Summary of Evidence

Our review demonstrates that for patients with low ASPECTS who are considered to have very little remaining salvageable brain tissue, there is a trend toward higher rates of sICH for patients who undergo EVT. Despite this, significantly more patients in the EVT group attain good functional outcomes (mRS of 0–2) at 90 days. However, as we will later discuss, there are important limitations of the study because all the studies included were observational in nature.

Compared to the HERMES collaboration meta-analysis^{Reference Goyal, Menon and van Zwam35} featuring the five landmark trials^{Reference Saver, Goyal and Bonafe3-Reference Berkhemer, Fransen and Beumer7} for EVT in large vessel occlusion ischemic stroke, our meta-analysis showed higher rates of SICH, mortality, and worse outcomes at 90 days. These are likely because most of the studies included in the HERMES meta-analysis excluded patients with low ASPECTS and/or large ischemic cores.^{Reference Saver, Goyal and Bonafe3-Reference Goyal, Demchuk and Menon5} Low ASPECTS has been shown to predict intracranial hemorrhage after EVT.^{Reference Nawabi, Kniep and Schön36,Reference Raychev, Saver and Jahan37} Thus, the difference in sICH rate (9.2% vs 4.4%) is most likely accounted for by the low ASPECTS of our patients (<6) compared to the ones included in the earlier trials (mean ASPECTS of 9).^{Reference Saver, Goyal and Bonafe3-Reference Goyal, Demchuk and Menon5} The previously reported 19% sICH rate in EVT patients with an ASPECTS of <6 from a subset of the HERMES collaboration^{Reference Román, Menon and Blasco12} was not corroborated by our review that only showed a 9.2% sICH rate. Similar to our findings, an earlier attempt at large vessel reperfusion with the use of intra-arterial thrombolytics (PROACT 2) also showed a sICH rate (10%). Despite this, the patients randomized to the intervention arm still had superior functional outcomes at 90 days.^{Reference Furlan, Higashida and Wechsler38} The pooled mortality rates in our patients in both the EVT and best medical therapy arms of our review are almost twice that found in the HERMES collaboration. Lower ASPECTS scores implying less salvageable brain and a higher chance of a malignant infarct likely underlie this finding as well.

A previous meta-analysis tackling the effect of ASPECTS on the outcomes of EVT patients suggested futility of the intervention for patients with low ASPECTS.^{Reference Phan, Saleh and Dmytriw29} What our study reveals is that despite the relatively lower good (mRS of 0–2) 90-day outcomes (27.7%) compared to the earlier trials (46.0%)^{Reference Goyal, Menon and van Zwam13} utilizing criteria that screened out large core infarct patients, there is still benefit compared to low ASPECTS patients only receiving best medical therapy who have a dismal 3.7% rate of good outcomes at 90 days.

Clinical benefit of EVT for stroke patients with low ASPECTS could for instance be strategic salvage of eloquent areas such as internal capsule and Rolandic cortex. Future directions in the use of ASPECTS for determining EVT eligibility should take into account that not all 10 points of the scoring system that correspond to different middle cerebral artery territories have the same clinical impact. In addition, reduction in net water uptake, a biomarker associated with the development of malignant edema, has also been shown to be decreased in low ASPECTS stroke patients achieving reperfusion after undergoing EVT. This implies that edema reduction may mediate the benefit seen in this subset of patients.^{Reference Broocks, Hanning and Flottmann39}

ASPECTS relies on the ability of the reader to determine early ischemic changes, such as focal swelling and parenchymal hypoattenuation in the territory of the middle cerebral artery.^{Reference Pexman, Barber and Hill40} It has been shown to have good interobserver reliability in its use for intra-arterial stroke treatment selection.^{Reference Gupta, Schaefer and Chaudhry41} However, a later study demonstrated limited interobserver agreement in scans taken less than 100 minutes from the known onset of symptoms.^{Reference Naylor, Churilov, Rane, Chen, Campbell and Yan42} Likewise, two recent ASPECTS interrater agreement studies utilizing both CT and MRI focused on EVT candidates also found insufficient agreement between clinicians.^{Reference Farzin, Fahed and Guilbert43,Reference Fahed, Lecler and Sabben44} Another modality used to determine the eligibility of patients for EVT, especially in the extended time period (> 6 hours), is perfusion scanning. Unlike, ASPECTS scoring which determines the core infarct based on radiologic changes in the brain parenchyma, perfusion scanning relies on quantifying blood flow to determine the extent of infarcted tissue. A study comparing the two modalities actually found that automated perfusion scanning overestimated the core size when compared to 24 hours post-EVT ASPECTS scans.^{Reference Tsang, Lenck and Hilditch45}

The DEFUSE 3 and EXTEND study established the role of automated perfusion imaging (Rapid processing of PerfusIon and Diffusion [RAPID] software) for selection of patients eligible for medical and mechanical reperfusion.^{Reference Ma, Campbell and Parsons46,Reference Albers, Marks and Kemp47} RAPID guides neurointerventionalists by effectively mapping out and ischemic core and salvageable penumbra. Because the software provides exact volume estimates for both core and penumbra, there is much less variability in interpretation. However, the added cost of the software for automated perfusion may pose a significant hurdle to public hospitals in developing nations eager to expand their endovascular program. Despite the limitations of ASPECTS, expanding the eligibility of large vessel occlusion ischemic strokes for EVT in terms of the scoring system may be a worthwhile endeavor, especially for these settings. In addition, certain peculiarities with perfusion imaging such as overestimation of penumbral size in patients with chronic ipsilateral carotid stenosis is not an issue for ASPECTS scoring because the latter interprets based on the morphology of the actual brain tissue. More recently, the prevalence of significant clinical-core mismatch and large core (>70 cc) based on RAPID automated perfusion in patients with ASPECTS ≥ 6 was found to be similar in both the early (<6 hours) and late (6–24 hours).^{Reference Desai, Tonetti and Molyneaux48} This new finding may expand the role of ASPECTS into the late window, especially in places with no access to perfusion imaging.

Limitations

The study has several limitations, the first being the marked heterogeneity found in the EVT group. Second, two of the four studies with data for median ASPECTS show a lower ASPECTS in the best medical therapy group compared to the EVT group (3 vs 5). This may account for the large difference in 90-day outcomes between the two groups as lower ASPECTS are predictive of worse clinical outcomes.^{Reference Hill49} Third, bias inherent to the retrospective nature of all the studies included could not be avoided. Fourth, the use of both MRI and CT in the determination of initial ASPECTS in the studies reviewed limits the applicability of the study. Disagreement between the two modalities for ASPECTS may be as high as 20%.^{Reference Hui, Obuchowski and John50} Fifth, there were significantly more diabetic patients in the best medical therapy group. This may have contributed to their poorer outcomes. Sixth, the definition used for sICH^{Reference Yaghi, Willey and Cucchiara26} was not uniform across all the studies included. Seventh, the mean onset to reperfusion time in the EVT group was less than 6 hours. Thus, the results have limited applicability to patients coming in beyond this time. Lastly, misclassification bias may result in some “low ASPECTS” patients actually having a “true” ASPECTS > 6. Similarly, the converse will also have significant implications in the interpretation of our systematic review’s findings. A comparison between the ASPECTS findings of a core laboratory and study investigators for an EVT trial found significant discrepancy between the scores.^{Reference Fahed, Ben Maacha and Ducroux27} Ongoing randomized clinical trials for EVT on patients with large core infarcts that utilize a core laboratory with uniform parameters will hopefully provide more conclusive data on the subject.^{Reference Yoshimura28,Reference Bendszus30-32} . Only data from these studies can definitively establish if EVT is really effective in achieving superior outcomes in low ASPECTS patients. These studies will also hopefully shed light on difference in outcomes in the low ASPECTS subgroups, that is, ASPECTS of 0–2 and 3–5.