Abstract
Background
Edaravone dexborneol, a novel neuroprotective agent with combined antioxidant and anti‐inflammatory properties, has demonstrated significant improvement in 90‐day functional outcomes for patients with acute ischemic stroke. This study aimed to evaluate the outcomes of edaravone dexborneol in patients with acute ischemic stroke with large infarct core.
Methods
This prospective, multicenter, parallel‐group, real‐world cohort study was conducted between December 2022 and October 2023 across 72 centers in China. Participants were categorized into an exposed group (receiving edaravone dexborneol 37.5 mg/dose every 12 hours for 14 days) and an unexposed group (not receiving edaravone dexborneol). Propensity score matching (1:1) was used to balance baseline characteristics, and clinical outcomes were compared between the groups. The primary efficacy outcome was the proportion of patients achieving a modified Rankin Scale score of ≤2 at 90 days.
Results
After matching, the 90‐day modified Rankin Scale ordinal shift was significantly better in the edaravone dexborneol group compared with the unexposed group (median: 2 [interquartile range, 1–4.5] versus 3 [interquartile range, 1–5]; unadjusted odds ratio [OR], 1.90 [95% CI, 1.04–3.46]; P=0.04). Patients in the edaravone dexborneol group had a higher rate of functional independence (58.8% versus 36.8%; unadjusted OR, 2.46 [95% CI, 1.23–4.90]; P=0.01) and a lower 90‐day mortality rate (11.8% versus 19.1%; unadjusted OR, 0.56 [95% CI, 0.22–1.46]; P=0.24).
Conclusions
In patients with acute ischemic stroke with large infarct core, edaravone dexborneol improved the likelihood of achieving favorable functional outcomes at 90 days.
Registration
URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05644223.
Keywords: edaravone dexborneol, large ischemic stroke, neuroprotective agent, outcomes, propensity score matching
Subject Categories: Cerebrovascular Disease/Stroke
Nonstandard Abbreviations and Acronyms
- AIS
acute ischemic stroke
- ASPECTS
Alberta Stroke Program Early CT Score
- EVT
endovascular treatment
- EXPAND
Effectiveness and Safety of Edaravone Dexborneol in Acute Ischemic Stroke
- LVO
large vessel occlusion
- mRS
Modified Rankin Scale
- NIHSS
National Institutes of Health Stroke Scale
Clinical Perspective.
What Is New?
Edaravone dexborneol significantly improved 90‐day functional outcomes in patients with acute ischemic stroke with large infarct core.
What Are the Clinical Implications?
Edaravone dexborneol may serve as a complementary therapy to standard reperfusion treatment.
Further randomized controlled trials are warranted to confirm its efficacy and define its optimal timing and patient selection in clinical practice.
Several landmark randomized controlled trials (RCTs) have established the safety and efficacy of endovascular treatment (EVT) for acute large vessel occlusion (LVO). 1 Recent advancements have extended the application of EVT to large ischemic strokes. Five RCTs have demonstrated the superiority of EVT over medical management for acute LVO with a large core infarct whereas a sixth trial was neutral. 2 , 3 , 4 , 5 , 6 , 7 The proportion of patients achieving a 90‐day modified Rankin Scale (mRS) score of 0 to 2 in the EVT group remains modest (14%–30%). 8 , 9 Neuroprotection has emerged as a promising strategy to address this limitation. Edaravone dexborneol, a novel neuroprotective agent combining edaravone and (+)‐borneol in a 4:1 ratio, has shown potential. 10 , 11 , 12 Edaravone acts by scavenging free radicals, reducing cerebral edema, and preventing delayed neuronal death, whereas borneol inhibits inflammation‐related proteins and mitigates brain injury. 11 , 13 , 14 , 15 This dual‐action mechanism offers hope for improving outcomes in stroke treatment.
A recent phase III, double‐blind, randomized controlled trial involving 1165 patients with acute ischemic stroke (AIS) (TASTE [Treatment of Acute Ischemic Stroke with Edaravone Dexborneol]) demonstrated that edaravone dexborneol significantly improved 90‐day functional outcomes compared with edaravone alone (67.18% versus 58.97%; odds ratio (OR), 1.42 [95% CI, 1.12–1.81]). 16 , 17 Despite these promising results, evidence regarding its efficacy and safety in large ischemic strokes setting remains limited. This EXPAND (The Effectiveness and Safety of Edaravone Dexborneol in Acute Ischemic Stroke) subgroup analysis aims to evaluate the role of edaravone dexborneol in this patient population.
METHODS
Data Availability
The data that support the findings of this study are available from the corresponding authors.
Study Population
This post hoc subgroup analysis study was a propensity‐matched analysis of the EXPAND trial. The EXPAND trial was a prospective, multicenter, 2‐arm, parallel, real‐world cohort study conducted between December 2022 and October 2023, with patients assigned at a 2:1 ratio. The decision to pursue intravenous thrombolysis or EVT was at the discretion of the treating teams. Eligible participants were recruited from 72 comprehensive stroke centers across China, adhering to the inclusion and exclusion criteria defined by the study protocol. The primary inclusion criteria were (1) age≥18 years; (2) clinical diagnosis of acute ischemic stroke; (3) provision of informed consent by the patient or a legally authorized representative; (4) hospital admission within 14 days of symptom onset, defined as the last time the patient was known to be well; and (5) a prestroke mRS score of 0 or 1. Exclusion criteria included (1) evidence of intracranial hemorrhage on neuroimaging, such as hemorrhagic stroke, epidural hematoma, subdural hematoma, intraventricular hemorrhage, or subarachnoid hemorrhage; (2) pregnancy, breastfeeding, or women of childbearing age unwilling to use contraception; (3) severe renal failure, defined as an estimated glomerular filtration rate <30 mL/min per 1.73 m2; (4) active malignancy or severe comorbidities with a life expectancy <90 days; (5) inability or unwillingness to provide written informed consent or complete follow‐up; and (6) other serious medical or psychiatric conditions deemed unsuitable for study participation by the investigator.
For this post hoc subgroup analysis, we included only patients with anterior circulation large infarct core, defined as an Alberta Stroke Program Early CT [Computed Tomography] Score (ASPECTS) of 0 to 5. Baseline noncontrast CT or magnetic resonance imaging scans were evaluated by a central imaging core laboratory to determine ASPECTS. Patients were then categorized based on whether they received edaravone dexborneol.
The ethics committee of Xuanwu Hospital Capital Medical University (ref. [2022]090) approved this study protocol. Local ethics committees of each study center approved the study. Participants or their legally authorized representatives provided written informed consent before the procedure and separate written informed consent for participation in the EXPAND registry before study enrollment.
Data Collection
The study prospectively collected the following variables: age, sex, baseline systolic and diastolic blood pressure, medical history (including prior stroke, hypertension, hyperlipidemia, diabetes, and heart disease), current smoking and heavy drinking status, prestroke mRS score, baseline National Institutes of Health Stroke Scale (NIHSS) score, time from symptom onset to admission, stroke cause based on TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification, lesion location (anterior, posterior, or both circulations), neuroimaging findings (ASPECTS), type of reperfusion therapy (none, intravenous, endovascular, or bridging), and follow‐up outcomes. All data were recorded in an electronic case report form, reviewed for completeness and consistency by monitors. Data management followed standard operating procedures established by the steering committee, with data entry, validation, and queries handled by dedicated data managers. A statistician oversaw data handling, ensuring accuracy and integrity. Imaging data were independently adjudicated by the Core‐Imaging Laboratory of Neurology, a blinded central neuroimaging core laboratory responsible for reviewing CT/magnetic resonance imaging and angiographic images without knowledge of treatment allocation. Clinical and imaging data were collected, transported, and preserved in strict compliance with the study protocol. Following database closure, the data were exported as a SAS data set for analysis.
Treatment or Intervention
The recommended dosage of edaravone dexborneol was 37.5 mg per dose (edaravone 30 mg; (+)‐borneol 7.5 mg) administered via intravenous infusion after stroke onset and every 12 hours for 14 days (Figure S1). In this real‐world cohort study, patients in the exposed arm received edaravone dexborneol without restrictions on timing or duration of administration. Patients who discontinued the infusion due to adverse events related to the investigational product remained in the exposed arm. Patients in both study arms were treated in acute stroke units or intensive care units following the latest Chinese guidelines for acute ischemic stroke management. Reperfusion therapy, including intravenous thrombolysis or endovascular intervention, was performed in eligible patients after obtaining informed consent. All patients were admitted to a stroke unit with cardiac monitoring, and supportive care was provided as needed. Hyperthermia (temperature>38 °C) was managed with antipyretics or physical cooling, and hyperglycemia and hypoglycemia were corrected accordingly. Blood pressure was closely monitored and controlled. Aspirin (initial dose 15–300 mg) was initiated within 24 hours in patients not receiving intravenous thrombolysis, or within 24 to 48 hours in those who underwent intravenous thrombolysis and had no intracranial hemorrhage on follow‐up CT. In patients with minor noncardioembolic ischemic stroke (NIHSS score≤3), dual antiplatelet therapy (aspirin and clopidogrel) was initiated within 24 hours of onset and continued for 24 days.
End Points
The primary efficacy outcome was a favorable outcome at 3 months, defined as a mRS score of 0 to 2. Secondary efficacy outcomes were the distribution of mRS scores, poor outcomes, defined as an mRS score of 5 to 6, and EuroQuality of Life 5‐Dimension 5‐Level score (EQ‐5D‐5L) at 3 months. Follow‐up at 3 months was conducted through standardized telephone interviews performed by trained investigators who were blinded to baseline and procedural data. Safety outcomes included symptomatic intracranial hemorrhage during hospitalization, defined according to the Heidelberg Bleeding Classification, any intracranial hemorrhage during hospitalization, and adverse events occurring during hospitalization.
Statistical Analysis
Descriptive statistics were used to summarize patient characteristics and outcomes. Continuous and ordinal variables were presented as medians with interquartile ranges, and categorical variables were reported as frequencies and percentages. Baseline and procedural characteristics between the 2 groups were compared using the Kruskal–Wallis test for continuous and ordinal variables and Fisher’s exact test for categorical variables. To ensure well‐balanced baseline characteristics between the groups, propensity score matching was performed. Covariates included a priori in the propensity score model were variables significantly or potentially associated with the treatment method (edaravone dexborneol versus no edaravone dexborneol), such as age, sex, baseline NIHSS score, history of stroke, hypertension, hyperlipidemia, diabetes, or heart disease, prestroke mRS score, TOAST subtype, and reperfusion therapy. 18 , 19 Matching was conducted using a 1:1 ratio without replacement, applying a greedy matching algorithm with a caliper width≤0.2 of the SD of the logit of the propensity scores. Statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC), with a 2‐sided P value of <0.05 considered statistically significant.
RESULTS
Baseline Characteristics
Of the 4684 patients enrolled in the EXPAND study, 4420 were excluded due to lost to follow‐up at 90 days (n=283), no ASPECTS information (n=4) and with ASPECTS value ≥6 (n=4133). Finally, 264 patients were included in the analysis. Among them, 82 patients (31.1%) did not receive edaravone dexborneol, and 182 (68.9%) received edaravone dexborneol (Figure 1). Baseline clinical and imaging characteristics, stratified by edaravone dexborneol treatment status, are summarized in Table 1. Before matching, patients who did not receive edaravone dexborneol had higher systolic blood pressure on admission compared with those who did (154 versus 146 mm Hg, P=0.01). A greater proportion of the no edaravone dexborneol group had a higher rate of hypertension (70.7% versus 59.3%), although this difference was not significant. More male patients received edaravone dexborneol (71.4% versus 67.1%), but this difference was also not statistically significant. There were no significant differences between groups regarding prior stroke, hyperlipidemia, diabetes, or heart disease, nor were there differences in smoking or alcohol consumption history. The prevalence of stroke subtypes, classified according to TOAST criteria, was similar between groups. Stroke severity on admission, assessed by the mRS score before stroke onset, NIHSS score, and ASPECTS, did not differ significantly between the 2 groups (P>0.05 for all). Among patients who did not undergo reperfusion therapy, a higher proportion did not receive edaravone dexborneol, but this difference was not statistically significant. In a propensity‐matched analysis, patients were matched by age, sex, NIHSS score, prior stroke, hypertension, hyperlipidemia, diabetes, heart disease, mRS score before onset, lesion location, TOAST subtype, and reperfusion therapy. After matching, no significant differences were observed between the 2 groups in any of these variables (P>0.05 for all). A summary of these matched baseline characteristics is also presented in Table 1.
Figure 1. Flow chart.
ASPECTS indicates Alberta Stroke Program Early CT [Computed Tomography] Score
Table 1.
Baseline Characteristics Before and After Matching
| Characteristic | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| No edaravone dexborneol (N=82) | Edaravone dexborneol (N=182) | P value | No edaravone dexborneol (N=68) | Edaravone dexborneol (N=68) | P value | |
| Age, y, median (IQR) | 67.0 (58.0–74.0) | 64.5 (56.0–73.0) | 0.14 | 66.0 (57.0–73.0) | 68.0 (59.0–75.0) | 0.38 |
| Male, n (%) | 55 (67.1) | 130 (71.4) | 0.47 | 47 (69.1) | 48 (70.6) | 0.85 |
| Systolic blood pressure, mm Hg, median (IQR) | 154.0 (140.0–170.0) | 146.0 (132.0–160.0) | 0.01 | 154.0 (138.0–172.0) | 144.5 (136.0–160.5) | 0.06 |
| Diastolic blood pressure, mm Hg, median (IQR) | 87.0 (76.0–96.0) | 85.0 (77.0–96.0) | 0.71 | 87.0 (76.0–96.5) | 82.5 (73.5–93.0) | 0.25 |
| Medical history, n (%) | ||||||
| Stroke | 15 (18.3) | 42 (23.1) | 0.38 | 12 (17.6) | 17 (25.0) | 0.30 |
| Hypertension | 58 (70.7) | 108 (59.3) | 0.16 | 50 (73.5) | 46 (67.6) | 0.74 |
| Hyperlipidemia | 7 (8.5) | 13 (7.1) | 0.15 | 5 (7.4) | 4 (5.9) | 0.94 |
| Diabetes | 21 (25.6) | 43 (23.6) | 0.84 | 19 (27.9) | 16 (23.5) | 0.83 |
| Heart disease | 19 (23.2) | 62 (34.1) | 0.08 | 17 (25.0) | 19 (27.9) | 0.70 |
| Current smoking, n (%) | 23 (28.0) | 55 (30.2) | 0.72 | 19 (27.9) | 20 (29.4) | 0.85 |
| Current heavy drinking, n (%) | 14 (17.1) | 34 (18.7) | 0.75 | 11 (16.2) | 12 (17.6) | 0.82 |
| Modified Rankin Scale score before onset, n (%) | ||||||
| 0 | 76 (92.7) | 172 (94.5) | 0.56 | 64 (94.1) | 63 (92.6) | 0.73 |
| 1 | 6 (7.3) | 10 (5.5) | 4 (5.9) | 5 (7.4) | ||
| National Institutes of Health Stroke Scale score, median (IQR) | 12.0 (5.0–20.0) | 12.5 (7.0–18.0) | 0.76 | 11.0 (5.0–16.0) | 12.0 (5.0–16.0) | 0.77 |
| Time from onset to admission, hour, median (IQR) | 5.7 (2.1–24.0) | 6.1 (2.5–14.6) | 0.73 | 6.5 (2.7–25.4) | 5.0 (2.0–14.1) | 0.10 |
| Time from onset to treatment, hour, median (IQR) | 13.7 (5.6–30.8) | … | 13.9 (4.4–32.7) | … | ||
| Trial of Org 10 172 in Acute Stroke Treatment subtype, n (%) | ||||||
| Large artery atherosclerosis | 34 (41.5) | 78 (42.9) | 0.23 | 30 (44.1) | 30 (44.1) | 0.95 |
| Cardiogenic embolism | 8 (9.8) | 23 (12.6) | 6 (8.8) | 6 (8.8) | ||
| Small vessel occlusion | 3 (3.7) | 3 (1.6) | 2 (2.9) | 1 (1.5) | ||
| Oher determined cause | 1 (1.2) | 12 (6.6) | 0 (0.0) | 0 (0.0) | ||
| Undetermined cause | 36 (43.9) | 66 (36.3) | 30 (44.1) | 31 (45.6) | ||
| Alberta Stroke Program Early CT Score on CT | ||||||
| Median (IQR) | 4.0 (2.0–5.0) | 4.0 (2.0–5.0) | 0.43 | 4.0 (2.0–5.0) | 4.0 (1.0–5.0) | 0.45 |
| Distribution, n (%) | ||||||
| 0 | 7 (8.5) | 15 (8.2) | 0.06 | 5 (7.4) | 8 (11.8) | 0.01 |
| 1 | 1 (1.2) | 16 (8.8) | 0 (0.0) | 10 (14.7) | ||
| 2 | 14 (17.1) | 19 (10.4) | 13 (19.1) | 5 (7.4) | ||
| 3 | 17 (20.7) | 23 (12.6) | 13 (19.1) | 10 (14.7) | ||
| 4 | 20 (24.4) | 44 (24.2) | 17 (25.0) | 14 (20.6) | ||
| 5 | 23 (18.0) | 65 (35.7) | 20 (29.4) | 21 (30.9) | ||
| Reperfusion therapy, n (%) | ||||||
| None | 42 (51.2) | 74 (40.7) | 0.26 | 35 (51.5) | 33 (48.5) | 0.79 |
| Intravenous treatment | 12 (14.6) | 29 (15.9) | 10 (14.7) | 13 (19.1) | ||
| Endovascular treatment or bridging | 28 (34.2) | 79 (43.4) | 23 (33.8) | 22 (32.4) | ||
Data are n (%) or median (IQR). CT indicates computed tomography; and IQR, indicates interquartile range.
Outcome Measures
Table 2 and Figure 2 present the primary outcome comparisons between patients with edaravone dexborneol and those without edaravone dexborneol. Before propensity score matching, patients with edaravone dexborneol had a more favorable 90‐day mRS ordinal shift (median: 2 [interquartile range, 1–4] versus 3 [interquartile range. 2–5]; adjusted OR [aOR], 1.83 [95% CI, 1.12–2.99]; P=0.02), a higher proportion of functional independence (51.1% versus 34.2%; aOR, 2.19 [95% CI, 1.14–4.22]; P=0.02), and a lower 90‐day mortality rate (10.4% versus 23.2%; aOR, 0.43 [95% CI, 0.18–1.03]; P=0.06) and symptomatic intracranial hemorrhage during hospitalization (1.1% versus 6.1%; aOR, 0.03 [95% CI, 0.001–0.71]; P=0.03).
Table 2.
Efficacy and Safety Outcomes
| Outcomes | Event/N (%) | Unadjusted | Multivariable adjusted | ||
|---|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | ||
| mRS score 0–2 at 90 d | |||||
| No edaravone dexborneol | 28 (34.2) | Reference | Reference | ||
| Edaravone dexborneol | 93 (51.1) | 2.02 (1.17–3.46) | 0.01 | 2.19 (1.14–4.22) | 0.02 |
| mRS score at 90 d* | |||||
| No edaravone dexborneol | 3.0 (2.0–5.0) | Reference | Reference | ||
| Edaravone dexborneol | 2.0 (1.0–4.0) | 2.08 (1.31–3.30) | 0.002 | 1.83 (1.12–2.99) | 0.02 |
| EQ‐5D‐5L score at 90 d† | |||||
| No edaravone dexborneol | 68.8 (62.9–74.6) | Reference | Reference | ||
| Edaravone dexborneol | 73.4 (69.9–77.0) | 4.66 (−2.08 to 11.40) | 0.17 | 5.09 (−1.86 to 12.04) | 0.15 |
| Symptomatic ICH during hospitalization | |||||
| No edaravone dexborneol | 5 (6.1) | Reference | Reference | ||
| Edaravone dexborneol | 2 (1.1) | 0.17 (0.03–0.90) | 0.04 | 0.03 (0.001–0.71) | 0.03 |
| ICH during hospitalization | |||||
| No edaravone dexborneol | 20 (24.4) | Reference | Reference | ||
| Edaravone dexborneol | 38 (20.9) | 0.82 (0.44–1.52) | 0.52 | 0.69 (0.34–1.39) | 0.30 |
| Mortality within 90 d | |||||
| No edaravone dexborneol | 19 (23.2) | Reference | Reference | ||
| Edaravone dexborneol | 19 (10.4) | 0.39 (0.19–0.78) | 0.008 | 0.43 (0.18–1.03) | 0.06 |
| Adverse event during hospitalization | |||||
| No edaravone dexborneol | 36 (43.9) | Reference | Reference | ||
| Edaravone dexborneol | 79 (43.4) | 0.98 (0.58–1.66) | 0.94 | 1.06 (0.61–1.87) | 0.83 |
Adjusted estimates of outcome were calculated using multiple regression with baseline covariates including age, sex, National Institutes of Health Stroke Scale score, history of stroke, history of hypertension, history of hyperlipidemia, history of diabetes, history of heart disease, mRS score before onset, Trial of Org 10 172 in Acute Stroke Treatment subtype, and reperfusion therapy. EQ‐5D‐5L indicates EuroQuality of Life 5‐Dimension 5‐Level; ICH, intracranial hemorrhage; mRS, modified Rankin Scale; and OR, odds ratio.
Common OR with its 95% CI was calculated using ordinal logistic regression for the outcome of mRS at 90 days.
β with 95% CI was calculated using linear regression for the outcome of EQ‐5D‐5L score at 90 d.
Figure 2. Modified Rankin Scale distribution at 90 days in (A) all patients and (B) propensity score matching data set.
Exposed group, patients received edaravone dexborneol; Unexposed group, patient did not receive edaravone dexborneol.
In the postmatched population of 136 patients (Table 3), the 90‐day mRS ordinal shift remained significantly better in the edaravone dexborneol group with to the non‐edaravone dexborneol group (median: 2 [interquartile range, 1–4.5] versus 3 [interquartile range, 1–5]; aOR, 1.90 [95% CI, 1.04–3.46]; P=0.04). Similarly, patients with edaravone dexborneol exhibited a higher rate of functional independence (58.8% versus 36.8%; unadjusted OR, 2.46 [95% CI, 1.23–4.90]; P=0.01) and a lower 90‐day mortality rate (11.8% versus 19.1%; unadjusted OR, 0.56 [95% CI, 0.22–1.46]; P=0.24).
Table 3.
Efficacy and Safety Outcomes in Propensity Score Matching Based Analysis Cohort
| Outcomes | No edaravone dexborneol (N=68) | Edaravone dexborneol (N=68) |
|---|---|---|
| Propensity score matching (1:1)‐based analysis | ||
| mRS score 0–2 at 90 d, n (%) | 25 (36.8) | 40 (58.8) |
| Unadjusted OR (95% CI) | Reference | 2.46 (1.23–4.90) |
| P value | 0.01 | |
| mRS score at 90 d, median (interquartile range) | 3 (1–5) | 2 (1–4.5) |
| Unadjusted common OR (95% CI) | Reference | 1.90 (1.04–3.46) |
| P value | 0.04 | |
| EuroQuality of Life 5‐Dimension 5‐Levelscore at 90 d, mean (95% CI) | 67.71 (61.29–74.12) | 74.04 (67.70–80.37) |
| Unadjusted β (95% CI) | Reference | 6.33 (−2.60 to 15.29) |
| P value | 0.16 | |
| Symptomatic ICH during hospitalization, n (%) | 3 (4.4) | 0 (0.0) |
| Unadjusted OR (95% CI) | … | … |
| P value | … | |
| ICH during hospitalization, n (%) | 17 (25.0) | 10 (14.7) |
| Unadjusted OR (95% CI) | Reference | 0.52 (0.22–1.23) |
| P value | 0.14 | |
| Mortality within 90 d, n (%) | 13 (19.1) | 8 (11.8) |
| Unadjusted OR (95% CI) | Reference | 0.56 (0.22–1.46) |
| P value | 0.24 | |
| Adverse event during hospitalization, n (%) | 29 (42.6) | 33 (48.5) |
| Unadjusted OR (95% CI) | Reference | 1.27 (0.64–2.49) |
| P value | 0.49 | |
The propensity for being in each group was calculated using logistic regression with baseline covariates including age, sex, National Institutes of Health Stroke Scale score, history of stroke, history of hypertension, history of hyperlipidemia, history of diabetes, history of heart disease, mRS score before onset, Trial of Org 10 172 in Acute Stroke Treatment subtype, and reperfusion therapy. ICH indicates intracranial hemorrhage; mRS, modified Rankin Scale; and OR, odds ratio.
We conducted an exploratory subgroup analysis stratified by age (<65 versus ≥65 years), baseline ASPECTS (<3 versus ≥3 points), stroke subtypes (atherothrombotic versus nonatherothrombotic), and reperfusion therapy (none versus intravenous thrombolysis or EVT). Using an ordinal logistic regression model, similar effects of the treatment allocation on the mRS score 0 to 2 were observed in all subgroups (P>0.05 for all interactions, Figure 3).
Figure 3. Odds ratios for the primary outcome in prespecified subgroups.
ASPECTS indicates Alberta Stroke Program Early CT Score; EVT, endovascular treatment; IVT, intravenous thrombolysis; and OR, odds ratio.
We further examined the effect of edaravone dexborneol stratified by time to treatment initiation. After adjusting for confounders, edaravone dexborneol administered within 6 hours of onset was significantly associated with functional independence (aOR, 2.85 [95% CI, 1.13–7.20]; P=0.03), as was treatment initiated between 6 and 24 hours (aOR, 2.34 [95% CI, 1.07–5.14]; P=0.04). However, this association was not significant when treatment was initiated after 24 hours (aOR, 1.73 [95% CI, 0.76–3.92]; P=0.19) (Table S1).
DISCUSSION
In this secondary analysis of a prospective registry clinical trial involving patients with AIS with a large infarct core presenting within 14 days of symptom onset, edaravone dexborneol use was associated with improved functional outcomes and a trend to reduced mortality at 90 days. To our knowledge, this is the first study to demonstrate the outcomes of edaravone dexborneol in this patient population.
Patients with AIS with a large infarct core typically experience poor neurological outcomes, including stroke progression, cerebral edema, and death. Advances in neurointerventional techniques have driven efforts to overcome the limitations of reperfusion therapy. Five recent RCTs have demonstrated the superiority of EVT over medical management for acute LVO with a large infarct core. 2 , 3 , 4 , 5 , 6 However, the proportion of patients achieving a 90‐day mRS score of 0 to 2 in the EVT group remains relatively low (14%–30%). Despite the recommendation of reperfusion therapy as the standard treatment for ischemic stroke, 1 , 20 nearly half of patients fail to benefit from its timely initiation, 1 , 21 , 22 , 23 , 24 highlighting the need for complementary strategies such as neuroprotection. Neuroprotection aims to enhance outcomes by salvaging, recovering, or regenerating neuronal and glial structure and function. Evidence from clinical trials investigating neuroprotective drugs suggests the potential feasibility and promise of this approach. 16 , 25 Additionally, a subgroup analysis of the ANGEL‐ASPECTS (Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core) trial found no significant association between infarct core volume growth and clinical outcomes. 26 This underscores the limitation of using infarct volume growth as a surrogate imaging marker for assessing cerebroprotection therapies. The concept of infarct size may be overly simplistic, as it represents only a volumetric measure and does not account for the qualitative or eloquent aspects of the infarct. Reperfusion may still rescue viable elements of the neurovascular unit within the infarcted region, potentially improving functional outcomes and explain even in the absence of imaging perfusion mismatch, improved outcomes could still be observed. 27 , 28 These findings highlight opportunities to further enhance prognosis in patients with AIS with a large infarct core.
Patients with large ischemic cores are less likely to derive substantial benefit from thrombectomy. Delays in performing the procedure, such as those caused by the need for long‐distance transport to an endovascular‐capable center or the lack of availability of the thrombectomy team, can result in enlargement of the ischemic core, reducing the likelihood of favorable outcomes. Similarly, the efficacy of intravenous thrombolysis with tissue‐type plasminogen activator diminishes over time, likely due to progressive ischemic core growth. 29 , 30 In these settings, neuroprotection offers a promising strategy by slowing ischemic core expansion, preserving at‐risk penumbral tissue, and increasing the number of patients who may be able to derive benefit reperfusion with either intravenous thrombolysis or thrombectomy. 29 Animal studies have shown that neuroprotective agents and high‐flow oxygen can impede the progression of the penumbra into the core. 31 , 32 These findings suggest that early neuroprotective intervention after ischemic stroke onset could extend the therapeutic window for both intravenous thrombolysis and thrombectomy. Our analysis demonstrated that the neuroprotective effects of edaravone dexborneol benefitted not only patients undergoing thrombectomy but also those treated with intravenous thrombolysis or medical management. This underscores its potential value, particularly for patients unable to access timely endovascular therapy, either due to delayed presentation beyond the golden time window or limited health care infrastructure in underdeveloped or developing regions. These findings highlight the potential broad applicability of edaravone dexborneol in improving outcomes across diverse treatment settings.
Our study has several limitations. First, as a nonrandomized study, it lacks the robustness of an RCT. We employed propensity score matching to minimize the influence of confounding factors arising from differences in baseline characteristics, aiming to approximate the outcomes typically observed in RCTs. However, it is important to acknowledge that propensity score matching may oversimplify complex relationships by assigning equal weight to covariates of varying importance. Future RCTs are needed to validate these findings in patients with large infarct cores. Second, the sample size was limited. Third, the findings of this study should be interpreted with caution, as >90% of the original registry population was excluded. Nonetheless, LVO accounts for 24% to 38% of all acute ischemic strokes, 33 and large core infarcts comprise up to 25% of LVO cases. 34 This proportion is consistent with previous reports. To aid interpretation, we provide a comparison of baseline characteristics between included and excluded patients (Table S2). Fourth, we did not collect blood samples, which prevented us from investigating the potential mechanisms underlying the observed treatment effects. Fourth, we did not include certain outcomes, such as drug‐related adverse effects, which limits the comprehensiveness of our analysis. Future studies should evaluate the impact of edaravone dexborneol on these outcomes. Finally, this trial was conducted exclusively among Chinese patients, limiting the generalizability of the findings to other ethnic groups. Additional studies in diverse populations are warranted to confirm these results.
CONCLUSIONS
In this secondary analysis of a prospective registry of patients with AIS and large infarct core, edaravone dexborneol use was associated with improved 90‐day functional outcomes and a trend toward reduced mortality in acute ischemic stroke patients with large infarct cores. These findings suggest a potential therapeutic benefit of edaravone dexborneol in this high‐risk population, particularly in settings where access to timely endovascular therapy may be limited. Further randomized controlled trials are warranted to validate these findings and to better define the role of edaravone dexborneol as an adjunctive neuroprotective strategy in large core ischemic stroke.
Sources of Funding
This research project was supported by the Industry‐University‐Research Innovation Fund for Chinese Universities (2023GY024), National Health Commission Capacity Building and Continuing Education Center Fund (W2024SNKT08), Project of Central Government Guiding Local Science and Technology Development (2025ZY0028).
Disclosures
Dr Nguyen reports being Associate Editor of Stroke, speaker for Genentech, kaneka, advisory board for Bayer, Brainomix, Route 92 (not related). The remaining authors have no disclosures to report.
Supporting information
Data S1 EXPAND investigators
Tables S1–S2
Figure S1
Acknowledgments
We thank all clinicians, statisticians, and imaging and laboratory technologists who were involved in the EXPAND registry.
This article was sent to Michelle H. Leppert, MD, MBA, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.125.044296
For Sources of Funding and Disclosures, see page 10.
Contributor Information
Thanh N. Nguyen, Email: thanh.nguyen@bmc.org.
Lianmei Zhong, Email: 13888967787@163.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1 EXPAND investigators
Tables S1–S2
Figure S1
Data Availability Statement
The data that support the findings of this study are available from the corresponding authors.