through May 18, 2022, who were randomly assigned within 24 hours from the time last known to be well to medical management alone or with mechanical thrombectomy. Intravenous thrombolysis was used for approximately 28% of the patients in both groups.

Among secondary endpoints, more thrombectomy patients had a 90-day mRS score of 0 to 2 (30.0% vs 11.6%; relative risk 2.62, 95% CI 1.69-4.06) or of 0 to 3 (47.0% vs 33.3%; RR 1.50, 95% CI 1.17-1.91). Results were similar across patient subgroups and trial sites, although the trial was underpowered for these comparisons.

Among the safety endpoints, thrombectomy significantly increased any intracranial hemorrhage within 48 hours (49.1% vs 17.3%; RR 2.71, 95% CI 1.91-3.84) but not symptomatic intracranial hemorrhage (6.1% vs 2.7%; RR 2.07, 95% CI 0.79-5.41).

Hemicraniectomy was numerically but not significantly more common after endovascular therapy than with medical management alone (7.4% vs 3.6%; RR 1.92, 95% CI 0.78-4.73). No significant differences emerged in other serious adverse events or in mortality within 90 days (21.7% vs 20.0%).

The researchers noted the comparable risks in the prior Japanese trial, although 63.3% of the ANGEL-ASPECT patients were enrolled in the 6- to 24-hour time window compared with 28.6% in the Japanese trial.

SELECT2

The SELECT2 trial, presented by Amrou Sarraj, MD, of University Hospitals Cleveland Medical Center and Case Western Reserve University in Ohio, enrolled 352 patients from the U.S., Canada, Europe, Australia, and New Zealand. Median age was 66.5 years, 41% were women, and 14% of the patients were Black. Median time from last known well to randomization was 9.31 hours, median ASPECTS value was 4, and the mean estimated ischemic-core volume was 80 mL.

Participants were randomly assigned to mechanical thrombectomy or medical care alone within 24 hours after onset of stroke due to occlusion of the internal carotid artery or the first segment of the middle cerebral artery. Standardized imaging evaluation comprised of noncontrast CT and, depending on site preference, either CT perfusion imaging or diffusion-weighted MRI. While the trial was sponsored by Stryker Neurovascular, its products were not specified to be used as part of the protocol, nor did it provide equipment for the trial. Thrombolytics were used for 20.8% of thrombectomy patients and 17.3% of controls.

Among the secondary outcomes, the proportion of patients with a 90-day mRS score of 0 to 2 was 20.0% in the thrombectomy group and 7.0% with medical care alone (RR 2.97, 95% CI 1.60-5.51) and for scores of 0 to 3 were 37.9% and 18.7%, respectively (RR 2.06, 95% CI 1.43-2.96).

Symptomatic intracranial hemorrhage was characterized as infrequent (0.6% with thrombectomy and 1.1% with medical care alone; RR 0.49, 95% CI 0.04-5.36). Mortality risk at 90 days was similar between groups (38.2% vs 40.8%; RR 0.91, 95% CI 0.71-1.18).

Early neurologic worsening -- an increase of 4 or more points on the NIH Stroke Scale -- was more common after thrombectomy (24.7% vs 15.5%; RR 1.59, 95% CI 1.03-2.45), and in a post hoc analysis was linked to worse functional outcomes at 90 days (generalized OR 0.58, 95% CI 0.45-0.74). These patients tended to have larger ischemic-core lesions to start with. However, no subgroups saw significantly different benefits of thrombectomy in the trial, including site-rated ASPECTS categories and enrollment based on large core volumes.

"This direction of effect persisted in patients with an ischemic-core volume greater than 100 mL and greater than 150 mL, although functional independence (a score on the modified Rankin scale of 0 to 2) was less frequent in these patients than in those with smaller ischemic cores," the researchers noted.

While both trials were stopped early, which raises questions of whether the magnitude of benefit seen from the intervention might have been larger than if the trials had continued, Jovin suggested that this wasn't likely to be much of a concern despite the modest sample sizes.

"What counts most in my mind is that they are positive," he said. "The treatment effects must be pretty solid, and we know that even a 5% treatment effect is something that would be significant to patients and to the community and the treatment effects -- they're way above that."