Impact of Age and Alberta Stroke Program Early Computed Tomography Score 0 to 5 on Mechanical Thrombectomy Outcomes

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Association/American Stroke Association guidelines. 1,2 These guidelines are based on several randomized clinical trials and endovascular therapy trials demonstrating superior efficacy of mechanical thrombectomy (MT) Stroke. 2021;52:2220-2228. DOI: 10.1161/STROKEAHA.120. 032430 July 2021 2221 CLINICAL AND POPULATION SCIENCES compared with medical therapy. [3][4][5][6][7][8][9][10] However, the presenting core infarction volume beyond which MT is futile or potentially harmful has not been established. [11][12][13] Data supporting MT use on low ASPECTS of 0 to 5 and its associated clinical outcomes is not conclusive, possibly due to the low volume of salvageable brain tissue and large core infarct volume, both of which predict a low functional independence rate and higher symptomatic intracranial hemorrhage (sICH) rate. [11][12][13] See related article, p 2229 In this study, we evaluated clinical outcomes in patients with AIS undergoing MT and presenting with large core infarct volume, as determined by a low ASPECTS (0-5), in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke). 14 We aimed to assess whether low ASPECTS was associated with worse functional outcome and higher rates of sICH compared with patients with higher ASPECTS. Furthermore, because advanced age is associated with low rates of functional independence and high rates of sICH and mortality, [15][16][17] we studied the combined effect of ASPECTS on the clinical outcome of MT stratified by age.

Data Availability
Requests for data access may be sent to the corresponding author.

Study Design and Participants
The STRATIS registry was a prospective, single-arm, multicenter, nonrandomized, observational study that evaluated the use of Solitaire Revascularization Device (Solitaire, Medtronic, Minneapolis, MN) and Mindframe Capture Low profile Revascularization (Mindframe, Medtronic, Minneapolis, MN) in 1000 patients with anterior circulation emergent large vessel occlusion at 55 centers within the United States between August 2014 and June 2016. Ethic committees and institutional review boards approval was obtained at each medical center. Subjects were provided a written informed consent before enrollment. The details and results of the STRATIS Registry are published elsewhere. 14 Patients who underwent MT per the study protocol were included based on the following inclusion criteria: (1) availability of ASPECTS before thrombectomy; (2) availability of angiographic data and clinical outcomes; (3) confirmed symptomatic intracranial emergent large vessel occlusion involving the internal carotid artery terminus or proximal middle cerebral artery; (4) confirmed National Institutes of Health Stroke Scale (NIHSS) scores of 8 to 30; (5) use of Medtronic marketreleased neurothrombectomy device as the initial device; (6) premorbid modified Rankin Scale (mRS) score of ≤1; and (7) arterial puncture within 8 hours of stroke onset.

Imaging Analysis
Angiographic procedural images, baseline images (before MT), and follow-up (after MT) parenchymal noncontrast computed tomography (NCCT) images were evaluated by an independent core laboratory blinded to clinical outcomes data. NCCT was evaluated, interpreted, and an Imaging Report Form was completed by an experienced physician (D.S. Liebeskind) using the ASPECTS scoring system. The reader evaluated each of the ten ASPECTS regions using all imaged slices. 18 After adjusting the window and level setting to optimize ASPECTS grading, a region was scored negatively if an early ischemic change with clear hypoattenuation or loss of gray-white matter differentiation was identified. Areas with early ischemic signs were deducted from the total ASPECTS of 10 to obtain the final ASPECTS score.

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with associated NIHSS score worsening of 4 or more points) based on 24-hour-NCCT post-MT.

Statistical Analysis
Student t tests were used for normally distributed continuous variables, the Mann-Whitney test was used for ordinal or nonnormal variables, and Fisher exact or χ 2 tests were used for categorical variables. Multivariate analysis was performed via stepwise logistic regression. Initial variable selection included successful recanalization, sICH, IV tPA (intravenous tissue-type plasminogen activator), ASPECTS and those with P<0.1 from univariate analyses. All analyses were performed by an independent statistician using SAS software (SAS Institute, Cary, NC). P<0.05 were considered significant. All supporting data from this study are available within the article.

Baseline Characteristics
Of the 984 patients enrolled in the STRATIS Registry, 763 (77.5%) had NCCT ASPECTS read by the imaging core lab and were included in this study ( Figure 1). Of these patients, 57 (7.5%) had ASPECTS of 0 to 5 and 706 (92.5%) had ASPECTS of 6 to 10. Among the ASPECTS of 0 to 5 group, 10 (17.5%) patients had ASPECTS of 0 to 3 and 47 (82.5%) had ASPECTS of 4 to 5. Baseline variables were compared among the ASPECTS of 0 to 5, and 6 to 10 groups (Table 1). Baseline variables further categorized into subgroups 0 to 3, 4 to 5, and 6 to 10 are found in Table I

Angiographic and Technical Outcomes
Procedural, angiographic, and clinical outcome comparisons are presented in Table 2. There was no difference in successful reperfusion rate among these groups. Complete reperfusion rates were lower in the ASPECTS of 0 to 5 versus the ASPECTS of 6 to 10 group (

Functional and Safety Outcomes
Clinical and safety outcome comparisons are presented in Table 2. Among 57 patients with ASPECTS of 0 to 5, 90-day outcome was reported in 52 (91.2%) patients.
There was a significantly lower rate functional independence in the ASPECTS of 0 to 5 cohort versus the ASPECTS of 6 to 10 group (28.8% versus 59.7%; P<0.001). There was no difference in functional independence rates between the ASPECTS of 0 to 3 group and the ASPECTS of 4 to 5 group (

Procedural and Clinical Outcomes
Procedural, clinical, and safety outcome comparisons are presented in Table 3. There was no difference in baseline

DISCUSSION
Our study showed that ASPECTS of 0 to 5 is associated with a low good functional outcome rate and high mortality rate in patients >75 years, indicating a lower clinical benefit of MT in this patient population. Conversely, patients ≤65 years of age with ASPECTS of 0 to 5, had similar rates of both good functional outcome and mortality relative to the overall patient population and were significantly better than patients >75 years. Younger age, low baseline NIHSS score, absence of symptomatic ICH, and early time from onset to groin puncture were each shown to be important and independent predictors of good functional outcome; accordingly, regardless of ASPECTS score, patients demonstrating these characteristics are likely to have favorable prognosis.
ASPECTS as a surrogate marker of core infarct volume correlates with clinical outcomes in patients with AIS. 18 However, the exact ASPECT score beyond which there is no clinical benefit from MT is not well-established since most recent clinical trials excluded patients with low ASPECTS (0-5). 1,[3][4][5][6][7][8][9][10][11]13 Limited data with small sample sizes preclude our ability to address this question that has both clinical and health care cost-related consequences. 20 This is also a high-priority research question according to the Stroke Therapy Academic Industry Roundtable group. 21 The low good functional outcome rate in patients with low ASPECTS is consistent with other studies. In a metaanalysis of 13 articles correlating baseline ASPECTS with clinical outcomes, mRS score of 0 to 2 was achieved in 17.1%, 35.7%, and 49.7% in the low (0-4), intermediate (5)(6)(7), and high (8-10) ASPECTS groups, respectively. 22 Another meta-analysis of 17 studies reported mRS score of 0 to 2 for 1378 patients with ASPECTS of 0 to 6; mRS score of 0 to 2 rate was 37.7% for ASPECTS of 6, 33.3% for ASPECTS of 5, 22.1% for ASPECTS of 4, 17.1% for  24 However, there was no remarkable benefit of MT for patients with ASPECTS of 0 to 2 (0% in MT versus 12% in the control group (adjusted OR, 0.00 [CI, 0.00-5.81]). 24 In the MR-CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), 6% (30/496) patients with ASPECTS of 0 to 4 were enrolled; 11 (36.7%) in the MT and 19 (6.3%) in the IV tPA treatment group, and mRS score of 0 to 2 was achieved in 1/11 (9%) of patients in the MT group versus 0/19 (0%) in the control group at 90 days. 13 These data suggest marginal or potentially no benefit of MT in patients with ASPECTS of 0 to 2 or 0 to 3. However, nonrandomized studies and meta-analyses evaluating the clinical benefit of MT in patients with low ASPECTS have mixed results, with some studies demonstrating improvement after MT even in patients with incomplete or failed recanalization, while others suggest MT is not beneficial in patients with low ASPECTS. 13,[22][23][24][25] We showed that mortality rate increased with decreasing baseline ASPECTS; however, there was a significant increase in sICH rate in both the ASPECTS of 0 to 6 versus 6 to 10 and ASPECTS of 4 to 5 versus 6 to 10 groups. However, the HERMES analysis of ASPECTS of 0 to 4 patients showed a higher sICH rate in the MT group ( 24 However, in the MR-CLEAN trial, the ASPECTS of 0 to 4 cohort did not show a significant difference in rates of sICH or 90-day mortality (4/11 [36%] in the MT group versus 8/19 [42%] in the IV tPA group). 13 Although advanced age is associated with worse outcome, patients with advanced age still benefit from MT compared with those treated with IV tPA alone. 15,24 Conversely, in the present study, functional independence rate decreased with increasing age in patients with low ASPECTS. This is consistent with the reduced good outcome (mRS score 0-2) rate in patients aged >70 years versus those aged <70 years (16.2% versus 40.3%, respectively), as reported in a recent meta-analysis by Cagnazzo et al. 23 Additionally, in the low ASPECTS (0-5) subgroup analysis of the RESCUE-Japan (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism) Registry 2, patients aged <75 years were more likely to have favorable outcome with MT (OR, 2.43 [CI, 0.98-6.01]) versus those aged ≥75 years (OR, 2.11 [CI, 0.51-8.78]). 26 Danière et al 27 conducted a low diffusion-weighted imaging-ASPECT (<5) study, reporting that only 10% (12/120) of patients >70 years achieved good outcome (mRS score 0-2). In an analysis of the MR-CLEAN registry, the authors found that there was no significant interaction between age and ASPECTS on mRS outcomes, indicating that endovascular therapy should not be withheld from elderly patients with low ASPECTS. 28 However, the authors did report an increased chance of sICH in elderly patients (age >71.8 years) with low ASPECTS. 28 One limitation of our study is that patients from the STRATIS Registry with NCCT ASPECTS that were read by an independent core lab (763/984 [77.5%]) only, yielding low ASPECTS treated rate with MT of 7.5%. However, this number is consistent with low ASPECTS patient enrollment rate of 6% and 10% in the MR-CLEAN trial and HERMES

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collaborative meta-analysis, respectively. 13,24 Moreover, the stratification of ASPECTS of 0-3 treated with MT only contained ten patients, making it difficult to draw conclusions from such a small sample size. Because our study uses registry-based data with less stringent criteria than randomized controlled trials, there are inherent selection biases. Additionally, we restricted the ASPECTS analysis on NCCT versus using diffusion-weighted imaging-ASPECTS, which may have yielded different efficacy and safety results of MT. 27 Our analysis also did not analyze infarcts by topographical region. The analysis of the NCCT by a single physician is a limitation, due to variation in ASPECTS analysis between observers. 29 Future research may include artificial intelligence semi-quantification of ASPECT score using unapproved tools that are currently available for research only such as RAPID-ASPECTS, e-ASPECTS, or VIZ-AI-ASPECTS. Another limitation is that low ASPECTS may not be as predictive of ischemic core volume, which has been reported with diffusion-weighted imaging-ASPECTS. 29

CONCLUSIONS
Our study demonstrated poor MT outcomes for AIS patients with low baseline ASPECTS (0-5), with poor functional independence rate and high rates of mortality and sICH. Moreover, patients with ASPECTS of 0 to 3 and patients >75 years of age had worse rates of functional independence and mortality among patients with ASPECTS of 0 to 5. Prospective randomized studies are warranted to establish the impact of low ASPECTS on MT outcomes in patients with AIS.