Impact of Collateral Circulation on Futile Endovascular Thrombectomy in Acute Anterior Circulation Ischemic Stroke

Study participants

For this secondary analysis, we selected participants from the ongoing Database of Acute ischemic Stroke Analysis Network (DASAN) which is to investigate the optimal evaluation method in patients with acute ischemic stroke. The database contains clinical and imaging data of participants with acute ischemic stroke due to large vessel steno-occlusion. The data were prospectively collected from two university hospitals, commencing on January 1, 2016. The inclusion criteria of the DASAN were as follows : 1) participants older than 18 years of age; 2) participants with acute ischemic stroke due to occlusion or severe stenosis of the internal carotid artery and/or M1 or M2 segment of the middle cerebral artery, or the basilar artery, and 3) participants who underwent brain CT and magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI), susceptibility weighted imaging, dynamic contrast-enhanced MR angiography, dynamic susceptibility MR perfusion, and fluid attenuated inversion recovery at admission. The inclusion criteria for this study were as follows : 1) participants who were treated with EVT for acute ischemic stroke due to occlusion of the internal carotid artery and/or M1 or M2 segment of the middle cerebral artery and associated symptoms who were evaluated within 8 hours of symptom onset; or 2) participants who had a DWI lesion and no visible signal change on fluid attenuated inversion recovery in wake-up stroke or unclear onset >8 hours from last known well. The exclusion criteria were patients who had the following : occlusion of posterior circulation, follow-up loss at 3 months, a mRS score >2 at baseline, death related to procedural complications or other causes except stroke such as pneumonia, cancer, etc., recurrent acute ischemic stroke within 90 days, and uninterpretable poor quality collateral map.

Participants were evaluated for demographic data, medical history, vascular risk factors, routine blood test results, brain imaging, and cardiologic tests. The severity of stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS). All participants underwent EVT, or intravenous thrombolysis followed by EVT. Reperfusion was assessed on the basis of conventional cerebral angiograms obtained at the end of the intra-arterial procedure and classified according to the modified TICI system as follows : 0, no reperfusion; 1, penetration with minimal reperfusion; 2a, <50% reperfusion; 2b, ≥50% reperfusion; 2c, near-complete reperfusion; and 3, complete reperfusion of the affected vascular territory [3]. Reperfusion status was classified as either successful reperfusion (modified TICI score of 2b to 3) or failed reperfusion (modified TICI score of 0 to 2a). Functional outcomes were assessed on day 90 using the mRS; unfavorable functional outcome was defined as a mRS score of ≥4 on day 90, which was considered an indicator of futile EVT in this study that can be excluded from the EVT [28]. Eighty-nine participants of the DASAN have been previously reported [7,11,12,21]. Previous articles dealt with the predictability of the collateral map or susceptibility-weighted imaging for functional outcomes or hemorrhagic transformation of participants with acute ischemic stroke, whereas in this manuscript, we report on futile EVT.

Imaging postprocessing and analysis

MRI was performed using 3-Tesla MRI machines (Magnetom Skyra [Siemens Healthcare, Erlangen, Germany] and Ingenia [Philips Healthcare, Best, Netherlands]). The acquisition parameters were the same as those in a previous study [21]. Using source data from dynamic contrast-enhanced MR angiography, 3-dimensional rotational arteriography was performed to determine the arterial status, and a multiphase MR angiography collateral map was reconstructed to evaluate the collateral perfusion status (Fig. 1). We generated the multiphase MR angiography collateral map by using an in-house program, which was composed of images in the arterial, capillary, early venous, late venous, and delay phases. The phases of the collateral map were automatically divided based on arterial and venous signal intensity-time curves obtained from region of interests on the normal side middle cerebral artery (MCA) and the superior sagittal sinus. The details of the methodology used were the same as those used in previous studies [21].

Fig. 1.

images of a man in his 50s (A-g) and a man in his 80s (h-n). The premorbid modified Rankin scale (mRS) score was 0 in both patients, and the national institutes of health Stroke Scale scores were 9 and 18, respectively. both patients underwent intravenous thrombolysis followed by endovascular thrombectomy, and successful reperfusion was achieved, as shown by a modified Thrombolysis in cerebral infarction Tici (mTici) scale score of 2c at 1.5 hours from symptom onset in the patient aged 50−59 and by a mTici scale score of 3 at 4 hours from symptom onset in the patient aged 80−89. dynamic contrast-enhanced magnetic resonance (mR) angiography (dce-mRA in [A and h]) at admission showed steno-occlusion of the left middle cerebral arteries (mcAs), and apparent diffusion coefficient (Adc) images (b and i) at admission showed similar size baseline lesions in the left mcA territories. The collateral maps derived from dce-mRA (c-f and j-m) of both patients show very poor collateral perfusion status (mAc 0 : collateral perfusion delay/defect more than one-half of the mcA territory in the late venous phase regardless of collateral perfusion status at previous phases) [7,21]. fluid-attenuation inversion recovery magnetic resonance image (flAiR) on day 1 in the patient in his 50s (g) shows a decreased extent of the baseline lesion. The 90-day mRS score of this patient was 2. computed tomography (cT) image on day 1 in the patient in his 80s shows progression of malignant edema (n). The 90-day mRS score of this patient was 5.

The collateral perfusion grading system was defined by using the MR acute ischemic stroke collateral (MAC) scores as follows : 5 (excellent), no or collateral perfusion delay in the MCA territory in the capillary phase; 4 (good), collateral perfusion delay ≤1/2 of MCA territory in the capillary phase and no or small delay in the early venous phase; 3 (intermediate to good), 1) collateral perfusion delay ≤1/2 of MCA territory in the capillary and early venous phases, 2) collateral perfusion delay >1/2 of MCA territory in the capillary phase and no or small delay of MCA territory in the early venous phase; 2 (intermediate to poor), collateral perfusion delay >1/2 of MCA territory in the capillary phase and ≤1/2 of MCA territory in the early venous phase; 1 (poor), collateral perfusion delay >1/2 of MCA territory in the early venous phase and ≤1/2 of MCA territory in the late venous phase; and 0 (very poor), collateral perfusion delay >1/2 of MCA territory until the late venous phase [7]. Two experienced neurointerventionists who were blinded to all clinical and other imaging data independently graded the MAC scores of the MR angiography collateral maps. Two raters determined the final scores by consensus. An experienced neurologist measured the infarct volume (in milliliters) using Medical Image Processing, Analysis, and Visualization (MIPAV) version 7.1.1 (National Institute of Health, Bethesda, MD, USA).

Statistical analysis

The participant characteristics are expressed as the mean± standard deviation, median (interquatile range, IQR), or number of participants (%). Differences in the distribution of patient characteristics among collateral perfusion grades were assessed using the chi-square test, Fisher’s exact test, analysis of variance and the Kruskal-Wallis test, as appropriate. The interrater agreement for collateral perfusion grading was tested using Cohen’s kappa coefficient. Multiple logistic regression analyses were conducted to identify independent predictors of unfavorable functional outcomes in all participants and participants who achieved successful reperfusion. Variables are presented in Table 1. We included predictors in multivariable models according to clinical significance in previous studies in multivariable models [7,19,20,24]. The results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). To examine the linearity of the relationship between collateral perfusion grades and functional outcomes, the likelihood ratio test for trends was used. Subgroup analyses using multiple logistic regression were conducted to identify independent predictors of favorable functional outcomes in participants with a collateral perfusion grade of MAC 0. The age threshold was analyzed for the prediction of favorable functional outcomes in participants with a collateral perfusion grade of MAC 0 using receiver operating characteristic analysis with calculation of the area under the curve and subsequent determination of Youden’s J index to establish cutoff points. Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA). A 2-sided p-value of <0.05 was considered significant.

Table 1.

Patient characteristics (n=214) according to collateral perfusion grade based on the collateral map

Participant characteristics and collateral perfusion grading

From January 2016 to March 2021, 214 of 633 participants were included in this study (Fig. 2). The mean age was 70±12 years (range, 33–94), and 60% were men (129 men and 85 women). The median baseline NIHSS score was 12 (IQR, 7–15), and the median baseline DWI lesion volume was 14.2 mL (IQR, 5.0–39.8). The median onset-to-door time was 44 minutes (IQR, 28–115), and the median onset-to-reperfusion time was 220 minutes (IQR, 170–315). A total of 116 participants (54.2%) underwent EVT, and 98 participants (45.8%) underwent intravenous thrombolysis followed by EVT. A total of 184 participants (86%) achieved successful reperfusion.

Fig. 2.

flowchart shows study selection according to the exclusion criteria. dASAn : database of Acute ischemic Stroke Analysis network, eVT : endovascular thrombectomy, mRS : modified Rankin scale.

The interrater correlation between the two observers showed almost perfect strength of agreement for collateral perfusion grading of the collateral map (weighted κ, 0.96; 95% CI, 0.93 to 0.98). The baseline clinical characteristics for each collateral perfusion grade are presented in Table 1. Lower baseline NIHSS scores and smaller baseline DWI lesion volumes were associated with higher collateral perfusion grades (all p<0.001). Other characteristics did not differ among participants in different collateral perfusion grades.

Predictors of unfavorable functional outcomes after EVT

The results of the univariable and multivariable logistic regression analyses performed to identify independent predictors of unfavorable functional outcomes in all participants are presented in Table 2. In the multivariable analysis, older age (OR, 2.40; 95% CI, 1.56 to 3.67; p<0.001), higher baseline NIHSS scores (OR, 1.12; 95% CI, 1.04 to 1.21; p=0.004), very poor collateral perfusion grade (OR, 35.09; 95% CI, 3.50 to 351.33; p=0.002), longer door-to-groin puncture time (OR, 1.08; 95% CI, 1.02 to 1.14; p=0.009), and failed reperfusion (OR, 3.73; 95% CI, 1.30 to 10.76; p=0.015) were independently associated with unfavorable functional outcomes. A linear negative association was found between collateral perfusion grades and functional outcomes (p=0.005 by linear trend test). In 184 participants (mean age, 70±12 years; 118 men) who achieved successful reperfusion, the multivariable analysis showed that older age (OR, 2.30; 95% CI, 1.44 to 3.67; p<0.001), higher baseline NIHSS scores (OR, 1.12; 95% CI, 1.03 to 1.22; p=0.006), very poor collateral perfusion grade (OR, 4.96; 95% CI, 1.42 to 17.37; p=0.012), and longer door-to-reperfusion time (OR, 1.09; 95% CI, 1.03 to 1.15; p=0.003) were independently associated with unfavorable functional outcomes (Table 3).

Table 2.

Results of logistic regression analysis : independent predictors of unfavorable functional outcomes^* in all participants (n=214)

Table 3.

Results of logistic regression analysis: independent predictors of unfavorable functional outcomes^* in the participants achieved successful reperfusion (n=184)^†

Despite significant results in the univariable analysis and clinical significance, we could not include several time variables in multivariable analyses because of the lack of those variables in some participants with unclear onset or failed reperfusion.

Predictors of favorable functional outcomes in participants with very poor collateral perfusion status (MAC 0)

We conducted subgroup analysis to identify independent predictors of favorable functional outcomes in 38 participants with MAC 0 collateral perfusion grade. This grade was revealed as the major predictor with the highest OR of unfavorable functional outcomes after EVT. The mean age was 73±11 years (range, 49–91), and 71.1% were men (27 men and 11 women). Of 38 participants, 30 participants showed unfavorable outcomes (78.9%). In univariable and multivariable analyses, younger age (mean, 65±10 years; range, 51–83 years in favorable outcomes vs. mean, 75±10 years; range, 49–91 years in unfavorable outcomes) (OR, 0.29; 95% CI, 0.10 to 0.85; p=0.025) and the presence of previous ischemic heart disease (four participants [50%] in favorable outcomes vs. two participants [6.7%] in unfavorable outcomes) (OR, 23.63; 95% CI, 2.07 to 269.53; p=0.011) were associated with favorable functional outcomes. The age threshold for favorable functional outcomes after EVT in participants with MAC 0 collateral perfusion grade was ≤73 years of age with 87.5% sensitivity (95% CI, 47.3 to 99.7) and 63.3% specificity (95% CI, 43.9 to 80.1) (Fig. 3).

Fig. 3.

An ROc curve was applied to analyze the efficacy of age for the prediction of favorable functional outcomes in participants with a collateral perfusion grade of mAc 0 after eVT. ROc : receiver operating characteristic, mAc : mR acute ischemic stroke collateral, eVT : endovascular thrombectomy.