Endovascular Therapy May Benefit Large-Core Strokes

Pauline Anderson

November 11, 2016

Endovascular treatment (ET) appears to benefit some stroke patients who present with a large ischemic core but with a large mismatch profile — significant volumes of viable but critically hypoperfused tissue.

The results are "very compelling" and consistent with those of a recent meta-analysis, said study author Raul G. Nogueira, MD, Department of Neurology, Emory University School of Medicine, Atlanta, Georgia.

"They show that there are patients who have historically been deemed unlikely to benefit from this therapy who in reality seem to benefit."

This study, the first to assess the effects of ET in patients with a large baseline ischemic core and large mismatch profile by using a matched case-control method, could have important implications for clinical practice, according to the authors.

The study was published online November 7 in JAMA Neurology.

Patients with large ischemic cores are usually not offered reperfusion treatment because it's believed that they will have a poor outcome.

The study included stroke patients who underwent multimodal computed tomography (CT) evaluation about 190 minutes after symptom onset, with intracranial internal carotid artery and/or middle-cerebral artery occlusion on CT angiography.

They had baseline ischemic cores greater than 50 mL (mean, approximately 80 mL), and significant volumes of viable but critically hypoperfused tissue (mean Tmax > 6 seconds and ischemic core > 200 mL).

Using a matched case-control method, researchers retrospectively analyzed 28 paired cases: those who underwent ET and those who did not. The decision to treat or not to treat a patient with a large infarct on presentation was left to the treating neuroendovascular specialist, with common agreement with the stroke team and patients' families.

The two groups were matched for age, baseline ischemic core volume on CT perfusion (CTP), and glucose levels.

The mean age was 62.25 years for the cases and 58.32 for the controls. Men made up 46% of the case group and 50% of the control group.

The primary outcome was the shift in the degree of disability among the treatment and control groups, as measured by the modified Rankin Scale (mRS) at 90 days. Scores on this scale range from 0 (fully independent) to 6 (dead).

Favorable Shift

The study showed that thrombectomy treatment was associated with a favorable shift in the overall distribution of 90-day mRS scores (odds ratio, 2.56; 95% confidence interval [CI], 2.50 - 8.47; P = .04).

Controlling for age, glucose level, and baseline ischemic core on CTP or Alberta Stroke Program Early CT (ASPECT) score yielded the same results.

In the intervention group, 25% had good outcomes (mRS score of 0 - 2), but none of the patients in the control group had a good outcome (P = .04).

The final ischemic volumes (FIVs) were significantly smaller in the treatment group (86.59 vs 241.99 mL; P < .001). Parenchymal hematoma type 2 occurred in 7% of the treatment group and 4% in the control group (P > .99). There were lower rates of hemicraniectomy and mortality in the intervention group.

The researchers created another matched study population with a baseline ischemic core greater than 70 mL that included 12 pairs.

This analysis showed a significant reduction in FIVs in the treatment group (109.80 vs 319.11 mL in the control group; P < .001) but only a nonsignificant improvement in the overall distribution of mRS scores that favored the treatment group (P = .18).

In the treatment group, 40% achieved functional independence compared with none in the control group (P = .24).

Marked Reduction

The "marked" reduction in FIVs in the treatment group should "theoretically lead to better functional outcomes," the authors say.

The benefits of this intervention seemed to be more pronounced for patients younger than 75 years. All older patients had poor outcomes, regardless of treatment, although Dr Nogueira pointed out that "the numbers are very small when you get to this point."

But since the treated patients were a little older, "if anything, the study was biased against the people who were treated, at least when it comes to age," said Dr Nogueira.

The new study results could affect who gets ET therapy, he said. "If physicians have patients who have a large stroke, many think there's nothing they can do, and that can be true if the whole brain tissue at risk has already died, but if there are still areas of the brain that haven't died yet, you can rescue those areas, and the patients will do better than if they didn't have treatment."

In the past, said Dr Nogueira, many doctors had a "nihilistic approach" toward stroke because until recently there hasn't been a lot to offer patients. "So in a way, it has become a self-fulfilling prophecy."

But now there's evidence that ET can be effective in a broader group of patients. In addition to the current study, a meta-analysis of recent trials (HERMES) came to a similar conclusion.

"Our results and their results essentially mirror each other," said Dr Nogueira.

However, in a previous trial — the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) — only 17% of patients with large cores had a good outcome after ET. That study used older devices, while this new study used stent retriever technology. These newer devices are "associated with safer, faster, and more complete reperfusion," the authors say.

The next step for Dr Nogueira and his team is to organize a randomized controlled trial. In the meantime, with these new results, "it's very reasonable to offer this treatment to a selective group of these patients," he said.

Mounting Data

In an accompanying editorial, David S. Liebeskind, MD, Neurovascular Imaging Research Core, University of California, Los Angeles, points out that the study "builds on mounting data from a variety of approaches with CT and MRI that question the way we use imaging and the process of how we consider optimal therapeutic strategies for patients with stroke."

The new results, in combination with other recent reports using different imaging definitions of large infarcts, suggest that individual stroke outcomes and novel opportunities to expand therapeutic benefit of endovascular thrombectomy are "undeniably multivariable and informed by multidimensional imaging," Dr Liebeskind writes.

He pointed out that delineating lesion size or extent of ischemic on CT or MRI is "fraught with difficulty" because parenchymal changes "may be almost imperceptible, and automated algorithms for volume calculation may use relatively arbitrary values of a single variable, acquired at a single time point in a dynamic process."

Dr Liebeskind concludes that the study authors "nicely suggest" that the response to ET may not be "black and white."

"There are likely infinite shades of gray or uncertainty that emanate from the extensive variability across individuals, illustrated by stroke imaging."

Imaging Criteria

For a comment, Medscape Medical News approached Ralph L. Sacco, MD, professor and Olemberg Chair of Neurology, chief of neurology, Jackson Memorial Hospital, and director, Clinical & Translational Science Institute, University of Miami, Florida.

Dr Sacco found the results "intriguing" and "promising," but because it was a small case-control study, he doesn't believe it will have a huge impact on practice.

"For evidence-based guidelines, we normally require randomized trials, although case-control studies can be helpful."

The study "provides further substantiation that we need to do more research on the imaging criteria," said Dr Sacco.

Currently, experts "grapple" with how to define ischemic core and profusion deficit criteria to most appropriately select patients for ET, said Dr Sacco. "There is still a lot of debate in terms of which measurement or technique to use," whether Tmax should be used, and whether CT or MRI should be used.

Two larger trials — DAWN and DEFUSE 3 — may provide some answers, he said. "These studies are trying to systematically define better quantitative imaging protocols for us to use in clinical practice."

As it stands now, said Dr Sacco, ET is typically considered appropriate in cases "where you have a small ischemic core but a huge profusion deficit, and that's usually the group that is most likely to have more of what is salvageable brain."

Experts sometimes exclude patients with a big ischemic core from receiving ET. "The concern is that they already have evidence of a big infarct and there is less to gain by doing ET," said Dr Sacco.

"This new study calls that into question by saying that despite having a reasonably moderate to large ischemic core, plus mismatch, there could still be benefit."

The study received no external funding. Dr Nogueira reported receiving support from Stryker Neurovascular, Covidien, and Penumbra. Dr Liebeskind reported working as a consultant to Stryker and Medtronic and is employed by the University of California, which holds a patent on retriever devices for stroke.

JAMA Neurol. Published online November 7, 2016. Abstract, Editorial

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