Abstract
Background
It remains uncertain whether patients with minor acute ischemic stroke with large vessel occlusion benefit from endovascular treatment (EVT). We aim to evaluate the outcomes of EVT in minor acute ischemic stroke with anterior circulation large vessel occlusion.
Methods and Results
Based on a nationwide prospective stroke registry, patients with minor acute ischemic stroke with anterior circulation large vessel occlusion within 24 hours of onset were divided into groups receiving standard medical treatment plus EVT or standard medical treatment alone. Primary outcome was excellent functional outcome defined as modified Rankin Scale score 0 to 1 at 90 days. In addition, a multivariable logistic regression model was used to analyze the effect of EVT guided by perfusion imaging. A total of 572 patients with median age 68 years (interquartile range=60–77) and median National Institutes of Health Stroke score 3 (interquartile range =2–4) were identified and 123 patients were treated with standard medical treatment plus EVT. EVT was not associated with excellent functional outcome (unadjusted odds ratio [OR], 0.771 [95% CI, 0.516–1.151]; adjusted OR, 0.793 [95% CI, 0.515–1.219]; P=0.290). However, therapy selection guided by perfusion imaging was a modifier of EVT effect on outcomes, as EVT was significantly associated with excellent functional outcome (60.0% versus 50.8%, unadjusted OR, 1.451 [95% CI, 0.643–3.272]; adjusted OR, 2.849 [95% CI, 1.006–8.067]; P=0.049) but not with symptomatic intracerebral hemorrhage in the imaging‐guided group.
Conclusions
Although functional outcomes in minor acute ischemic stroke caused by anterior circulation large vessel occlusion were not improved from the routine use of EVT, our results suggested that EVT guided by perfusion imaging could be beneficial for those patients.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT 04487340.
Keywords: endovascular treatment, large vessel occlusion, minor acute ischemic stroke, perfusion imaging
Subject Categories: Cerebrovascular Disease/Stroke
Nonstandard Abbreviations and Acronyms
- AIS
acute ischemic stroke
- CTP
computed tomographic perfusion
- EVT
endovascular treatment
- IVT
intravenous thrombolysis
- LVO
large vessel occlusion
- mRS
modified Rankin Scale
- NIHSS
National Institutes of Health Stroke Scale
- sICH
symptomatic intracerebral hemorrhage
- SMT
standard medical treatment
Clinical Perspective
What Is New?
Overall outcomes were similar in standard medical treatment plus endovascular treatment as compared with standard medical treatment alone in patients with minor acute ischemic stroke with anterior circulation large vessel occlusion.
Standard medical treatment plus endovascular treatment achieved a higher rate of excellent functional outcome at 90 days than standard medical treatment alone when guided by perfusion imaging.
What Are the Clinical Implications?
In minor acute ischemic stroke caused by anterior circulation large vessel occlusion, perfusion imaging could be considered to guide endovascular treatment.
Minor acute ischemic stroke (AIS) is a common medical condition accounting for more than 50% of AIS. 1 Of the patients with minor AIS, 28.3% are unable to discharge home, and 28.5% cannot walk independently. 2 For approximately 21% of patients, minor AIS is caused by large vessel occlusion (LVO), which is thought to be associated with early neurological deterioration and poor outcome. 3 Intravenous thrombolysis (IVT) is currently recommended for patients with mild but disabling symptoms. 4 However, the benefit of IVT could be hampered in patients with minor AIS with LVO because of the substantial risk of early neurological deterioration and poor 3‐month outcome. 5
Endovascular treatment (EVT) is recommended for patients with stroke and anterior circulation LVO with National Institutes of Health Stroke Scale (NIHSS) score ≥6. 4 , 6 Nevertheless, it remains uncertain whether EVT is superior to standard medical treatment (SMT) alone in minor AIS with LVO. Several observational studies have compared clinical outcomes between EVT plus SMT and SMT alone in these patients, 7 , 8 , 9 , 10 , 11 , 12 , 13 with controversial results partially owing to single‐arm nature, small sample sizes, and unavailable data regarding stroke type of initial deficit (disabling or nondisabling). 7 , 9 , 10 , 13 , 14 Meanwhile, perfusion imaging including computed tomographic perfusion (CTP) scan can reflect the pathophysiological state of patients with AIS and is recommended as a selection criterion in patients with LVO beyond a 6‐hour window, 4 which may select patients suitable for EVT in minor AIS with LVO.
Based on these considerations, we aim to (1) investigate the efficacy and safety of EVT in a large multicentric cohort of patients with minor AIS with anterior circulation LVO; and (2) hypothesize that therapy selection guided by perfusion imaging would increase the benefits of EVT in minor AIS with LVO.
METHODS
Data Availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Study Design
This study was a retrospective analysis based on a prospective multicenter stroke registry, CASE‐II (Computer‐based Online Database of Acute Stroke Patients for Stroke Management Quality Evaluation; NCT 04487340). Initiated in 2016, CASE‐II was designed to examine the current status of stroke care in China for developing strategies to improve stroke care. The study protocol was approved by the ethics committee of the Second Affiliated Hospital of Zhejiang University, School of Medicine. The study was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent for EVT was obtained from all patients or their legally authorized representatives. Because patient information in the CASE‐II was deidentified and anonymized before being released to the researchers, the informed consent requirement for this study was waived by the institutional review board.
Patient Selection
This study collected data between March 2017 and June 2021. We included patients with the following characteristics: (1) age ≥18 years old; (2) baseline NIHSS ≤5; (3) arrived at stroke centers within 24 hours of onset; and (4) anterior circulation LVO on pretreatment cerebral angiographic‐imaging (internal carotid artery, first segment of the middle cerebral artery, second segment of middle cerebral artery, anterior cerebral artery occlusion on computed tomographic angiography, magnetic resonance angiography, or digital subtraction angiography); and (5) treated with SMT (including IVT), with or without additional EVT. Patients without prestroke functional independence (modified Rankin Scale [mRS] score ≥2) and lost to follow‐up at 90 days after stroke onset were excluded. Patients with minor AIS were defined as patients with an admission NIHSS score of 0 to 5. Minor nondisabling AIS was identified as baseline NIHSS ≤5 and a score 0 or 1 on each baseline NIHSS score item (items 1a to 1c being 0). 15
Treatments
Patients were divided into the SMT group or EVT group according to the treatment they received. The SMT group received treatment based on current guidelines, including IVT, antiplatelet drugs, systematic anticoagulation, or combinations of these medical treatments. 4 Patients in the EVT group received SMT plus EVT, including those who eventually received rescue EVT because of neurological deterioration. EVT included mechanical thrombectomy with stent retrievers or aspiration catheter, balloon angioplasty, stenting, intra‐arterial thrombolysis, or combinations of these approaches.
Data Collection
We recorded patients' baseline characteristics; stroke risk factors; prior medication history; NIHSS score on admission, before performing EVT, and at 24 hours; type of initial deficit (disabling or nondisabling stroke); onset to door time; onset to needle time; presumed stroke cause assessed based on the Trial of ORG 10172 in Acute Stroke Treatment classification 16 ; type of treatment; recanalization evaluated on 24‐hour follow‐up imaging using arterial occlusive lesion scale 17 ; and mRS score before onset and 90 days. For patients receiving EVT, we additionally collected the time interval between symptom onset and groin puncture.
Study Outcomes
The primary outcome was the mRS score 0 to 1 at 90 days. Meanwhile, good functional outcome (mRS score 0–2) was used as the secondary outcome. All patients were followed up at 90 days by certified external clinical evaluators during a standardized telephone interview. All telephone interviews were recorded and traceable. The mRS is a 7‐level scale for assessing neurologic functional disability, which ranges from 0 to 6. 18 Grade 0 represents no symptoms at all. Grade 1 represents no significant disability despite symptoms (able to carry out all usual duties and activities). Grade 2 represents slight disability (unable to carry out all previous activities but able to look after own affairs without assistance). Grade 3 represents moderate disability (requiring some help, but able to walk without assistance). Grade 4 represents moderately severe disability (unable to walk without assistance, and unable to attend to own bodily needs without assistance). Grade 5 represents severe disability (bedridden, incontinent, and requiring constant nursing care and attention). Grade 6 represents death.
Safety outcomes were the rate of symptomatic intracerebral hemorrhage (sICH) and 90‐day mortality. sICH was defined as intracranial hemorrhage at 24 hours associated with an increase of ≥4 points of NIHSS from baseline, according to the ECASS II (European Cooperative Acute Stroke Study II) trial. 19
Radiologic Assessment
We evaluated perfusion parameters (ischemic core volume and penumbra volume) on baseline CTP, the location of the vessel occlusion on baseline vessel imaging (computed tomographic angiography, magnetic resonance angiography, or digital subtraction angiography), vessel recanalization on follow‐up computed tomographic angiography or MRA within 24 hours, and the presence of intracerebral hemorrhage on follow‐up computed tomography or magnetic resonance imaging. Ischemic core was defined as relative cerebral blood flow <30% on CTP, hypoperfusion was defined as time to max (Tmax) >6 s, and penumbra was defined as hypoperfused lesion beyond core infarct. Vessel recanalization was evaluated using arterial occlusive lesion scale, which was classified as recanalization (score of 2 or 3) and no recanalization (score of 0 or 1).
Patients who underwent CTP at baseline and determined whether to perform EVT according to perfusion imaging evaluation were assigned to the imaging‐guided group. The perfusion imaging evaluation criteria were referenced to the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trial. 20 The evaluation criteria were ischemic core volume <70 mL, penumbra ≥15 mL, and mismatch ratio ≥1.8. Patients for whom it was determined whether to perform EVT without perfusion imaging evaluation were assigned to the nonimaging‐guided group.
Statistical Analysis
We compared baseline characteristics and outcomes between the SMT groups and EVT groups. Continuous variables were described as mean ± SD or median (interquartile range) and categorical variables as numbers and percentages. Univariate analysis was performed using the Mann–Whitney U‐test, t‐test, χ2 test, or Fisher's exact test. Multivariable logistic regression model was used to evaluate study outcomes. All baseline variables with a P value <0.1 were then included in the multivariable logistic regression analysis to adjust for the effects of confounding variables.
For propensity score matching analysis, patients with EVT and SMT were matched 1:1 to eliminate the potential bias owing to imbalance in baseline covariate distributions. Propensity score matching was based on the main variables that could potentially influence treatment choice (EVT versus SMT), including age, female sex, baseline NIHSS score, atrial fibrillation, stroke cause, prestroke antithrombotic therapy, and IVT. We used a conservative caliper size of 0.1 SDs of the logit of the propensity score matching to provide adequate matching. Between‐group differences in baseline characteristics were compared using standardized difference (difference > 0.1 was considered meaningful).
To analyze the effect of EVT guided by perfusion imaging, we compared the rate of clinical outcomes between treatment groups in the imaging‐guided group and nonimaging‐guided group. Subgroup analyses were performed by stratifying patients with different baseline characteristics. Treatment effect size heterogeneity across subgroups was tested by including the corresponding multiplicative interaction term into the binary logistic regression model. A significant interaction (P < 0.05) term indicates that the estimated heterogeneity between treatments differs between different subgroups. We also conducted sensitivity analysis to assess the robustness of the main results in patients who received reperfusion therapy (EVT or IVT alone) and by excluding patients receiving rescue EVT, respectively. Two‐tailed P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 25.0 (IBM Co., Armonk, NY). Figures were drawn using GraphPad Prism 8 (GraphPad Software Inc., San Diego, CA).
RESULTS
Patient Characteristics
According to the inclusion and exclusion criteria, we identified 657 patients with minor AIS with anterior circulation LVO within 24 hours after onset. We further excluded 85 patients: (1) 28 patients without prestroke functional independence; and (2) 57 patients lost to follow‐up at 90 days. The remaining 572 patients constituted the study population. The flow chart is shown in Figure 1.
Figure 1. Flow chart of patient selection.
EVT indicates endovascular treatment; LVO, large vessel occlusion; mRS, modified Rankin scale; and SMT, standard medical treatment.
A total of 449 patients were treated with SMT alone, and 123 patients were treated with SMT plus EVT. The median age was 68, and 183 (32.0%) were women, median NIHSS score at baseline was 3, and median onset‐to‐door time was 166 minutes. About 92.5% (529) of patients kept NIHSS score ≤5 before treatment, and 43 (7.5%) patients aggravated to NIHSS score >5 before treatment. Among the entire cohort, 331 (57.9%) patients achieved excellent functional outcomes, 415 (72.6%) patients achieved good functional outcomes, 19 (3.3%) patients had sICH, and 35 (6.1%) patients died within 90 days. Baseline characteristics of patients with and without 90‐day mRS measurement are shown (Table S1).
There were 58 of 123 (47.2%) patients receiving perfusion imaging in the EVT group and 150 of 449 (33.4%) patients receiving perfusion imaging in the SMT group. Patients in the EVT group were more likely to receive perfusion imaging at baseline than the SMT group (P=0.006). Moreover, there were 58 of 208 (27.9%) patients treated with SMT plus EVT in patients with perfusion imaging and 65 of 364 (17.6%) patients treated with SMT plus EVT in patients without perfusion imaging (Figure S1 and Table S2). In the EVT group, the proportion of excellent functional outcome of patients with minor disabling AIS and minor nondisabling AIS was 49.2% and 36.8% (P=0.199), respectively. In the SMT group, the proportion of excellent functional outcome of patients with minor disabling AIS and minor nondisabling AIS was 36.5% and 42.6% (P=0.201), respectively.
Baseline Characteristics
Table 1 summarizes baseline characteristics in the 2 treatment groups. Compared with the SMT group, patients in the EVT group had higher NIHSS score on admission (median [interquartile range], 3 [2–5] versus 3 [1–4]; P=0.032), lower proportion of prior antiplatelet usage (18 of 123 patients [14.6%] versus 108 of 449 patients [24.1%]; P=0.027), and lower rate of IVT (67 of 123 patients [54.5%] versus 289 of 449 patients [64.4%]; P=0.047).
Table 1.
Characteristics of Patients With Endovascular Treatment Versus Standard Medical Treatment in Minor Strokes With Large Vessel Occlusion
| Characteristic | Unmatched | Propensity score matching | ||||
|---|---|---|---|---|---|---|
| EVT (N=123) | SMT (N=449) | P Value | EVT (N=117) | SMT (N=117) | Standardized difference* | |
| Age, y, median (IQR) | 69 (60–76) | 68 (59–77) | 0.771 | 69 (60–76) | 68 (58–79) | 0.094 |
| Female sex | 41 (33.3) | 142 (31.6) | 0.744 | 41 (35.0) | 32 (27.4) | 0.161 |
| Medical history | ||||||
| Current smoking | 40 (32.5) | 155 (34.5) | 0.748 | 39 (33.3) | 43 (36.8) | 0.072 |
| Hypertension | 75 (61.0) | 299 (66.6) | 0.285 | 71 (60.7) | 81 (69.2) | 0.174 |
| Diabetes | 21 (17.1) | 78 (17.4) | 1.000 | 21 (17.9) | 20 (17.1) | 0.022 |
| Hyperlipidemia | 10 (8.1) | 40 (8.9) | 0.859 | 10 (8.5) | 6 (5.1) | 0.122 |
| Coronary heart disease | 11 (8.9) | 26 (5.8) | 0.216 | 11 (9.4) | 7 (6.0) | 0.117 |
| Atrial fibrillation | 25 (20.3) | 61 (13.6) | 0.086 | 19 (16.2) | 20 (17.1) | 0.023 |
| Previous stroke/transient ischemic attack | 19 (15.4) | 77 (17.1) | 0.785 | 19 (16.2) | 14 (12.0) | 0.115 |
| Prior antiplatelet usage | 18 (14.6) | 108 (24.1) | 0.027 | 18 (15.4) | 17 (14.5) | 0.024 |
| Prior anticoagulant usage | 5 (4.1) | 7 (1.6) | 0.145 | 3 (2.6) | 3 (2.6) | 0.001 |
| Baseline measurements | ||||||
| Baseline National Institutes of Health Stroke Scale score, median (IQR) | 3 (2–5) | 3 (1–4) | 0.032 | 3 (2–5) | 3 (2–5) | 0.060 |
| Minor nondisabling acute ischemic stroke | 68 (56.7) | 274 (61.0) | 0.402 | 64 (56.1) | 72 (61.5) | 0.108 |
| Onset to door, median (IQR), min | 165 (60–360) | 166 (80–435) | 0.155 | 165 (61–343) | 180 (86–521) | 0.375 |
| Onset to groin puncture, median (IQR), min | 372 (219–549) | NA | NA | 375 (220–554) | NA | NA |
| Onset to needle, median (IQR), min | 167 (101–234) | 171 (114–232) | 0.809 | 167 (101–234) | 172 (107–245) | 0.003 |
| Systolic blood pressure, mean (SD), mm Hg | 149 ± 23 | 152 ± 21 | 0.255 | 150 ± 22 | 153 ± 21 | 0.144 |
| Diastolic blood pressure, mean (SD), mm Hg | 85 ± 16 | 84 ± 13 | 0.959 | 85 ± 15 | 85 ± 13 | 0.007 |
| Intravenous thrombolysis | 67 (54.5) | 289 (64.4) | 0.047 | 67 (57.3) | 66 (56.4) | 0.017 |
| Occlusion sites | 0.851 | 0.225 | ||||
| Internal carotid artery | 34 (27.6) | 110 (24.5) | 33 (28.2) | 24 (20.5) | ||
| Middle cerebral artery, first segment | 59 (48.0) | 213 (47.4) | 57 (48.7) | 55 (47.0) | ||
| Middle cerebral artery, second segment | 20 (16.3) | 83 (18.5) | 17 (14.5) | 23 (19.7) | ||
| Anterior cerebral artery | 10 (8.1) | 43 (9.6) | 10 (8.5) | 15 (12.8) | ||
| Stroke cause | 0.024 | 0.271 | ||||
| Large artery atherosclerosis | 78 (63.4) | 292 (65.0) | 77 (65.8) | 70 (59.8) | ||
| Cardioembolic etiology | 30 (24.4) | 67 (14.9) | 25 (21.4) | 20 (17.1) | ||
| Other etiology | 2 (1.6) | 6 (1.3) | 2 (1.7) | 2 (1.7) | ||
| Undetermined etiology | 13 (10.6) | 84 (18.7) | 13 (11.1) | 25 (21.4) | ||
| Recanalization | 114/122 (93.4) | 250/422 (59.2) | <0.001 | 108 (93.1) | 63 (56.8) | 1.428 |
Categorical variables are expressed as numbers (%) and continuous variables as median (IQR) or mean (SD). EVT indicates endovascular treatment; IQR, interquartile range; NA, not available; and SMT, standard medical treatment.
The difference between the groups divided by the pooled SD; a value >0.1 is interpreted as a meaningful difference.
Association Between EVT and Outcomes
Crude rates of excellent functional outcome (mRS score 0–1), good functional outcome (mRS score 0–2), sICH, and mortality in each treatment group are presented in Table 2. Details about the 90‐day mRS score for the 2 treatment groups are presented in Figure S2. No significant difference was found in excellent functional outcome between the EVT and SMT group (52.8% versus 59.2%; unadjusted odds ratio [OR], 0.771 [95% CI, 0.516–1.151]; adjusted OR, 0.793 [95% CI, 0.515–1.219]; P=0.209). Similarly, there was no difference between groups concerning the good functional outcome (adjusted OR, 0.798 [95% CI, 0.513–1.243], P=0.319). EVT was not significantly associated with mortality (adjusted OR, 1.863 [95% CI, 0.864–4.015]; P=0.112). The rate of sICH was higher in the EVT group than in the SMT group (10 of 123 patients [8.1%] versus 9 of 449 patients [2.0%]; P=0.002), with an adjusted OR of 3.760 (95% CI, 1.373–10.294; P=0.010).
Table 2.
Multivariable Analysis for Primary and Secondary Outcomes and Safety Outcomes
| Unmatched | Propensity score matching | |||||||
|---|---|---|---|---|---|---|---|---|
| EVT | SMT | Adjusted OR (95% CI)* | P value | EVT | SMT | Adjusted OR (95% CI)† | P value | |
| mRS at 90 d, median (IQR)‡ | 1 (0–3) | 1 (0–3) | 1.201 (0.835–1.726) | 0.324 | 1 (0–3) | 1 (0–3) | 1.186 (0.725–1.941) | 0.496 |
| Primary outcome | ||||||||
| mRS 0–1 | 65 (52.8) | 266 (59.2) | 0.793 (0.515–1.219) | 0.290 | 61 (52.1) | 71 (60.7) | 0.733 (0.416–1.292) | 0.282 |
| Secondary outcome | ||||||||
| mRS 0–2 | 84 (68.3) | 331 (73.7) | 0.798 (0.513–1.243) | 0.319 | 79 (67.5) | 86 (73.5) | 0.722 (0.385–1.353) | 0.309 |
| Safety outcomes | ||||||||
| 24‐h symptomatic intracerebral hemorrhage | 10 (8.1) | 9 (2.0) | 3.760 (1.373–10.294) | 0.010 | 9 (7.7) | 2 (1.7) | 4.267 (0.833–21.860) | 0.082 |
| Mortality at 90 d | 11 (8.9) | 24 (5.3) | 1.863 (0.864–4.015) | 0.112 | 10 (8.5) | 5 (4.3) | 2.345 (0.700–7.855) | 0.167 |
Categorical variables are expressed as numbers (%) and continuous variables as median (IQR). EVT indicates endovascular treatment; IQR, interquartile range; mRS, modified Rankin Scale; OR, odds ratio; and SMT, standard medical treatment.
Adjusted by baseline characteristics with a P value <0.1 in univariate analysis.
Adjusted by baseline characteristics with a standardized difference > 0.1 in univariate analysis after propensity score matching analysis.
Shift analysis by ordinal regression for OR.
Association Between EVT and Outcomes When Guided by Perfusion Imaging
Baseline characteristics of the nonimaging‐guided group and the imaging‐guided group are presented in Table S3. Crude rates of clinical outcomes are available in Table 3.
Table 3.
Crude Rates of Each Outcome in 2 Treatment Groups According to Selection Guided by Perfusion Imaging
| EVT (N=123) | SMT (N=449) | P value* | Adjusted OR (95% CI)† | P value‡ | |
|---|---|---|---|---|---|
| mRS 0–1 | |||||
| Imaging‐guided group (n=150) | 18/30 (60.0) | 61/120 (50.8) | 0.418 | 2.849 (1.006–8.067) | 0.049 |
| Nonimaging‐guided group (n=422) | 47/93 (50.5) | 205/329 (62.3) | 0.028 | 0.582 (0.356–0.949) | 0.030 |
| mRS 0–2 | |||||
| Imaging‐guided group | 22 (73.3) | 88 (73.3) | 1.000 | 2.399 (0.705–8.169) | 0.162 |
| Nonimaging‐guided group | 62 (66.7) | 243 (73.9) | 0.190 | 0.635 (0.374–1.076) | 0.091 |
| 24‐h symptomatic intracerebral hemorrhage | |||||
| Imaging‐guided group | 0 (0) | 0 (0) | NA | NA | NA |
| Nonimaging‐guided group | 10 (10.8) | 9 (2.7) | 0.003 | 4.343 (1.550–12.169) | 0.005 |
| Mortality at 90 d | |||||
| Imaging‐guided group | 0 (0) | 6 (5.0) | 0.600 | NA | NA |
| Nonimaging‐guided group | 11 (11.8) | 18 (5.5) | 0.060 | 2.736 (1.161–6.447) | 0.021 |
Categorical variables are expressed as numbers (%).
P values obtained by univariate analysis.
Adjusted by baseline characteristics with a P value <0.1 in univariate analysis.
P values obtained by multivariable analysis.
EVT indicates endovascular treatment; mRS, modified Rankin Scale; NA, not available; OR, odds ratio; and SMT, standard medical treatment.
Efficacy Outcomes
In the imaging‐guided group, multivariable logistic regression analysis showed that EVT was associated with higher odds of excellent functional outcome (60.0% versus 50.8%, unadjusted OR, 1.451 [95% CI, 0.643–3.272]; adjusted OR, 2.849 [95% CI, 1.006–8.067]; P=0.049; Table 3), after adjusting for age, baseline NIHSS score, previous stroke, coronary heart disease, diabetes, hypertension, IVT, and vessel occlusion sites.
Safety Outcomes
EVT was associated with higher odds of mortality in the nonimaging‐guided group (11.8% versus 5.5%, adjusted OR, 2.736 [95% CI, 1.161–6.447]; P=0.021) but not in the imaging‐guided group (no patients receiving EVT in this group died). Regarding sICH, EVT was associated with higher odds of sICH in the nonimaging‐guided group (10.8% versus 2.7%, adjusted OR, 4.343 [95% CI, 1.550–12.169]; P < 0.001) but not in patients whose therapy selection was guided by perfusion imaging (no patients in this group had sICH; Table 3).
Propensity Score Matching Analysis
We matched 117 pairs of patients who received EVT and SMT. The distributions of patient characteristics between 2 groups in the matched sample were similar (available in Table 1). No significant difference was found in excellent functional outcome between the EVT and SMT group after propensity score matching (52.1% versus 60.7%; adjusted OR, 0.733 [95% CI, 0.416–1.292]; P=0.282, Table 2). There was no difference in the proportion of 90‐day good functional outcome in the EVT group and the SMT group (79 of 117 patients [67.5%] versus 86 of 117 patients [73.5%]; P=0.309), either. Mortality at 90 days occurred in 10 of 117 patients (8.5%) in the EVT group and 5 of 117 patients (4.3%) in the SMT group (P=0.167). The rate of sICH was 7.7% (9 of 117 patients) in the EVT group and 1.7% in the SMT group (2 of 117 patients; P=0.082; Table 2). Successful recanalization was achieved in 108 (93.1%) patients in the EVT group.
Subgroup Analysis
When analysis was stratified according to predefined subgroups, some significant heterogeneity in the treatment effect size was found (Figure 2). EVT was associated with lower odds of excellent functional outcome in patients with baseline NIHSS score ≤3 (adjusted OR, 0.523 [95% CI, 0.291–0.940]; P=0.030) and atrial fibrillation (adjusted OR, 0.297 [95% CI, 0.090–0.977]; P=0.046).
Figure 2. Forest plots for primary outcome in unmatched patients with different baseline characteristics.
This forest plot summarizes the odds ratio obtained for comparison of endovascular treatment and standard medical treatment on primary outcome (mRS score 0–1) across all prespecified subgroups. The odds ratio was calculated by using binary logistic regression taking the following variables into account: age, baseline NIHSS score, onset to door time, hypertension, diabetes, coronary heart disease, previous stroke/transient ischemic attack, IVT, and location of occlusion. ACA indicates anterior cerebral artery; AIS acute ischemic stroke; CE, cardioembolic etiology; EVT, endovascular treatment; ICA, internal carotid artery; IVT, intravenous thrombolysis; LAA, large artery atherosclerosis; MCA‐M1, first segment of the middle cerebral artery; MCA‐M2, second segment of middle cerebral artery; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; OE, other etiology; OR, odds ratio; SMT, standard medical treatment; and UE, undetermined etiology.
Sensitivity Analysis
Sensitivity analyses were conducted in patients who received reperfusion therapy and by excluding patients receiving rescue EVT. Only the rate of sICH was significantly higher in the EVT group than in the IVT alone group (adjusted OR, 3.513 [95% CI, 1.212–10.182]; P=0.021) (Tables S4 through S7).
DISCUSSION
The present nationwide cohort study found that EVT did not lead to better functional outcomes at 90 days after stroke onset and was associated with higher rates of sICH in patients with minor AIS with anterior circulation LVO when compared with SMT alone. However, selection guided by perfusion imaging significantly enhanced the benefit of EVT, namely EVT being related with better functional outcomes but not with an increase in the rate of sICH.
The absence of benefit of EVT is consistent with the findings of most previous studies. 7 , 10 , 11 , 12 , 13 , 21 , 22 , 23 An observational multicenter study reported EVT was effective to recanalize the occluded vessel but increased the risk of serious bleeding significantly without improving the functional outcome, suggesting that EVT was not justified routinely in minor strokes. 7 Another study demonstrated a shift toward a lower NIHSS score in patients with an LVO stroke presenting with mild symptoms who underwent primary thrombectomy as compared with best medical therapy alone. 8 However, both studies have small sample sizes, thus limiting their statistical power. The lack of improved clinical outcomes in the EVT group in our study may be attributed to several reasons. First, patients with minor AIS may experience intrinsic ischemic preconditioning owing to their good collateral circulation status, 13 which could limit the advantages of EVT. Furthermore, performing EVT might result in bleeding or reperfusion injury. Overall, current findings suggest that EVT should not be regularly considered in patients with unselected minor AIS with LVO.
Current guidelines recommend using perfusion imaging to guide the administration of EVT in the extended time window, 4 although it remains controversial in patients with minor AIS. Haussen et al used CTP to determine the ischemic core and perfusion defect for mild strokes, and their findings were in favor of EVT. 8 In contrast, another study of 47 mildly symptomatic patients with AIS owing to LVO who presented a target mismatch >15 mL and mismatch ratio >1.8 on perfusion imaging found no significant difference of NIHSS score shift from admission to discharge between medical management and EVT group. 12 Both studies were underpowered by the small sample size and monocentric design. Based on a relatively large multicenter analysis, we show that EVT as compared with SMT alone is associated with higher rates of excellent functional outcome in patients guided by perfusion imaging. Several possible factors may explain this. First, a salvageable ischemic penumbra may still be detected after selection by perfusion imaging in patients with minor AIS. Second, recanalization of the occluded vessel after EVT could rescue the ischemic brain tissue, although it may progress to infarct in patients within the SMT group. These findings, therefore, indicate that selection guided by perfusion imaging is an important modifier of the impact of EVT on functional outcomes in patients with minor AIS.
The rate of sICH at 24 hours was 8.1% in the EVT group of the present study, which was comparable with other studies (1.18%–11.8%). 7 , 10 , 13 , 24 The association between EVT and high sICH rates observed here could be explained by the complications of EVT procedure, such as endothelial cell injury, vessel rupture, and potential reperfusion injury. Another possible explanation is the higher proportion of atrial fibrillation and the higher score of baseline NIHSS in the EVT group, which are both extensively reported risk factors for sICH. 25 , 26
Currently, the evidence for the effectiveness of EVT in minor AIS with LVO is sparse and ambiguous, and randomized clinical trials are just in preparation or underway (ENDO‐LOW [Endovascular Therapy for Low NIHSS Ischemic Strokes], NCT 04167527, and MOSTE [Minor Stroke Therapy Evaluation], NCT 03796468). In practice, patients may hesitate to make the decision whether to receive EVT because of mild or quickly resolved symptoms and high costs. Our results demonstrated the benefit of EVT in patients with minor AIS when guided by perfusion imaging, providing a potential subgroup of patients with LVO and mild symptoms who could benefit from EVT. Additionally, our results may shed light on the importance of perfusion imaging in treatment triage for patients with minor AIS with LVO, pointing out one possible direction for future randomized clinical trials.
The nonrandomized design is the fundamental limitation. The potential risk of selection bias existed although we use the method of propensity score matching to balance the differences between the 2 treatment groups. Second, the large number of patients who received SMT alone compared with EVT may suggest the existence of a lack of equipoise among participating centers regarding the decision‐making process of EVT in patients with stroke with mild symptoms. Third, the subgroup analysis may not be sufficiently powered. Larger sample size study and randomized trials are needed to confirm this finding. Fourth, the analyses of mRS score at 90 days may be subject to potential bias because of the loss to follow‐up, although this influence was minimal in our study because of comparable baseline characteristics among patients with and without the 90‐day mRS measurements. Last, the mRS may not be sensitive enough to assess the functional prognosis of patients with minor AIS, 13 and we have not been able to detect a significant difference in our primary outcome. The outcome measure of individual daily living such as Barthel Index would be better to compare clinical outcomes of these patients in future studies.
CONCLUSIONS
Our study does not support the routine use of endovascular therapy in unselected patients with minor AIS with anterior circulation LVO. However, our results do suggest that endovascular therapy could be beneficial for patients when guided by perfusion imaging. Randomized trials are needed to confirm these findings.
Sources of Funding
This study was supported by the National Natural Science Foundation of China (81971101, 82171276) and the Science Technology Department of Zhejiang Province (2018C04011).
Disclosures
The authors declare that they have no competing interests.
Supporting information
Tables S1–S7
Figures S1–S2
R. Xue and W. Zhong contributed equally.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.122.027326
For Sources of Funding and Disclosures, see page 9.
References
- 1. Reeves M, Khoury J, Alwell K, Moomaw C, Flaherty M, Woo D, Khatri P, Adeoye O, Ferioli S, Kissela B, et al. Distribution of National Institutes of Health stroke scale in the Cincinnati/Northern Kentucky stroke study. Stroke. 2013;44:3211–3213. doi: 10.1161/strokeaha.113.002881 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Smith EE, Fonarow GC, Reeves MJ, Cox M, Olson DM, Hernandez AF, Schwamm LH. Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue‐type plasminogen activator: findings from get with the guidelines‐stroke. Stroke. 2011;42:3110–3115. doi: 10.1161/strokeaha.111.613208 [DOI] [PubMed] [Google Scholar]
- 3. Rajajee V, Kidwell C, Starkman S, Ovbiagele B, Alger J, Villablanca P, Vinuela F, Duckwiler G, Jahan R, Fredieu A, et al. Early MRI and outcomes of untreated patients with mild or improving ischemic stroke. Neurology. 2006;67:980–984. doi: 10.1212/01.wnl.0000237520.88777.71 [DOI] [PubMed] [Google Scholar]
- 4. Powers W, Rabinstein A, Ackerson T, Adeoye O, Bambakidis N, Becker K, Biller J, Brown M, Demaerschalk B, Hoh B, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50:e344–e418. doi: 10.1161/str.0000000000000211 [DOI] [PubMed] [Google Scholar]
- 5. Mazya M, Cooray C, Lees K, Toni D, Ford G, Bar M, Frol S, Moreira T, Sekaran L, Švigelj V, et al. Minor stroke due to large artery occlusion. When is intravenous thrombolysis not enough? Results from the SITS international stroke thrombolysis register. Eur Stroke J. 2018;3:29–38. doi: 10.1177/2396987317746003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Turc G, Bhogal P, Fischer U, Khatri P, Lobotesis K, Mazighi M, Schellinger P, Toni D, de Vries J, White P, et al. European stroke organisation (ESO)‐ European Society for Minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischemic stroke. J Neurointerv Surg. 2019;11:535–538. doi: 10.1136/neurintsurg-2018-014568 [DOI] [PubMed] [Google Scholar]
- 7. Urra X, San Román L, Gil F, Millán M, Cánovas D, Roquer J, Cardona P, Ribó M, Martí‐Fàbregas J, Abilleira S, et al. Medical and endovascular treatment of patients with large vessel occlusion presenting with mild symptoms: an observational multicenter study. Cerebrovasc Dis. 2014;38:418–424. doi: 10.1159/000369121 [DOI] [PubMed] [Google Scholar]
- 8. Haussen D, Bouslama M, Grossberg J, Anderson A, Belagage S, Frankel M, Bianchi N, Rebello L, Nogueira RG. Too good to intervene? Thrombectomy for large vessel occlusion strokes with minimal symptoms: an intention‐to‐treat analysis. J Neurointerv Surg. 2017;9:917–921. doi: 10.1136/neurintsurg-2016-012633 [DOI] [PubMed] [Google Scholar]
- 9. Nagel S, Bouslama M, Krause L, Küpper C, Messer M, Petersen M, Lowens S, Herzberg M, Ringleb P, Möhlenbruch M, et al. Mechanical thrombectomy in patients with milder strokes and large vessel occlusions. Stroke. 2018;49:2391–2397. doi: 10.1161/strokeaha.118.021106 [DOI] [PubMed] [Google Scholar]
- 10. Dargazanli C, Arquizan C, Gory B, Consoli A, Labreuche J, Redjem H, Eker O, Decroix J, Corlobé A, Mourand I, et al. Mechanical thrombectomy for minor and mild stroke patients harboring large vessel occlusion in the anterior circulation: a multicenter cohort study. Stroke. 2017;48:3274–3281. doi: 10.1161/strokeaha.117.018113 [DOI] [PubMed] [Google Scholar]
- 11. Volny O, Zerna C, Tomek A, Bar M, Rocek M, Padr R, Cihlar F, Nevsimalova M, Jurak L, Havlicek R, et al. Thrombectomy vs medical management in low NIHSS acute anterior circulation stroke. Neurology. 2020;95:e3364–e3372. doi: 10.1212/wnl.0000000000010955 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Wolman D, Marcellus D, Lansberg M, Albers G, Guenego A, Marks M, Dodd R, Do H, Wintermark M, Martin B, et al. Endovascular versus medical therapy for large‐vessel anterior occlusive stroke presenting with mild symptoms. Int J Stroke. 2020;15:324–331. doi: 10.1177/1747493019873510 [DOI] [PubMed] [Google Scholar]
- 13. Goyal N, Tsivgoulis G, Malhotra K, Ishfaq M, Pandhi A, Frohler M, Spiotta A, Anadani M, Psychogios M, Maus V, et al. Medical management vs mechanical thrombectomy for mild strokes: an international multicenter study and systematic review and meta‐analysis. JAMA Neurol. 2020;77:16–24. doi: 10.1001/jamaneurol.2019.3112 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Toth G, Ortega‐Gutierrez S, Tsai J, Cerejo R, Al Kasab S, Uchino K, Hussain M, Bain M, Bullen J, Samaniego EJN. The safety and feasibility of mechanical thrombectomy for mild acute ischemic stroke with large vessel occlusion. Neurosurgery. 2020;86:802–807. doi: 10.1093/neuros/nyz354 [DOI] [PubMed] [Google Scholar]
- 15. Wang X, Tao L, Zhou Z, Li X, Chen HS. Antiplatelet vs. R‐tPA for acute mild ischemic stroke: a prospective, random, and open label multi‐center study. Int J Stroke. 2019;14:658–663. doi: 10.1177/1747493019832998 [DOI] [PubMed] [Google Scholar]
- 16. Adams H, Bendixen B, Kappelle L, Biller J, Love B, Gordon D, Marsh EJS. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke. 1993;24:35–41. doi: 10.1161/01.str.24.1.35 [DOI] [PubMed] [Google Scholar]
- 17. Zaidat O, Yoo A, Khatri P, Tomsick T, von Kummer R, Saver J, Marks M, Prabhakaran S, Kallmes D, Fitzsimmons B, et al. Recommendations on angiographic revascularization grading standards for acute ischemic stroke: a consensus statement. Stroke. 2013;44:2650–2663. doi: 10.1161/strokeaha.113.001972 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. van Swieten J, Koudstaal P, Visser M, Schouten H, van Gijn JJS. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604–607. doi: 10.1161/01.str.19.5.604 [DOI] [PubMed] [Google Scholar]
- 19. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, et al. Randomised double‐blind placebo‐controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European‐Australasian acute stroke study investigators. Lancet. 1998;352:1245–1251. doi: 10.1016/s0140-6736(98)08020-9 [DOI] [PubMed] [Google Scholar]
- 20. Albers G, Marks M, Kemp S, Christensen S, Tsai J, Ortega‐Gutierrez S, McTaggart R, Torbey M, Kim‐Tenser M, Leslie‐Mazwi T, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378:708–718. doi: 10.1056/NEJMoa1713973 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Sarraj A, Hassan A, Savitz S, Grotta J, Cai C, Parsha K, Farrell C, Imam B, Sitton C, Reddy S, et al. Endovascular thrombectomy for mild strokes: how low should we go? Stroke. 2018;49:2398–2405. doi: 10.1161/strokeaha.118.022114 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Manno C, Disanto G, Bianco G, Nannoni S, Heldner M, Jung S, Arnold M, Kaesmacher J, Müller M, Thilemann S, et al. Outcome of endovascular therapy in stroke with large vessel occlusion and mild symptoms. Neurology. 2019;93:e1618–e1626. doi: 10.1212/wnl.0000000000008362 [DOI] [PubMed] [Google Scholar]
- 23. Wu X, Khunte M, Payabvash S, Zhu C, Brackett A, Matouk C, Gandhi D, Sanelli P, Malhotra A. Outcomes after thrombectomy for minor stroke: a meta‐analysis. World Neurosurg. 2021;149:e1140–e1154. doi: 10.1016/j.wneu.2020.12.047 [DOI] [PubMed] [Google Scholar]
- 24. Seners P, Perrin C, Lapergue B, Henon H, Debiais S, Sablot D, Girard Buttaz I, Tamazyan R, Preterre C, Laksiri N, et al. Bridging therapy or IV thrombolysis in minor stroke with large vessel occlusion. Ann Neurol. 2020;88:160–169. doi: 10.1002/ana.25756 [DOI] [PubMed] [Google Scholar]
- 25. Tian B, Tian X, Shi Z, Peng W, Zhang X, Yang P, Li Z, Zhang X, Lou M, Yin C, et al. Clinical and imaging indicators of hemorrhagic transformation in acute ischemic stroke after endovascular thrombectomy. Stroke. 2021;53:1674–1681. doi: 10.1161/strokeaha.121.035425 [DOI] [PubMed] [Google Scholar]
- 26. van Kranendonk K, Treurniet K, Boers A, Berkhemer O, van den Berg L, Chalos V, Lingsma H, van Zwam W, van der Lugt A, van Oostenbrugge R, et al. Clinical and imaging markers associated with hemorrhagic transformation in patients with acute ischemic stroke. Stroke. 2019;50:2037–2043. doi: 10.1161/strokeaha.118.024255 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S7
Figures S1–S2
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.