Down to the Core of the Paradox: Thrombectomy in Large Stroke and Favorable Outcome — Do Time and Mismatch Matter?

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Down to the Core of the Paradox: Thrombectomy in Large Stroke and Favorable Outcome — Do Time and Mismatch Matter?

Chen J, Nie X, Wang M, Zhang D, Sun D, Pan Y, Huo X, Li Z, Miao Z, for the ANGEL-ASPECT Study Group. Time-Dependent Impact of Mismatch Profiles on Outcomes Following Endovascular Thrombectomy for Large Ischemic Stroke. Stroke. 2026;57:641–649.

Patients with large-core infarctions have long been considered poor candidates for reperfusion therapy.(Why?) Although six recent randomized controlled trials evaluating endovascular therapy (EVT) versus medical management have since largely challenged this view, only 20 to 30% of these patients achieve functional independence at 90 days. In small-core infarctions, perfusion mismatch between the irreversibly damaged tissue of the core and the salvageable penumbra has become the cornerstone of EVT decision-making, particularly in the late time window. However, whether the same principle applies to large-core infarctions is uncertain. Notably, previous subgroup analyses yielded conflicting results, and it remains unknown whether perfusion mismatch can reliably inform EVT decisions in large-core infarctions across different time windows.

The authors performed a secondary, post hoc analysis of the ANGEL-ASPECT trial, a multicenter randomized controlled trial comparing EVT with medical management in adults aged 18-80 years with acute ischemic stroke and large-core infarction of the anterior circulation defined as: ASPECTS 3-5 within 24 hours, or core volume 70-100mL and either ASPECTS 0-2 within 24 hours or ASPECTS > 5 at 6-24 hours. Perfusion mismatch was defined using two criteria: (1) mismatch ratio ≥ 1.8 and mismatch volume ≥ 15mL, or (2) mismatch radio ≥ 1.2 and mismatch volume ≥ 10mL. Unadjusted logistic regression assessed the association between treatment and 90-day functional independence (mRS 0–3), including treatment-by-mismatch interaction within each time stratum (≤6 versus >6 hours) and treatment-by-time interaction in the overall cohort. Secondary outcomes included recanalization, 90-day mRS distribution, mortality, and intracranial hemorrhage.

Using the most stringent definition, 346 of the 426 participants (81%) displayed a perfusion mismatch. In the early time window (≤ 6 hours), EVT was associated with higher odds of functional independence at 90 days among patients with a perfusion mismatch compared with medical management alone (49 vs 28%; OR 2.41 [95% CI 1.28–4.55]), whereas no benefit was observed in those without a mismatch. In the late window, EVT conferred no significant advantage, aside from a non-significant trend toward benefit in the no-mismatch group. Treatment-by-mismatch and treatment-by-time interaction tests were not statistically significant for primary and secondary outcomes. Sensitivity analyses excluding wake-up stroke yielded consisted results. Any ICH occurred more frequently in the EVT group, while rates of symptomatic ICH were comparable across treatment arms.

Overall, this post hoc analysis suggests that among patients with large-core infarctions, those imaged within the early time window and exhibiting a perfusion mismatch may, as predicted by the core/penumbra model, derive the greatest benefit from EVT, whereas benefit in the late-time window appeared less dependent on mismatch status. These results contrast with subgroup analyses from SELECT-2,1 which reported EVT benefit irrespective of mismatch status, but partially align with those of TESLA,2 which did not meet its primary endpoint yet, somewhat unexpectedly, suggested a trend toward EVT benefit primarily in patients without a mismatch. Notably, some patients with no apparent mismatch still experienced favorable outcomes with EVT in extended time windows, further challenging the large-core paradox. Such findings may reflect favorable baseline characteristics; however, alternative explanations, including imaging limitations, overestimation of the core, residual tissue viability (so-called heterogeneity within the core), and reduction of vasogenic edema, cannot be excluded.3

Considering the limited subgroup sizes, potential selection bias with high prevalence of perfusion mismatch, and the unadjusted nature of the statistical analyses, these findings should be interpreted with caution. Current guidelines do not support selecting or excluding patients from EVT solely based on perfusion imaging,4 and further studies are needed to clarify how perfusion mismatch profiles and imaging timing should inform EVT decisions in large stroke.