Maximizing the Benefit of Endovascular Therapy in “Large Core” Strokes.

Effective Endovascular Therapy (EVT) for Ischemic Stroke: 10 years of Expanding Use

Endovascular therapy (EVT to remove thrombi in major cerebrovascular arteries has revolutionized the treatment of acute ischemic stroke since publication of five critical randomized trials in 2015. Effective EVT therapy was first demonstrated in patients with occlusions of the internal carotid artery and/or major middle cerebral artery trunk within 6 hours from onset with imaging on CT and MRI that didn't show large areas of evolving cerebral ischemia/infarction. Subsequent trials used imaging and the clinical exam to identify patients beyond 6 hours from onset who had smaller areas of evolving severe cerebral ischemia and infarction and larger areas of "salvageable" brain that had decreased cerebral perfusion but had yet to progress to infarction. These patients with a "mismatch" between smaller areas of "ischemic core" and larger areas of salvageable brain, defined as the penumbra, also benefited substantially from EVT in the DAWN and DEFUSE 3 trials. Subsequent randomized trials of patients with basilar artery thrombosis similarly demonstrated the effectiveness of EVT.

The Benefit of EVT in Patients with Large Ischemic Cores

The current Scientific Advisory summarizes the results of six clinical trials which address the next important clinical question: Can EVT improve outcome in those patients with a large "ischemic core" as measured by non-contrast CT, diffusion imaging on MRI, or CT perfusion imaging? Understanding these trials first requires how to interpret imaging of the "ischemic core."

As the Scientific Advisory states, "core, in the setting of ischemic stroke, is defined as the volume of cerebral tissue that is irreversibly injured or infarcted." But imaging of decreased density on non-contrast CT, diffusion-weighted change on MRI, and regions of very low estimated blood flow on CT perfusion are not equivalent to ischemic infarction/ischemic core on subsequent pathologic examination of the brain. They are better considered as good, but not perfect, predictors of cerebral infarction or the true ischemic core. These imaging markers of "ischemic core" are less predictive of irreversible infarction the earlier the images are obtained from stroke onset and become much better predictors as time after stroke onset progresses. Regardless of the imaging modality and time from stroke onset, the larger the area of "ischemic core", the greater likelihood of a poor functional outcome.

Physicians often don't want to take on cases where the outcome is generally poor, complications are higher, etc. But physicians must differentiate between predictors of poor outcome and treatment benefit. The scientific advisory summarizing the large core trials clearly illustrates this difference. Prior EVT trials of patients with smaller ischemic cores report that nearly half of participants were functionally independent at 90 days. In contrast, only one-fifth (19.5%) of patients with large ischemic cores treated with EVT in these six trials achieved functional independence. This underscores the severe disease in this patient population and the predictive value of imaging. However, this rate of functional independence after EVT was more than double that of maximum medical therapy (7.5%), suggesting a number-needed-to-treat of approximately 8 to prevent one functionally dependent outcome. Thus, imaging predicts outcome but doesn't predict the benefit of EVT in the populations of patients selected for the six trials.

Similarly, independent ambulation was achieved more frequently by patients with large ischemic cores treated with EVT. The ANGEL-ASPECT trial most notably underscored this advantage, with 47.0% of EVT patients regaining the ability to walk independently versus 33.3% for maximal medical therapy. The SELECT2 trial also demonstrated EVT's benefit, although with a slightly narrower gap of 37.9% for EVT against 18.7% for maximal medical therapy. This pattern persisted throughout the trials, confirming the robustness of EVT's impact on mobility outcomes.

Where Are the Data for EVT in Large Core Patients Still Lacking

The results from these six clinical trials examining the efficacy of endovascular therapy (EVT) consistently show a substantial benefit of EVT with regards to functional independence and ambulation, but the trials varied in how patients were selected clinically and by type of imaging. Subgroups of patients from these trials with more limited data regarding the benefit of EVT include age 85 years and older, prestroke disability (mRS > 1), vessel tortuosity, treatment after 12 hours from onset, very large cores on CT and MRI imaging (ASPECTS of 0-2) treated after 6 hours from onset, CT perfusion measurements of ischemic core > 150 cc, no core-penumbra mismatch on perfusion imaging, and use of intravenous lytic therapy. Thus, while these trials provide strong evidence of EVT's benefit in patients who have good pre-stroke functional status (mRS 0-1) and significant stroke severity (NIHSS ≥ 6) with occlusion of the ICA or proximal middle cerebral artery and a larger ischemic core (ASPECTS 3-5) on initial imaging, data are limited to support EVT treatment of patients with matched core/perfusion, very advanced age, and those with very large cores (ASPECTS of 0-2) beyond 6 hours from last known normal. These underrepresented subgroups warrant additional study in ongoing or future trials.

Summary

 Effective stroke treatment has once again expanded to include some of the sickest ischemic stroke patients as determined by brain imaging. Implementation of the new scientific data will require a change in mindset for those interventionalists and stroke physicians who previously excluded these patients from treatment because of their poorer prognosis and lack of evidence for EVT. There is no doubt that patients with large ischemic cores will generally have poorer functional outcomes after EVT than less sick patients, but there is also no doubt that EVT in a good majority of these patients provides the best chance to improve their odds of a better outcome.