Endovascular Thrombectomy for the Treatment of Large Ischemic Stroke: A Systematic Review and Meta-Analysis of Randomized Control Trials

Abstract

BACKGROUND AND OBJECTIVES:

Endovascular thrombectomy has previously been reserved for patients with small to medium acute ischemic strokes. Three recent randomized control trials have demonstrated functional benefit and risk profiles for thrombectomy in large-volume ischemic strokes. The primary objective of the meta-analysis was to determine the combined benefit of endovascular thrombectomy in patients with large-volume ischemic strokes and to determine the risk of adverse events after treatment.

METHODS:

We systematically searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Scopus, the Cochrane Central Register, and Google Scholar for randomized trials published between January 1, 2010, and February 19, 2023. We included trials specifically comparing endovascular thrombectomy with medical therapy in adults with acute ischemic stroke with large-volume infarctions (defined by Alberta Stroke Program Early Computed Tomography Score 3-5 or a calculated infarct volume of >50 mL). Data were extracted based on prespecified variables on study methods and design, participant characteristics, analysis approach, and efficacy/safety outcomes. Results were combined using a restricted maximum-likelihood estimation random-effects model. Studies were assessed for potential bias and quality of evidence. The primary outcome was an overall ordinal shift across modified Rankin scale scores toward a better outcome at 90 days after either treatment arm.

RESULTS:

Three thousand forty-four studies were screened, and 29 underwent full-text review. Three randomized trials (N = 1011) were included in the analysis. The pooled random-effects model for the primary outcome favored endovascular thrombectomy over medical management, with a generalized odds ratio of 1.55 (95% CI 1.25-1.91, I² = 42.84%). There was a trend toward increased risk of symptomatic intracranial hemorrhage in the thrombectomy group, with a relative risk of 1.85 (95% CI 0.94-3.63, I² = 0.00%).

CONCLUSION:

In patients with large-volume ischemic strokes, endovascular thrombectomy has a clear functional benefit and does not confer increased risk of significant complications compared with medical management alone.

ABBREVIATIONS:

ASPECTS

Alberta Stroke Program Early Computed Tomography Score

ET

Endovascular thrombectomy

HC

hemicraniectomy

IH

intracranial hemorrhage

INPLASY

International Platform of Registered Systematic Review and Meta-analysis Protocols

MM

medical management

NIHSS

National Institutes of Health Stroke Scale

NNT

number needed to treat

No.

number

NR

not reported

RCT

randomized control trial

REML

restricted maximum likelihood

RR

relative risks.

Endovascular thrombectomy (ET) has revolutionized the management for patients with acute large vessel occlusions. Numerous randomized control trials (RCTs) have demonstrated significant benefit in functional outcome (modified Rankin scale [mRS]) compared with medical management alone.^1-4 Moreover, the benefits of ET have been supported even with increasing time from stroke onset to intervention.^1,5,6 Most of the patients included in these RCTs did not have large-volume ischemic infarcts based on either computed tomography perfusion studies or the Alberta Stroke Program Early Computed Tomography Score (ASPECTS).^2,7 Current guidelines support ET for large-vessel ischemic strokes with a ASPECTS of ≥6, but the role of ET in patients with large-volume infarcts defined as ASPECTSs 3–5 or core volumes of >50–70 mL has been less well-defined because of perceived risk of intracranial hemorrhage (IH) or the absence of functional benefit.⁸

In the past year, three multicenter RCTs have been published specifically investigating the benefits of ET in patients with large vessel occlusions and ASPECTSs of 3-5 while excluding those with very low ASPECTSs of 0–2. The Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism–Japan Large Ischemic Core Trial (RESCUE-Japan LIMIT), Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients with a Large Infarct Core (ANGEL-ASPECT), and Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT2) trials were conducted in Japan, China, and an international conglomerate (North America, Europe, Australia, and New Zealand), respectively.^9-11 These multicenter RCTs have all have demonstrated differing margins of benefit in functional outcome after ET in large-volume ischemic strokes, and they have also reported differing rates of IH.^9-11 We sought to perform a systematic review of the literature to identify any recent RCTs that included large-volume ischemic strokes and to subsequently perform a meta-analysis of these results. This study's aims were to (1) determine if ET leads to improved outcomes measured through mRS in adult patients with large ischemic strokes when compared with medical management and (2) understand the safety of ET in patients with large ischemic strokes by comparing rates of symptomatic IH and other adverse events.

METHODS

We conducted a systematic review and meta-analysis according to a prespecified protocol registered at the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) (registration number (INPLASY) (registration number INPLASY202320107, eAppendix 1, http://links.lww.com/NEU/D889). This report adheres to guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement.¹²

Eligibility Criteria and Information Sources

We included RCTs specifically comparing ET with medical management in the setting of an acute ischemic stroke with large-core or large-volume infarct as defined by ASPECTSs of 3–5 or a calculated core infarct of >50–70 mL. We limited our selection to studies on adult patients (>18 years old). Clinical and observational studies, case series with available abstracts and published as full-scale original articles, brief reports in peer-reviewed academic journals, pilot reports, opinion pieces, theses, conference proceedings, letters, editorials, meta-analysis, reviews, surgical technique papers, case reports, abstracts, presentations, and any non-English language publications without translations were excluded.

Search Strategy

We systematically searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Scopus, the Cochrane Central Register of Controlled Trials, and Google Scholar. Because the first thrombectomy trials were published nearly 2 decades ago, we limited our search article published between January 1, 2010, and February 19, 2023.¹³ The search strategy included broad key words to identify studies on patients with ischemic stroke, large vessel occlusion, endovascular treatment, endovascular therapy, and thrombectomy with filters to limit time range (since 2010) and in some instances filters to identify RCTs. The details of the search strategy used on each database are included in eAppendix 2, http://links.lww.com/NEU/D890.

Selection Process

After exclusion of duplicates, two reviewers independently screened articles for relevance first based on titles and abstracts and subsequently through full-text review to identify articles meeting eligibility criteria. Disagreements between reviewers were resolved in both phases by either consensus or with a third reviewer. For the selection process, we relied on the Covidence systematic review software (Veritas Health Innovation, available at www.covidence.org.)¹⁴

Data Collection

Two investigators independently extracted data from each trial meeting eligibility criterion using a standardized excel collection form. Data were extracted according to the protocol and included variables on study characteristics, design, demographic data of enrolled participants, analysis approach (intention-to-treat vs per-protocol), efficacy and safety outcomes of interest as outlined in the protocol, and adherence to reporting guidelines.¹⁵ We also extracted data for a prespecified subgroup analysis on the primary outcome using time from stroke onset to randomization, and site of arterial occlusion (internal carotid artery [ICA] or middle cerebral artery [MCA], infarct core volume, and ASPECTS).

Outcomes

The primary outcome for the meta-analysis was an overall ordinal shift across the range of mRS scores toward a better outcome at 90 days. Secondary outcomes included functional independence defined as an mRS score of 0–2 at 90 days and independent ambulation defined as an mRS score of 0–3 at 90 days. Safety outcomes included symptomatic IH, any IH, death at 90 days, and need for decompressive HC.

Risk of Bias Assessment

Two investigators with no affiliation to the studies meeting eligibility criteria independently assessed risk of bias for each study using the Cochrane Risk-of-Bias in randomized trials (RoB 2) tool (eAppendix 3, http://links.lww.com/NEU/D891).^16,17 Disagreements were resolved by consensus or consulting with a third reviewer.

Data Synthesis

Results of the included trials were combined through meta-analysis to obtain summary estimates of effect sized for each of the prespecified primary and secondary outcomes. Generalized odds ratios for ordinal shift in mRS scores toward a better outcome were combined by using a random‐effect model with restricted maximum-likelihood estimation. All other outcomes were binary, and relative risk (RR) ratios were estimated by combining data from all studies also using a random‐effect model with restricted maximum-likelihood estimation. Subgroup analysis was performed only on the primary outcome. Trials with missing data were not used in the meta-analysis. This only occurred in two instances for safety outcomes alone.

We also performed sensitivity analyses by exploring how global effect sizes and P-values were affected by adjusting to the between-study variance parameter τ² (eAppendix 4, http://links.lww.com/NEU/D892). Statistical heterogeneity and the magnitude of heterogeneity were assessed using Cochran χ² tests and the I² statistic, respectively. Publication bias was assessed using the Egger test and visually using funnel plots (eAppendix 5, http://links.lww.com/NEU/D893).¹⁸ Statistical analyses were performed using STATA/MP version 17 (StataCorp) and R Statistical Software (v4.2.3; R Core Team 2021; R Foundation for Statistical Computing. https://www.R-project.org/). The number needed to treat (NNT) for the primary ordinal outcome was estimated with Agresti's generalized odds ratio method using the genodds package (v1.1.2).¹⁹ NNT was estimated for secondary outcome using the bcii community–contributed program available for use with STATA.²⁰ The alpha was set at 0.05, and all tests of significance were two-sided. To reduce the potential for type I error because of multiple testing, we used Bonferroni corrections to adjust P-values. Data and syntax used for the analysis have been made publicly available through GitHub (https://github.com/estevezdo/Thrombectomy-in-Large-Volume-Strokes-SysRev-Metan).

Strength of the Evidence

We relied on the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the evidence that thrombectomy compared with standard care improves outcomes as measured with the mRS.²¹ The combined outcomes were assigned an overall grade of high, moderate, low, or insufficient. This process was completed initially by a single investigator and with consensus after being reviewed by all investigators.

RESULTS

A total of 3044 studies were screened by title and abstract. Twenty-nine studies underwent full-text review for potential meta-analysis inclusion. Of these, only three studies met the prespecified inclusion criteria. The most common reasons for study exclusion on initial screening were the wrong study protocol (ie, not a randomized control trial) and failure to specifically investigate patients with ASPECTSs of 3–5 or volumes of >50–70 mL. Figure 1 demonstrates the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for screening and study inclusion/exclusion. The included studies were assessed for bias using the Cochrane RoB 2 tool.^16,17 Using the Grading of Recommendations Assessment, Development, and Evaluation approach, all evidence from the include studies was assigned a high level (eAppendix 6, http://links.lww.com/NEU/D894).²¹

FIGURE 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for study screening and inclusion/exclusion.

Among the three studies, 1011 patients were included in the meta-analysis. Of these, 510 patients were randomized to ET, and 501 to medical management. Of the 757 patients with available data, 687 (90.7%) had ASPECTSs of 3–5. Table 1 shows the demographic and clinical characteristics of the three included trials. For the overall ordinal shift across the range of mRS scores toward a better outcome at 90 days, Huo et al, Sarraj et al, and Yoshimura et al reported ORs of 1.37 (95% CI 1.11-1.69), 1.51 (95% CI 1.20-1.89), and 2.43 (95% CI 1.35-4.37), respectively. A total of 119/507 (23.5%) and 46/498 (9.2%) patients had functional independence (mRS 0-2) at 90 days in the ET and medical management groups, respectively. A total of 206/507 (40.6%) and 120/498 (24.1%) patients were functional ambulators (mRS 0-3) at 90 days in the ET and medical management groups, respectively. In the ET and medical management groups, 24/507 (4.7%) and 13/498 (2.6%) patients had symptomatic IH, respectively. The primary, secondary, and safety outcomes of the included trials are shown in Table 2.

TABLE 1.

Demographic and Clinical Characteristics of Three Included Randomized Control Trials

Characteristic	Huo et al10		Sarraj et al9		Yoshimura et al11
	ET	MM	ET	MM	ET	MM
Patients randomized	231	225	178	174	101	102
Lost to follow-up	0	0	1	3	0	0
Analysis of the intention-to-treat population	230	225	178	174	100	102
Analysis of the per-protocol population	219	222	174	162	94	94
Median age (IQR)—y	68 (61-73)	67 (59-73)	66 (58-75)	67 (58-75)	76.6 ± 10.0a	75.7 ± 10.2a
Median NIHSS score at admission (IQR)b	16 (13-20)	15 (12-19)	19 (15-23)	19 (15-22)	22 (18-26)	22 (17-26)
ASPECTS value based on CTd
ASPECTSs <3	32 (13.9)	30 (13.3)	0	0	5 (5.0)	3 (2.9)
ASPECTSs ≥3	198 (86.0)	195 (86.7)	67 (74.8)	32 (37.4)	96 (95.0)	99 (97.1)
Median infarct-core volume (IQR)e—mL	60.5 (29-86)	63 (31-86)	81.5 (57-118)	79 (62-111)	94 (66-152)	110 (74-140)
Time from stroke onset to randomization <6 h	82 (35.7)	85 (37.8)	17 (30.1)	5 (11.4)	71 (70.3)	74 (72.6)
Time from stroke onset to randomization ≥6 h	148 (64.3)	140 (62.2)	50 (41.0)	27 (21.3)	30 (29.7)	28 (27.4)
Occlusion site—No. (%)c
ICA	83 (36.1)	81 (36.0)	80 (44.9)	66 (37.9)	47 (46.5)	49 (48.0)
M1 segment	145 (63.0)	142 (63.1)	91 (51.1)	100 (57.5)	74 (73.3)	70 (68.6)
M2 segment	2 (0.9)	2 (0.9)	7 (3.9)	8 (4.6)	0	3 (2.9)

ASPECT, Albert Stroke Program Early Computed Tomography Score; CT, computed tomography; ET, endovascular thrombectomy; ICA, internal carotid artery; MCA, middle cerebral artery; MM, medical management; NIHSS, National Institutes of Health Stroke Scale; No., number; NR, not reported.

^aAge reported as mean ± SD.

^bScores on the NIHSS, an ordinal scale that is used to evaluate the severity of stroke, range from 0 to 42, with higher scores indicating greater neurological deficit.

^cThe M1 segment is the first and main segment middle cerebral artery, and the M2 segment is the first branch of the main trunk of the middle cerebral artery.

^dASPECTS values range from 0 to 10, with lower values indicating larger infarction.

^eThe ischemic-core volume is the volume of irreversibly damaged brain tissue with relative cerebral blood flow of less than 30% of that of the contralateral hemisphere (based on CT perfusion) or an apparent diffusion coefficient of less than 620 × 10⁻⁶ mm² per second (based on magnetic resonance imaging).

TABLE 2.

Primary, Secondary, and Safety Outcomes of Three Included Randomized Control Trials

Outcome	Huo et al10		Sarraj et al9		Yoshimura et al11
	ET (N = 230)	MM (N = 225)	ET (N = 178)	MM (N = 174)	ET (N = 100)	MM (N = 102)
Primary outcome
	Median score on the mRS at 90 d (IQR)b				mRS score of 0–3 at 90 d—no. (%)
	4 (2-5)	4 (3-5)	4 (3-6)	5 (4-6)	31 (31.0)	13 (12.7)
Treatment effect [95% CI]a	1.37 [1.11-1.69]		1.51 [1.20-1.89]		2.43 [1.35-4.37]
Secondary outcomes
Functional independence at 90 d—No. (%)b mRS 0–2	69 (30.0)	26 (11.6)	36/177 (20.3)	12/171 (7.0)	14 (14.0)	8 (7.8)
Independent ambulation at 90 d—No. (%)b mRS 0–3	108 (47.0)	75 (33.3)	67/177 (37.9)	32/171 (18.7)	31 (31.0)	13 (12.7)
Safety outcomes
Symptomatic intracranial hemorrhage within 48 h—No. (%)c,d	14 (6.1)	6 (2.7)	1 (0.6)	2 (1.1)	9 (9.0)	5 (4.9)
Any intracranial hemorrhage within 48 h—No. (%)	113 (49.1)	39 (17.3)	NR	NR	58 (58.0)	32 (31.4)
Death within 90 d—No. (%)	50 (21.7)	45 (20.0)	68/177 (38.4)	71/171 (41.5)	18 (18.0)	24 (23.5)
Decompressive hemicraniectomy during hospitalization—No. (%)	17 (7.4)	8 (3.6)	NR	NR	10 (10.0)	14 (13.7)

ET, endovascular thrombectomy; MM, medical management; mRS, modified Rankin scale; No., number; NR, not reported.

^aThe treatment effect is reported for the primary outcome as a generalized odds ratio with the 95% CI for the ordinal shift in the distribution of scores on the mRS toward a better outcome.

^bScores on the mRS range from 0 to 6, with higher scores indicating greater disability.

^cHou et al.¹⁰ defined symptomatic intracranial hemorrhage according to the Heidelberg bleeding classification (an increase in the NIHSS score of ≥4 points or an increase in the score for an NIHSS subcategory of ≥2 points with any intracranial hemorrhage on imaging).²⁷

^dSarraj et al⁹ and Yoshimura et al¹¹ defined symptomatic intracranial hemorrhage according to Safe Implementation of Thrombolysis in Stroke–Monitoring Study criteria (parenchymal hemorrhage type 2 or remote parenchymal hemorrhage associated with an increase of 4 or more points in the NIHSS score at the 24-hour follow-up).²⁶

For the primary outcome of overall ordinal shift across the range of mRS scores toward a better outcome at 90 days, the generalized odds ratio from the combined studies was 1.55 (95% CI 1.25-1.91, τ² = 0.01, I² = 42.84%) and a NNT of 4.466 (95% CI 3.256-7.283). For the secondary outcome of functional independence (mRS 0-2) at 90 days, the combined results favored ET over medical management with RR 2.53 [95% CI 1.84-3.47, τ² = 0.00, I² = 0.00%] and a NNT 7.025 [95% CI 5.243-10.281]. For the secondary outcome of independent ambulation (mRS 0-3) at 90 days, the combined study results also favored ET over medical management with a RR of 1.78 [95% CI 1.29-2.46, τ² = 0.05, I² = 56.80%] and a NNT of 6.048 [95% CI 4.518-9.276]. The forest plots of these random-effects models are shown in Figure 2. When looking at safety outcomes, there was a trend toward increased risk of symptomatic IH with the ET group and a RR of 1.85 (95% CI 0.94-3.63, τ² = 0.00, I² = 0.00%). There was an increased risk of any IH in the ET group in the studies by Yoshimura et al and Huo et al, with a RR 2.30 (95% CI 1.51-3.49, τ² = 0.06, I² = 70.22%). There were no significant differences between death at 90 days and need for decompressive hemicraniectomy (HC) for the two treatment arms of the combined studies with a RR of 0.95 (95% CI 0.78-1.16, τ² = 0.00, I² = 0.00%) and a RR of 1.22 (95% CI 0.44-3.40, τ² = 0.39, I² = 70.28%), respectively. The forest plots of the random-effects models for the safety outcomes are shown in Figure 2. The forest plots for the subgroup random-effects models for time from the stroke onset to randomization (<6 or ≥6 hours), location of occlusion (ICA or MCA), core volume (<70 or ≥70 mL), and admission ASPECTS (<3 or ≥3) are shown in Figure 3.

FIGURE 2.

Forest plots for combined results using a restricted maximum-likelihood estimation random-effects model for primary, secondary, and safety outcomes. HC, hemicraniectomy; mRS, modified Ranking scale; REML, restricted maximum likelihood.

FIGURE 3.

Forest plot of combined results in subgroup analysis using a restricted maximum-likelihood estimation random-effects model. ASPECTS, Albert Stroke Program Early Computed Tomography Score; ICA, internal carotid artery; MCA, middle cerebral artery; REML, restricted maximum likelihood.

DISCUSSION

This combined analysis of the RESCUE-Japan LIMIT, SELECT2, and ANGEL-ASPECT trials, which enrolled patients with large-core anterior circulation ischemic strokes within 24 hours of last seen well and randomly assigned to ET or medical care only, confirms the benefit of thrombectomy in 90-day mRS improvements.^9-11 The benefit of ET was also confirmed in proportions of 90-day functional independence and independent ambulation. Regarding safety of ET in this population, analysis of data from all three trials found no significant difference in proportions of symptomatic IH and mortality. SELECT2 also demonstrated a benefit of ET in patients ≥12 hours from onset, further emphasizing the benefit and safety margin of ET even in these late window patients. While other similar multicenter RCTs are currently underway, the present meta-analysis provides the best current evidence available for the benefit of ET in large-core and large-volume ischemic strokes.

Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE), Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT), Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME), and Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial (EXTEND-IA) trials, all published in 2015, provided the first high-level medical evidence, supporting the use of ET in selected patients with anterior circulation large-artery occlusion ischemic stroke.^3,4,22-24 These trials were designed as explanatory trials; the investigators sought to maximize the chance of detecting a benefit with ET by excluding patient subgroups, such as those with large cores, for whom benefit seemed less certain. Large-core infarctions have been excluded largely out of concern that post-thrombectomy brain hemorrhage risk would be significant or that the functional benefit would be minimal. However, a meta-analysis of observational studies found favorable results after thrombectomy for patients with acute ischemic stroke and large ischemic cores, typically defined as ASPECTSs of <6, without significantly increased risk of hemorrhage.²⁵ The three trials included in the present meta-analysis are the first multicenter RCT of ET for patients with large-core infarctions or ASPECTSs of 3–5.

This study detected a significant benefit with ET for two subgroups that were not found to be significant in the individual studies. While patients with MCA occlusions benefited from thrombectomy in the SELECT2, and ANGEL-ASPECT trials, patients with ICA occlusions were not found to benefit in the individual trials. In the combined analysis, patients with ICA occlusions were found to benefit; this likely reflects the greater severity of ICA occlusions vs MCA occlusions, as well as a greater clot burden and number of needed thrombectomy passes, and therefore a slimmer margin of benefit with ET. Similarly, neither the SELECT2 nor the ANGEL-ASPECT trial found a benefit with ET for patients with ASPECTSs <3, whereas the combined analysis did find a benefit for this small subgroup. This likely reflects the greater severity of very low ASPECTS strokes, possibly reduced collateral circulation to the affected territory, and a narrower margin of benefit with ET. Both ANGEL-ASPECT and RESCUE-Japan LIMIT evaluated the risk of decompressive HC between groups, and the meta-analysis did not suggest an increased risk of HC in the ET group compared with the medical management arm. It is also important to consider the prestroke functional status of these patients. All 3 RCTs included only patients with a prestroke mRS of 0–1. Thus, the findings of the RCTs and this meta-analysis underscore potential interventional benefit only in those patients with excellent prestroke functional status. No RCT has yet investigated the role of ET in patients with a prestroke mRS of >1. However, a large-volume infarction in this population is still likely to harbor a very poor functional outcome, regardless of intervention.

Limitations of this study include limitations of the trials themselves and limitations of the meta-analysis. Regarding the trials themselves, the RESCUE-Japan LIMIT relied only on ASPECTS for identification of patients with a large core, whereas the SELECT2 and ANGEL-ASPECT trials also used perfusion imaging, which might have improved accuracy in patient selection in those trials compared with the RESCUE-Japan LIMIT trial. Enrollment in the SELECT2 and ANGEL-ASPECT trials was halted early because of efficacy, raising the possibility of overestimation of the treatment effect. This also limited the statistical power of the subgroup analyses. Although the RESCUE-Japan LIMIT and ANGEL-ASPECT trials enrolled only Japanese and Chinese patients, raising questions about the generalizability of the findings to non-Asian populations, the SELECT2 trial largely comprised non-Asian study subjects and provides evidence that benefit of ET for large-core infarctions extends across ethnic groups.

All three RCTs incorporate a radiological-symptomatic classification scheme to determine symptomatic IH. SELECT2 and RESUE-Japan LIMIT trials defined symptomatic IH according to Safe Implementation of Thrombolysis in Stroke–Monitoring Study criteria, whereas ANGEL-ASPECT defined this outcome by the Heidelberg bleeding classification.^26,27 However, the Safe Implementation of Thrombolysis in Stroke–Monitoring Study symptomatic IH criteria were developed before ET devices were being used, which might have limited the SELECT2 and RESUE-Japan LIMIT trials from capturing all hemorrhagic complication effects from device recanalization. In addition, symptoms associated with a hemorrhagic complication are variable and are not clearly represented by just an increase in a National Institutes of Health Stroke Scale of ≥4 shortly after hemorrhage. Thus, the true severity of hemorrhagic complications in the context of a large ischemic stroke might have also been underestimated in these studies.

This meta-analysis was limited by the fact that RESCUE-Japan LIMIT had a different primary end point from the other two trials, which constrained combined subgroup analyses only to the SELECT2 and ANGEL-ASPECT trials. This meta-analysis was also limited by the pooled data available from the included studies; a meta-analysis including individual patient data would permit a more granular and precise assessment of the treatment effect. It is important to consider the risk of publication bias especially in studies of this impactful nature, and the presented meta-analysis is unable to take into account potentially negative, unpublished data. However, to date, this is the strongest evidence available to support ET in large-volume/large-core ischemic stroke.

CONCLUSION

The findings of this study strengthen the evidence for benefit of ET over medical management for patients with acute ischemic stroke and large-core infarctions. There was no increased risk of symptomatic IH or other adverse events in this group compared with medical management. ET should not be withheld for patients with ASPECTSs of 3–5 or large ischemic cores based on perfusion imaging. Other multicenter RCTs are currently underway, and these future results, whether supportive or contradictory, must be considered in the context of this meta-analysis.

Funding

Research reported in this publication was supported in part by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R25NS079188 (D.E.O.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was also completed while D.E.O. was a Cornwall Clinical Scholar supported by UAB.

Disclosures

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

SUPPLEMENTAL DIGITAL CONTENT

eAppendix 1. Study design and protocol as registered with International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) (registration number INPLASY202320107).

eAppendix 2. Search strategy details for individual databases.

eAppendix 3. Cochrane risk-of-bias 2 tool results for included randomized trials.

eAppendix 4. Results of sensitivity analyses for both primary outcomes and secondary outcomes. A, Sensitivity analysis results for overall ordinal shift in modified Ranking scale (mRS) toward improvement. B, Sensitivity analysis results for functional independence (mRS 0-2). C, Sensitivity analysis results for ambulatory independence (mRS 0-3).

eAppendix 5. Publication bias funnel plot for generalized odds ratio for ordinal shift in modified Rankin scale. Results from the regression-based Egger test for small-study effects suggests asymmetry in the funnel plot and potential for publication bias (P = .0459).

eAppendix 6. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment for quality of evidence.

COMMENTS

This is a meta-analysis examining the latest randomized clinical trials (RCTs) on large core. One of the primary limitations of this study is that it does not include an analysis of individual patient data (IPD). Collaborations such as the HERMES group have previously demonstrated the value of IPD analysis by extracting pooled patient-level data from five RCTs.^1a This approach provides more detailed information about subgroups of patients who might have been under-represented in the individual studies. Despite this limitation, the timely publication of this meta-analysis summarizes important information that is already influencing medical practice and expanding the indication for acute mechanical thrombectomy (MT). The authors emphasize the substantial benefits of MT for patients with a large core, with a number needed to treat (NNT) of 4 (95% CI 3.256-7.283) for patients to achieve a better outcome at 90 days. The outcome is measured as an ordinal shift across the range of modified Rankin Scale (mRS) scores. The NNT to achieve functional independence, defined as an mRS score of 0–2 at 90 days, was found to be 7 (95% CI 5.243-10.281). The meta-analysis also highlights methodological differences among the studies. The positive results of the TESLA trial presented at the European Stroke Conference solidify the indication of MT in patients with a large core.^2a However, several important questions need to be addressed in future analyses. For instance, what is the best definition of large core? How can artificial intelligence assist in identifying the optimal candidates for MT? Furthermore, how will this new indication for MT impact the number of patients requiring hemicraniectomy? Further research should explore these aspects to enhance our understanding of ischemic strokes with a large core.

Edgar A. Samaniego

Iowa City, IA, USA