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ANGEL-ASPECT

Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct

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Year of Publication: 2023

Authors: X. Huo, G. Ma, X. Tong, ..., for the ANGEL-ASPECT Investigators

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2023;388:1272-83. DOI: 10.1056/NEJMoa2213379

Link: https://doi.org/10.1056/nejmoa2213379

PDF: https://www.ccmu.edu.cn/docs/2023-02/667...e19e4757a61.pdf

Clinical Question

In patients with acute ischemic stroke and a large infarct core (ASPECTS 3-5, or infarct-core volume 70-100 mL) due to anterior-circulation large-vessel occlusion within 24 hours, does endovascular therapy improve functional outcomes compared to best medical management?

Study Overview

Objective

Endovascular therapy in patients with acute ischemic stroke and large infarct core (ASPECTS 3-5, or infarct-core volume 70-100 mL) presenting within 24 hours.

Study Summary

In Chinese patients with acute anterior-circulation LVO stroke and large infarct core (ASPECTS 3-5, or infarct-core volume 70-100 mL) within 24 hours of last known well, endovascular therapy produced a favorable shift in 90-day mRS (generalized OR 1.37, 95% CI 1.11-1.69; P=0.004) and higher functional independence, without a mortality benefit and with numerically more symptomatic intracranial hemorrhage.

Intervention

Endovascular thrombectomy (stent retriever and/or contact aspiration, with optional angioplasty, stenting, or intra-arterial thrombolysis) plus best medical management, versus best medical management alone.

Patients per Arm

231 EVT, 225 medical management (456 total randomized; 230 vs 225 in full-analysis population after 1 EVT withdrawal)

Bottom Line

In Chinese patients with acute ischemic stroke and a large infarct core (ASPECTS 3-5, or infarct-core volume 70-100 mL) due to anterior-circulation large-vessel occlusion presenting within 24 hours, endovascular therapy produced a favorable shift in 90-day mRS distribution (generalized OR 1.37, 95% CI 1.11-1.69; P=0.004) and higher rates of functional independence, but did NOT reduce 90-day mortality (21.7% vs 20.0%, HR 1.00; P=0.99) and was associated with numerically higher symptomatic (6.1% vs 2.7%) and significantly higher any (49.1% vs 17.3%) intracranial hemorrhage.

        Major Points
        456 patients underwent randomization (231 to endovascular therapy, 225 to medical management) at 46 Chinese stroke centers; 1 EVT patient withdrew consent, leaving 230 vs 225 in the full-analysis (ITT) population. Trial stopped early at second interim analysis for efficacy.
Primary outcome (ordinal shift in 90-day mRS): median mRS 4 (IQR 2-5) EVT vs 4 (IQR 3-5) medical; Wilcoxon-Mann-Whitney generalized odds ratio 1.37 (95% CI 1.11 to 1.69); P=0.004.
Functional independence (mRS 0-2) at 90 days: 69/230 (30.0%) EVT vs 26/225 (11.6%) medical (relative risk 2.62, 95% CI 1.69-4.06).
mRS 0-3 at 90 days: 108/230 (47.0%) EVT vs 75/225 (33.3%) medical (RR 1.50, 95% CI 1.17-1.91).
Death from any cause at 90 days: 50/230 (21.7%) EVT vs 45/225 (20.0%) medical (HR 1.00, 95% CI 0.65-1.54; P=0.99) — no mortality benefit.
Symptomatic intracranial hemorrhage within 48 h: 14/230 (6.1%) EVT vs 6/225 (2.7%) medical (RR 2.07, 95% CI 0.79-5.41; P=0.12); any intracranial hemorrhage within 48 h 113/230 (49.1%) vs 39/225 (17.3%) (RR 2.71, 95% CI 1.91-3.84; P<0.001).
Target-artery recanalization at 36 h: 169 (85.8%) EVT vs 67 (36.4%) medical (RR 2.46, 95% CI 1.96-3.08).

      

Design

Study Type: Multicenter, prospective, randomized, open-label, blinded end-point (PROBE) superiority trial

Randomization: 1

Blinding: Blinded end-point design: outcome assessors and imaging core laboratory staff blinded to treatment assignment; patients and treating clinicians were not blinded (open-label intervention).

Enrollment Period: October 2, 2020 to May 18, 2022 (terminated early at second interim analysis for efficacy)

Follow-up Duration: 90 days (primary outcome)

Centers: 46

Countries: China

Sample Size: 456

Analysis: Intention-to-treat (ITT) as main analysis; per-protocol as sensitivity analysis; safety analyzed in the ITT/full-analysis population. Because the proportional-odds assumption for the ordinal logistic-regression model of the primary outcome was not satisfied, the Wilcoxon-Mann-Whitney generalized odds ratio (95% CI) was used in an assumption-free ordinal analysis. Secondary binary outcomes analyzed with Cochran-Mantel-Haenszel (relative risks with 95% CI, adjusted for site); 90-day mortality with Cox proportional-hazards model with site as random effect. Two-sided alpha adjusted to 0.046 (O'Brien-Fleming spending function for two interim analyses). Statistical analyses performed with SAS software, version 9.4 (SAS Institute).

Inclusion Criteria

Age 18 to 80 years.
Acute ischemic stroke within the previous 24 hours (from last known well).
National Institutes of Health Stroke Scale (NIHSS) score 6 to 30.
Prestroke modified Rankin scale score of 0 or 1.
Large-vessel occlusion of the initial segment (M1) of the middle cerebral artery or the intracranial segment of the distal internal carotid artery (or both), on CTA or MRA.
Imaging (one of the following): ASPECTS 3-5 on noncontrast CT within 24 h of stroke onset (no limitation on infarct-core volume); OR ASPECTS 0-2 within 24 h AND infarct-core volume 70-100 mL; OR ASPECTS >5 on NCCT between 6 and 24 h AND infarct-core volume 70-100 mL.

Exclusion Criteria

Midline shift or clinical signs of herniation.
Mass effect on baseline imaging.
High risk of hemorrhage.
Acute bilateral strokes.
Multiple intracranial occlusions.

Baseline Characteristics

Characteristic	Control	Active
Group	Medical Management (N=225)	Endovascular Therapy (N=230)
Age - Median (IQR) - yr	67 (59-73)	68 (61-73)
Male sex no. (%)	144 (64.0)	135 (58.7)
Median NIHSS score (IQR)	15 (12-19)	16 (13-20)
Median ASPECTS (IQR)	3 (3-4)	3 (3-4)
Median infarct volume at baseline (IQR) - ml	63 (31-86)	60.5 (29-86)
Occlusion site - ICA no. (%)	81 (36.0)	83 (36.1)
Occlusion site - M1 segment no. (%)	142 (63.1)	145 (63.0)
Occlusion site - M2 segment no. (%)	2 (0.9)	2 (0.9)
Ipsilateral extracranial ICA occlusion no. (%)	35 (15.6)	41 (17.8)
IV thrombolysis no. (%)	63 (28.0)	66 (28.7)
Awoke with stroke symptoms no. (%)	78 (34.7)	69 (30.0)
Median time from onset to randomization (IQR) - hr	7.7 (5.1-13.0)	7.6 (5.0-11.9)

Arms

Field	Endovascular Therapy Group	Control
Intervention	Endovascular therapy (thrombectomy with stent retriever or contact-aspiration system, with balloon angioplasty, stent implantation, or intra-arterial thrombolysis as needed) plus best medical management. Device choice and technique at the discretion of the treating neurointerventionalist. Intravenous alteplase (0.9 mg/kg) or urokinase (1.0-1.5 million IU) if eligible.	Best medical management alone per Chinese Stroke Association guidelines, including intravenous alteplase (0.9 mg/kg) or urokinase (1.0-1.5 million IU) if eligible, antiplatelet therapy, and other supportive care.
Duration	90 days	90 days

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Ordinal shift in the distribution of scores on the modified Rankin Scale (mRS) at 90 days (range 0-6; higher scores = greater disability).	Primary	Median mRS 4 (IQR 3-5); N=225	Median mRS 4 (IQR 2-5); N=230		0.004
Functional independence (mRS 0-2) at 90 days	Secondary	11.6% (26/225)	30.0% (69/230)	2.62
mRS 0-3 at 90 days	Secondary	33.3% (75/225)	47.0% (108/230)	1.5
NIHSS score 0-1 or improvement in score by ≥10 points at 36 h	Secondary	1.8% (4/225)	5.7% (13/230)	4.29
Target-artery recanalization at 36 h (mAOL grade 2 or 3 on CTA/MRA)	Secondary	36.4% (67/184)	85.8% (169/197)	2.46
Symptomatic intracranial hemorrhage within 48 h (sICH, Heidelberg criteria)	Adverse	2.7% (6/225)	6.1% (14/230)	2.07	0.12
Any intracranial hemorrhage within 48 h	Adverse	17.3% (39/225)	49.1% (113/230)	2.71	<0.001
Death from any cause at 90 days	Adverse	20.0% (45/225)	21.7% (50/230)	1	0.99
Decompressive hemicraniectomy during hospitalization	Adverse	3.6% (8/225)	7.4% (17/230)	1.92	0.15
Serious adverse events	Adverse	38.2% (86/225)	40.0% (92/230)		0.70

Criticisms

Trial stopped early at the second interim analysis after 336 patients had complete outcome data (456 randomized; 455 completed 90-day follow-up), which can inflate estimated treatment effects.
Open-label design (no blinding of patients or site personnel), though outcome assessment was blinded.
Study population exclusively Chinese (high prevalence of intracranial atherosclerotic disease), limiting generalizability to other populations.
Only ~28% of patients received intravenous thrombolysis, and urokinase (rather than alteplase) was used in a small subset — may have disadvantaged the medical-management group.
No patients with ASPECTS >5 (6-24 h) and infarct-core volume 70-100 mL were actually enrolled, so no conclusions can be drawn about that subgroup.
Patients >80 years were excluded, limiting applicability to the oldest stroke population.
Numerically higher symptomatic intracranial hemorrhage in the EVT group (not statistically significant); significantly more any-intracranial hemorrhage; no mortality benefit.

Subgroup Analysis

The primary-outcome effect of endovascular therapy was similar across prespecified subgroups (age, NIHSS score, ASPECTS value, time from onset to randomization, occlusion site, use of intravenous thrombolysis, awoke with stroke symptoms, ipsilateral extracranial ICA occlusion, infarct-core volume, and stroke subtype) per Figure 3. Trial was not powered for subgroup analyses.

Funding

Supported by unrestricted grants from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology.

Based on: ANGEL-ASPECT (The New England Journal of Medicine, 2023)