In recent years, mechanical thrombectomy (MT) has demonstrated its compelling efficacy in reducing mortality and functional dependence for patients with acute ischemic stroke (AIS) due to anterior proximal vessel occlusion (PVO) [1,2]. Patients with an unfavorable imaging profile at baseline, assessed using magnetic resonance imaging (MRI) diffusion weighted imaging (DWI) volume core (≥70 mL) [1], or the computed tomography (CT)-based-Alberta Stroke Program Early CT score (ASPECTS) <6, were excluded in four of the seven randomized clinical trials that validated MT in AIS-PVO [3], precluding to draw strong conclusions in this subgroup. Hence they are typically not offered MT in clinical practice [1], despite converging evidence suggesting a benefit of MT despite large ischemic core (LIC), with almost 25% of patients experiencing favorable functional outcome after MT [3-9].

Perfusion imaging is used in the diagnostic work up of AIS to identify hypo-perfused yet not infarcted (e.g., ‘at-risk’ or ‘salvageable’) brain tissue [10], and to estimate the core perfusion mismatch ratio (CPMR) [2]. Nonetheless, perfusion data remain very scarce in patients with LIC before MT, while they are critically needed to pragmatically design future randomized trials, and better select patients for MT until then.

We hypothesized that perfusion imaging may enhance the effective selection of AIS-PVO patients with LIC by determining those likeliest to benefit from revascularization and tested this hypothesis in a cohort study using data from a multicenter cohort, by comparing the rates of favorable functional outcome, symptomatic intracerebral hemorrhage (sICH), and case-fatality in patients with DWI assessed baseline LIC (>70 mL) and perfusion who received MT versus patients who were treated with intravenous thrombolysis only. The hypothesis driving this analysis was that in patients with baseline large infarct cores, identification of significant remaining penumbral tissue, as assessed using CPMR, would translate to better outcomes after MT.

In this multicenter collaborative study we showed that (1) MT is strongly beneficial on clinical outcome of patients with large infarct core at baseline, and persisting core/penumbral mismatch (CPMR >1.72 in our sample and by extension >1.8), with no heterogeneity in treatment effect across strata of CPMR and (2) that MT does not increase the odds of sICH and mortality.

The question of the best treatment approach for AIS-PVO patients with large infarct at baseline remains unanswered, despite being amongst the most timely and relevant in acute stroke care. There is indeed a critical need to assess treatment opportunities expansion to those patients that were excluded from princeps MT trials (especially patients with LIC, that are at critical risk of poor functional outcomes and for which guidelines remain ambiguous), and may in turn not be offered MT, despite a potential benefit. Until the results of dedicated trials such as Exploration of the limits of mechanical thrombectomy indications in a single action-Large Stroke Therapy Evaluation (IN EXTREMIS-LASTE) or Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time Window (TENSION) become available, the community faces a challenge in the treatment strategy for this subgroup.

Expectedly, our results are in line with previous studies [3,4,7,19-21] demonstrating the direct correlation between larger infarct core sizes decreased odds of favorable functional outcome. In our sample as a whole, for every 10 mL increase in core volume, there was a 22% increase in the risk of unfavorable outcome, and a 26% increase in the risk of 90 days functional dependence. Our results, in that sense, confirm that presenting with a large infarct at baseline is of poorer prognosis and do support careful expectations’ management with families and caregivers.

Less intuitively, but substantiating our working hypothesis, increasing CPMR was also associated with lower chance of favorable outcome, with an odd decrease of 81% for every mismatch unit increase. This finding was not unexpected, since patients with higher CPMRS are at inherent higher risk for infarct progression within the hypo-perfused area, until recanalization or if recanalization doesn’t occur, or not fast enough. In our sample, the benefit of MT over the control group became significant above a CPMR of 1.72 corresponding to a minimal penumbral volume of 50.4 mL (e.g., if the patient has a core volume of exactly 70 mL) and was stable in the stratified subgroup of patients with CPMRS above 1.7. Although the conceptual framework supporting the benefit of MT in patients with PVO and target mismatch has been substantiated by a large number of publications, including the cornerstone studies from the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) group [13,22], there is still limited dedicated studies in the specific subgroup of patients with larger infarcts at baseline. Rebello et al. [5] demonstrated in a sample of 24 patients with large infarct cores assessed using CT perfusion (cerebral blood flow <30%; 70 mL) and an penumbra volumes (Tmax >6 seconds) above 40 to 50 mL that MT was associated with significant reduction in final infarct volumes (110±65 mL vs. 319±147 mL, P<0.001) but only a nonsignificant improvement in the overall distribution of mRS scores favoring the treatment group (P=0.18). These neutral results with regards to clinical outcome, are likely due to insufficient power, in this subgroup limited by a binary design that excluded patients with limited mismatch, precluding to further test interaction between MT effects and CPMR. More recently, Campbell et al. [15] showed in post hoc analyses of individual patient level data from The Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration, that amongst the 583 patients with computed tomography perfusion (CTP), the interaction between CPMR and endovascular treatment effect was not significant (P=0.15), but statistical power was strongly limited by the small number of patients not meeting criteria (less than 5% with a CPMR <1.8 amongst the 583 patients with CTP). In this study, CTP mismatch volume was negatively associated, in univariate analysis, with functional improvement (common odds ratio per 10 mL 0.96; 95% CI, 0.93 to 0.99; P=0.009) reinforcing the conceptual balance paradox by which larger mismatch volumes are associated with decreased favorable outcomes due to increased possibilities of infarct progression, and in turn explaining the increasing benefit of MT as CPMR increases, a notion that had not been confirmed before our study in patients with larger infarct cores.

In secondary analyses, we did not show a significant association between MT and the risk of sICH, and there was conversely a positive interaction between infarct core volume and treatment group, in favor of MT. There’s been several reports on the risk of sICH after MT in LIC, none of which showed an increase in the risk of sICH after MT except in the HERMES collaboration [3] where, for patients with ASPECTS 0-4, sICH was more frequent in the MT group, although not significantly (adjusted cOR, 3.94; 95% CI, 0.94 to 16.49; P interaction=0.025), and not reproduced when restricting the sample to patients with DWI volume ≥70 mL were no significant difference of sICH between EVT (1/23, 4.3%) and best medical treatment (2/37, 5.4%) was found [3,15]. Of critical note, the most important predictor of sICH and parenchymal hemorrhage is core volume, independent of treatment modality [3,7,19,20,23], likely explaining that successful reperfusion was associated with lower sICH in many “real life” recent studies [7,19,20]. Whether the benefits of not revascularizing a patient to prevent sICH, outweigh those of revascularization to prevent infarction extension is unknown, but very unlikely, especially in patients with important mismatch, at highest risk for infarct progression and progression to malignant infarction. Our study was neither powered nor designed to answer this question.

There’s a long ongoing debate on optimal imaging modality (CT or MRI) for AIS-PVO patients’ selection for revascularization strategies [24-26]. The main risk of patients’ selection in the context of AIS is over-selection, that is, to decline a patient a treatment that may have been beneficial. For patients with LIC, the question of over-selection is amongst the timeliest in modern stroke care. The first level of over-selection may happen at the core assessment level (e.g., dismissing a patient because of large infarct). Interestingly, in the HERMES collaboration [3], the treatment benefit in patients with ASPECTs 0-4 derived from the aggregation of CT and MRI ASPECTs data, and was likely contingent on the disproportionately larger effect size seen in the MRI subgroup (aOR, 3.57; 95% CI, 1.22 to 10.39 vs. aOR, 1.68; 95% CI, 0.58 to 4.87 in the CT group). Similarly, Campbell et al. [15] demonstrated that CTP was associated with significantly halved proportion of patients functional independence (OR, 0.47; 95% CI, 0.30 to 0.72; P=0.0007), and also with less functional improvement (cOR, 0.51; 95% CI, 0.36 to 0.72; P=0.0001) when compared to MRI, both studies reinforcing the notion that MRI may better select patients for MT, but at the inherent risk of overselecting. In that sense, our study provides critical answers with regards to outcome in patients with LIC by the use of MRI with known higher conspicuity and reproducibility to detect and measure infarct core when compared to CT (especially when ASPECTs is used) [27]. The second level of over-selection, accounting that patients are considered for MT even with a LIC, is perfusion imaging. Our study showed, using strict post processing method, that patients with a CPMR above 1.72 (and by extension, over 1.8) demonstrated more favorable outcomes when treated with MT but the benefit increase was expectedly linear and not sudden at a discrete threshold of 1.72. While this finding suggests that patients with lower CPMR are likely to also benefit from MT, more subjects would be needed to demonstrate it, the benefit would likely be lesser, and this would need to be confirmed in a larger scale study. Importantly, we did not demonstrate any harm derived from MT in patients with lower CPMR.

Altogether, by comforting patho-physiologically plausible and statistically stable answers the question of the benefit of MT in patients with LIC at baseline and persisting salvageable tissue, our study raises ethical and philosophical considerations. There is growing evidence that by withholding MT by fear of potential harm for some patients, we may actually dismiss a much larger of patients that may have benefited from revascularization. In that sense, by demonstrating the continuum of unfavorable outcome paralleling the increases in core as well as mismatch volumes, and by showing the increasing benefit of MT with increasing CPMR, we actually fuel the argument that perfusion imaging is not needed as it may delay revascularization in eligible patients (and be used to decline MT to patients with CPMRS in the lower ranges, despite potential benefit). With no evidence of harm from MT in any of the explored configurations in our sample and the above-mentioned continuums in treatment benefit increases, it may be reasonable not to withhold treatment based on strict-cut offs (e.g., the study specific 1.72, applicable only to our sample, or the more common 1.8), but to adjust treatment decisions to both outcome and patients/families’ centered expectations. Results from future trials may yield more definite answers to these questions, although the authors are not aware of any ongoing large randomized study using perfusion imaging as a selection criterion in patients with LIC.

Our study has limitations, most inherent to its design. It was a retrospective analysis, with a high risk of selection bias in included cases and important number of excluded cases due to the limited penetration of perfusion imaging for AIS amongst French centers and to the yet unusual use of MT in patients with LIC. For similar reasons, our sample size did not allow for a split into a derivation and a validation cohort, but we aimed at substantiating our estimates by various sensitivity analyses, which proved to be stable. We acknowledge that our control group was biased, by the fact that it included only patients who received intravenous tPA, and that this bias may have yielded underestimated estimates of the benefit of MT over best medical management. Lastly, using CPMR instead of CT allowed for more precise estimates of ischemic infarct cores, but make our results less generalizable beyond the pathophysiological rationale it provides.

In patients currently deemed ineligible for MT due to large infarct ischemic cores at baseline, CPMR identifies patients strongly benefiting from MT. These finding provide a data-driven framework supporting both the relevance of CPMR perfusion assessment at the acute phase of AIS due to PVO in patients with LIC, and the notion that there is no strict plausible cutoff in core or penumbral volumes above or below which MT may become harmful by comparison to best medical treatment alone. Our results may help at informing the design of future randomized trials and may, further, help inform clinical practice for more individualized decision making in this subgroup until higher level evidence becomes available.