Advanced Imaging Trumps Time of Onset for Late Window Stroke Therapy

Pauline Anderson

July 29, 2021

Dr Gregory W. Albers

When it comes to selecting patients for endovascular thrombectomy (EVT), advanced imaging is more important than time from stroke onset, results of a pooled analysis of previous randomized controlled trials suggest.

The new analysis showed that when patient selection for EVT is based on advanced imaging, benefits from the intervention extend up to 24 hours after symptom onset.

The results demonstrate that "imaging trumps the stopwatch," principal investigator Gregory W. Albers, MD, director of the Stanford Stroke Center and professor of neurology at Stanford University, California, told Medscape Medical News.

"A tremendous number of patients can benefit from late-window stroke therapy," said Albers. "To identify them, you need to do the more advanced imaging, ideally profusion imaging, which allows you to identify the largest number of those lucky individuals who can be treated late."

The study was published online July 26 in JAMA Neurology.

Data From Six Key Trials

For the study, investigators used pooled data from six randomized clinical trials.

One study was Diffuse 3, in which patients did not receive treatment beyond 16 hours of stroke onset. Investigators used the target profusion mismatch approach to select patients with a salvageable profile. Here, imaging shows the amount of dead tissue and a profusion map to indicate how big the stroke will be without treatment, said Albers.

"Target mismatch means that the already dead region is smaller than how big the stroke is going to be," he noted.

Another study, the DAWN trial, included patients up to 24 hours after a stroke and used a clinical mismatch imaging technique to select patients. With this approach, experts look at the amount of dead tissue in imaging and use results of a clinical exam using the National Institutes of Health Stroke Scale (NIHSS) to determine stroke severity. A "mismatch" is having numerous symptoms but a relatively small amount of dead tissue.

Although DAWN investigators didn't use the target mismatch approach, they collected data that allowed them to determine whether some patients had target mismatch, said Albers.

"Both these studies had hugely positive results, but the clinical mismatch was more restrictive, so a smaller percentage of patients will be identified as having a favorable profile with the clinical than with the target profusion mismatch," he noted.

More Patients Will Benefit

The other four trials in the analysis included patients both within 6 hours of a stroke and beyond. In these studies, the vast majority of enrolled patients didn't have advanced imaging, although for those that did, researchers could classify them as target or clinical mismatch.

These trials, too, showed overall benefit of EVT but not a statistically significant benefit in a subgroup of a small number of patients beyond 6 hours.

Researchers categorized those without information on the imaging profile and treated beyond 6 hours of a stroke as "undetermined."

The primary outcome of this new analysis was change in 90-day modified Rankin Score (mRS) and the secondary outcome was the rate of mRS scores of 0 to 2 at 90 days.

Researchers adjusted for age, sex, baseline stroke severity based on NIHSS score, site of occlusion (internal carotid artery vs M1 segment of the middle cerebral artery vs M2 segment of the middle cerebral artery), Alberta Stroke Program Early CT Score (ASPECTS), and time from stroke onset to randomization.

Data from the 372 patients with both imaging profiles and 90-day mRS scores were assessed. Of these, 96.5% met criteria for the target perfusion mismatch profile, 79.3% met criteria for the clinical mismatch profile, and 76.1% met criteria for both the target perfusion and clinical mismatch profiles.

Both mismatch groups experienced treatment benefit in terms of lower overall disability and a higher likelihood of functional independence at 90 days (clinical mismatch subgroup: odds ratio (OR), 3.57; 95% CI, 2.29 - 5.57; P < .001; target perfusion mismatch subgroup: OR, 3.13; 95% CI, 2.10 - 4.66; P = .001).

"We knew since DAWN that the clinical profile worked great to 24 hours, but it's more restrictive," said Albers. "Now we know that the target approach works great to 24 hours and it's less restrictive, meaning more people can benefit in this very late time window."

"Time Doesn't Matter"

The results for the undetermined profile group were inconclusive, revealing a nonsignificant favorable numerical difference in overall disability and functional independence at 90 days.

This group had "a very mixed result," said Albers. "If you try to look at people who don't have the imaging, they don't do nearly as well. It reinforces the idea that you really do need this imaging in the late time window."

Thrombectomy was associated with equal benefits among patients with the two mismatch profiles, not only for the entire 6- to 24-hour window, but also within each of three time tertiles (6.0-9.5 hours, 9.6-12.7 hours, and 12.8-24.0 hours).

However, Albers noted the benefit didn't decrease over time, which was surprising. "What this is saying is that the time doesn't matter," he said.

"This shows that if you come in at 18 hours, say, and you still have a good imaging profile, you have a huge treatment effect, so it's really important for these people who come in late to get the imaging," he explained.

What determines why some who present soon after a stroke don't have salvageable tissue while others who present much later do? It all comes down to "collateral," how well other blood vessels can take over where there's damage, said Albers.

Diseases such as diabetes, hypertension, and atherosclerosis play a role in determining this collateral, as might certain genes, and age is not that big a factor, said Albers.

"Robust" Data

In an accompanying editorial, Jean-Claude Baron, MD, Department of Neurology, Hôpital Sainte-Anne, Université de Paris, France, notes that the design and sample size of the new analysis allows for "robust" conclusions.

"The results are clear," he writes. "Thrombectomy was associated with equal benefits among patients with the two mismatch profiles, not only for the entire 6- to 24-hour window but also within each time tertile."

Applying this finding to routine care would substantially increase the currently small proportion of patients presenting more than 6 hours after stroke onset who could receive this beneficial and reasonably safe therapy, said Baron.

"This particularly applies to the patients in the 16- to 24-hour window who fulfill the target mismatch criteria, which are more inclusive than the clinical mismatch criteria."

It seems sensible that the results of this new study, and their implications, "would be implemented in forthcoming international guidelines," Baron writes.

However, he added, the question of whether a subset of patients with larger ischemic core volumes (> 70 mL) could benefit from thrombectomy beyond 6 hours "remains unanswered."

Also still unclear is whether thrombectomy might be associated with benefits among selected patients beyond 24 hours, he adds.

Albers reports receiving consulting fees from Genentech and owning equity in iSchemaView outside the submitted work.  

JAMA Neurol. Published online July 26, 2021. Abstract, Editorial

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