Medical Management Versus Endovascular Treatment for Large-Vessel Occlusion Anterior Circulation Stroke With Low NIHSS

Apostolos Safouris, MD; Lina Palaiodimou, MD; Sándor Nardai, MD; Odysseas Kargiotis, MD; George Magoufis, MD; Klearchos Psychogios, MD; Marius Matusevicius, MD; Katharina Feil, MD; Niaz Ahmed, MD; Lars Kellert, MD; Stavros Spiliopoulos, MD; Elias Brountzos, MD; István Szikora, MD; Amrou Sarraj, MD; Nitin Goyal, MD; Diana Aguiar de Sousa, MD; Daniel Strbian, MD; Valeria Caso, MD; Andrei V. Alexandrov, MD; Georgios Tsivgoulis, MD

Disclosures

Stroke. 2023;54(9):2265-2275.

Abstract and Introduction

Abstract

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with National Institutes of Health Stroke Scale score of 0 to 5 is common in clinical practice but has not yet been proven safe and effective. Our objective is to assess whether EVT on top of best medical treatment (BMT) in AIS patients with large-vessel occlusion of the anterior circulation presenting with mild symptoms is beneficial compared with BMT.

Methods: We searched MEDLINE, SCOPUS, and reference lists of retrieved articles published until December 28, 2022. A systematic literature search was conducted to identify clinical trials or observational cohort studies evaluating patients with AIS due to anterior circulation large-vessel occlusion and admission National Institutes of Health Stroke Scale score ≤5 treated with EVT versus BMT alone. The primary outcome was excellent functional outcome (modified Rankin Scale score 0–1) at 3 months. The protocol had been registered before data collection (PROSPERO).

Results: Eleven observational eligible studies were included in the meta-analysis, comprising a total of 2019 AIS patients with National Institutes of Health Stroke Scale score ≤5 treated with EVT versus 3171 patients treated with BMT. EVT was not associated with excellent functional outcome (risk ratio, 1.10 [95% CI, 0.93–1.31]). When stratified for different study design (per-protocol versus intention-to-treat), there were no significant subgroup differences. EVT was not associated with good functional outcome (modified Rankin Scale score 0–2; risk ratio, 1.01 [95% CI, 0.89–1.16]) or reduced disability at 3 months (common odds ratio, 0.92 [95% CI, 0.60–1.41]). Symptomatic intracranial hemorrhage was more common in the patients receiving EVT (risk ratio, 3.53 [95% CI, 2.35–5.31]). No correlation was found between EVT and mortality at 3 months (risk ratio, 1.34 [95% CI, 0.83–2.18]). The same overall associations were confirmed in the sensitivity analysis of studies that performed propensity score matching.

Conclusions: EVT appears equivalent to BMT for patients with anterior circulation large-vessel occlusion AIS with low baseline National Institutes of Health Stroke Scale, despite the increased risk for symptomatic intracranial hemorrhage.

Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022334417.

Graphic Abstract: A graphic abstract is available for this article.

Introduction

Current American Heart Association/American Stroke Association and European Stroke Organization guidelines strongly recommend endovascular treatment (EVT) for acute ischemic stroke (AIS) patients with large-vessel occlusion (LVO) and National Institutes of Health Stroke Scale (NIHSS) score of ≥6, Alberta Stroke Program Early Computed Tomography Score of ≤6, up to 6 hours from symptom onset based on high quality data (Class IA).^[1,2] Real-world data suggest that 1 in 25 patients with AIS presenting in the emergency department with NIHSS score <6 harbors an underlying LVO.^[3] Despite mild initial symptoms, up to 20% of these patients may deteriorate without acute recanalization therapy.^[4,5] Even in transient ischemic attack patients, LVO may be recognized in up to 1 in 10 patients and predicts functional decline.^[6,7] Therefore, using the term mild for a stroke with low NIHSS in the context of LVO may be misleading.^[8] Nearly 1 in 4 AIS patients with LVO and minor symptoms primarily treated with best medical treatment (BMT) will not achieve functional independence at 3 months.^[9] Only a minority among those treated with intravenous thrombolysis (IVT) will achieve recanalization, suggesting that IVT may not be enough.^[10,11] We have previously performed a multicenter retrospective study followed with a systematic review and meta-analysis of available observational studies on patients presenting with NIHSS score of <6 and treated with EVT versus BMT for anterior circulation LVO.^[12] In a pooled analysis of 251 patients, we documented no independent association between treatment groups and safety or efficacy outcomes and a nonsignificant trend toward greater risk for symptomatic intracranial hemorrhage (sICH) in the EVT group (4.4% versus 0.9% in BMT). A single-center series independently reported similar sICH rates,^[13] prompting an editorial advising caution about overtreating this specific LVO subgroup with EVT.^[14] Clinical registries also question the safety of EVT in unselected AIS patients with LVO presenting with minor symptoms.^[15] Our previous meta-analysis received criticism for not reporting the rate of patients that were initially treated conservatively but consequently had to receive EVT due to early neurological deterioration.^[16] Because rescue EVT might be performed in >10% of LVO patients with NIHSS score of <6,^[17] treatment cross-over necessitates studies with an intention-to-treat (ITT) design to fully elucidate the prognosis of the BMT group. Unfortunately, we lacked data on early neurological deterioration and rescue EVT rates at the time.^[18]

In view of this clinical equipoise and in the absence of randomized data, we have performed an updated systematic review and meta-analysis to evaluate the safety and effectiveness of EVT in anterior circulation LVO patients presenting with NIHSS score of <6 compared with BMT.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Main Characteristics of Studies Included in the Systematic Review (n=11)
Source	Study type	Country	Period of recruitment	No. of centers	EVT no (IVT no)	BMT no (IVT no)	BMT/EVT ratio*	Occlusion site EVT, %	Occlusion site BMT, %	Outcomes assessed	Main exclusion criteria	Selection for EVT	Selection of BMT	Propensity score matching
Per protocol
Abbas et al,³⁰ 2021	Retrospective analysis of prospectively collected data	USA	2015–2021	1	41 (14)	42 (20)	1	ICA 37%, M1/A1 63%	ICA 10%, M1/A1 90%	mRS score 0–2, NIHSS shift, sICH, mortality, infarct size, length of hospital stay	Baseline mRS score >2, dementia	All consecutive patients, clinical judgement for treatment	Equal number with EVT, unspecified criteria	No
Da Ros et al,³¹ 2018	Retrospective analysis of prospectively collected data	Italy	2014–2015 for BMT, 2015–2017 for EVT	2	32 (19)	24 (24)	0.8	ICA+M1 14%, M1 41%, M2 45%	M2 100%	mRS score 0–1, mRS score 0–2, NIHSS shift, ENI, sICH, discharge to home	Baseline mRS score >0	All consecutive patients if IVT was ineffective/contraindicated, or in case of fluctuation of symptoms	All consecutive patients treated with IVT	No
Goyal et al,¹² 2020	Retrospective analysis of prospectively collected data	Multinational	2013–2017	16	138 (74/137)	113 (47)	0.8	eICA 7%, iICA 7%, M1 59%, M2 25%, Tandem 4%	eICA 18%, iICA 8%, M1 35%, M2 40%, Tandem 1%	mRS, sICH, aICH, NIHSS shift, successful reperfusion, length of hospital stay	Baseline mRS score >1, previous stroke	All consecutive patients in the respective single-center prospective registries, no criteria for EVT mentioned	All consecutive patients in the respective prospective single-center registries	Yes
Kim et al,³² 2022	Retrospective analysis of prospective national stroke registry	South Korea	2015–2019	16	149 (2)	934 (115)	6.3	eICA 13%, iICA 12%, M1 46%, M2/distal 24%, tandem 4%	eICA 22%, iICA 6%, M1 33%, M2/distal 32%, tandem 8%	mRS, mortality, any hemorrhage, significant hemorrhage				Yes, but only odd ratios reported
Manno et al,³³ 2019	Retrospective analysis of prospective national stroke registry	Switzerland	2014–2017	NR	137 (69)	175 (175)	1.3	ICA 20%, M1 38%, M2 42%	ICA 13%, M1 12%, M2 75%	mRS, mortality, sICH	Baseline mRS score >2	All consecutive patients in comprehensive stroke centers, no criteria for EVT mentioned	All consecutive patients treated with IVT in comprehensive stroke centers	Yes
Xue et al,³⁴ 2022	Retrospective analysis of a prospective multicenter stroke registry	China	2017–2021	NR	123	449	3.7	ICA 28%, M1 48%, M2 16%, ACA 8%	ICA 25%, M1 47%, M2 19%, ACA 10%	mRS, sICH, mortality	Baseline mRS score >1	All consecutive patients, no criteria for EVT mentioned	All consecutive patients	Yes
Feil et al,³⁵ 2022†	Retrospective comparison of a national stroke EVT registry to a multinational IVT registry	EVT: Germany BMT: Europe	EVT: 2015–2019 BMT: 2006–2019	EVT: 25 BMT: 104	352 (270)	709 (709)	2	NR	NR	mRS, sICH, mortality		All consecutive EVT patients on a prospective, multicenter and observational registry in Germany	IVT centers with a 3-mo follow-up rate of ≥70%	Not done for anterior circulation
Intention to treat
Alexandre et al,³⁶ 2022	Retrospective analysis of prospectively collected data	Italy	1/2016–12/2020	9	272 (109)	41 (30)	0.2	iICA+M1 9%, iICA+M2 3%, M1 45%, M2 44%	iICA+M1 12%, iICA+M2 10%, M1 27%, M2 51%	mRS score 0–1, mRS score 0–2, PH1, PH2, mortality	Baseline mRS score >1, tandem (eICA+M1/M2) occlusion	All consecutive patients, no criteria for EVT mentioned	All consecutive patients, rescue EVT included	No
Messer et al,³⁷ 2017	Retrospective analysis of prospectively collected data	Germany	1998–2015	1	8 (5)	46 (46)	5.8	ICA/MCA 25%, M1 75%	ICA/MCA 26%, M1 26%, M2 48%	mRS score 0–1, mRS score 0–2, sICH, mortality		All consecutive patients, no criteria for EVT mentioned	All consecutive patients treated with IVT, rescue EVT included	No
Sarraj et al,³⁸ 2022	Retrospective pooled, patient-level analysis of 3 RCTs‡ and analysis of prospectively collected data	Multinational	10/2010–3/2020	15+3 RCTs	286 (72/247)	254 (114)	0.9	eICA 13%, iICA 12%, M1 47%, M2 28%	eICA 9%, iICA 12%, M1 28%, M2 50%	mRS score 0–1, mRS score 0–2, mRS score 0–3, mRS score 5–6, sICH, mortality		All consecutive patients receiving perfusion imaging, no criteria for EVT mentioned	All consecutive patients receiving perfusion imaging, rescue EVT included	Yes
Seners et al,³⁹ 2020	Retrospective analysis of prospectively collected data	France	2006–2018	45	214	384 (384)	1.8	ICA+pM1 7%, ICA+dM1 3%, ICA+M2 4%, pM1 17%, dM1 33%, M2 36%	ICA+pM1 1%, ICA+dM1 3%, ICA+M2 6%, pM1 7%, dM1 22%, M2 62%	mRS score 0–1, mRS score 0–2, any ICH, sICH		All consecutive patients, no criteria for EVT mentioned	All consecutive patients treated with IVT, rescue EVT included	No

A1 indicates anterior cerebral artery; aICH, asymptomatic ICH; BMT, best medical treatment; eICA, extracranial ICA; END, early neurological deterioration; ENI, early neurological improvement defined as an NIHSS score of 0–1 at 24 h; EVT, endovascular treatment; ICA, internal carotid artery; iICA, intracranial ICA; M1, middle cerebral artery; mRS, modified Rankin Scale, 3-mo throughout the table unless otherwise stated; NIHSS, National Institutes of Health Stroke Scale; NR, not reported; NA, not applicable; PH, parenchymal hemorrhage; RCT, randomized controlled trial; and sICH, symptomatic intracerebral hemorrhage; any intracerebral hemorrhage on imaging with an increase of at least 4 NIHSS points within 24 h or resulting in death within 24 h after intervention.
*Number of patients in the BMT arm to number of patients in the EVT arm.
†Data regarding anterior circulation were sent by the corresponding author.
‡EXTEND-IA trial (Extending the Time for Thrombolysis in Emergency Neurological Deficits – IntraArterial); EXTEND-IA TNK trial, (Tenecteplase vs Alteplase Before Endovascular Thrombectomy in Ischemic Stroke); and EXTEND-IA TNK trial part 2 (Tenecteplase vs Alteplase before Endovascular Thrombectomy in Ischemic Stroke).

Table 2. Overview of Analyses for Primary and Secondary Outcomes, Stratified by Study Design
Variable	Overall			Per protocol			Intention to treat			Subgroup differences
Variable	No. of studies	Risk ratio (95% CI)	I², P for Cochran Q	No. of studies	Risk ratio (95% CI)	I², P for Cochran Q	No. of studies	Risk ratio (95% CI)	I², P for Cochran Q	P value
Primary outcome
Excellent functional outcome (mRS score 0–1) at 3 mo	10	1.10 (0.93–1.31)	92%, <0.01	6	1.09 (0.82–1.44)	95%, <0.01	4	1.08 (0.98–1.19)	27%, 0.25	0.96
Secondary outcomes
Good functional outcome (mRS score 0–2) at 3 mo	11	1.01 (0.89–1.16)	93%, <0.01	7	1.00 (0.81–1.23)	95%, <0.01	4	1.02 (0.96–1.07)	0%, 0.84	0.85
Reduced disability*	4	0.92 (0.60–1.41)	72%, 0.01	3	0.76 (0.60–0.96)	0%, 0.63	1	2.08 (1.16–3.75)	NA	<0.01
sICH	9	3.53 (2.35–5.31)	5%, 0.39	6	3.58 (2.16–5.95)	0%, 0.97	3	4.73 (0.83–26.81)	84%, 0.01	0.76
Mortality at 3 mo	9	1.34 (0.83–2.18)	50%, 0.04	6	1.34 (0.71–2.53)	68%, <0.01	3	1.32 (0.58–3.01)	0%, 0.91	0.98

mRS indicates modified Rankin Scale; NA, not applicable; and sICH, symptomatic intracranial hemorrhage.
*Unadjusted common odds ratio (shift analysis across all mRS scores).

Authors and Disclosures

Apostolos Safouris, MD, Lina Palaiodimou, MD, Sándor Nardai, MD, Odysseas Kargiotis, MD, George Magoufis, MD, Klearchos Psychogios, MD, Marius Matusevicius, MD, Katharina Feil, MD, Niaz Ahmed, MD, Lars Kellert, MD, Stavros Spiliopoulos, MD, Elias Brountzos, MD, István Szikora, MD, Amrou Sarraj, MD, Nitin Goyal, MD, Diana Aguiar de Sousa, MD, Daniel Strbian, MD, Valeria Caso, MD, Andrei V. Alexandrov, MD and Georgios Tsivgoulis, MD

Stroke Unit, Metropolitan Hospital, Piraeus, Greece (A. Safouris, O.K., K.P.). Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Greece (A. Safouris, L.P., G.T.). Department of Neurosurgery, National Institute of Mental Health, Neurology and Neurosurgery, Department Section of Neurointervention, Semmelweis University, Budapest, Hungary (A. Safouris, S.N., I.S.). Neuroradiology Department, Metropolitan Hospital, Piraeus, Greece (G.M.). Interventional Radiology Department, "Attikon" University Hospital, Athens, Greece (G.M., S.S., E.B.). Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (M.M., N.A.). Department of Neurology, Karolinska University Hospital, Stockholm, Sweden (M.M., N.A.). Department of Neurology, Ludwig-Maximilians-Universitaet (LMU) Munich, Germany (K.F., L.K.). Department of Neurology and Stroke, Eberhard-Karls University Tuebingen/Universitaetsklinikum Tuebingen (UKT), Germany (K.F.). Department of Neurology, University Hospitals Cleveland Medical Center, OH (A. Sarraj). Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH (A. Sarraj). Department of Neurology, University of Tennessee Health Science Center, Memphis (N.G., A.V.A., G.T.). Department of Neurosurgery, University of Tennessee Health Science Center and Semmes Murphey Neurologic and Spine Clinic, Memphis (N.G.). Stroke Center, Lisbon Central University Hospital, and Faculty of Medicine, University of Lisbon, Portugal (D.A.D.S.). Department of Neurology, Helsinki University Hospital and University of Helsinki, Finland (D.S.). Stroke Unit, Santa Maria Della Misericordia Hospital, University of Perugia, Italy (V.C.). Department of Neurology, Banner University Hospital, University of Arizona, Phoenix (A.V.A.).

Correspondence to
Georgios Tsivgoulis, MD, Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Rimini 1, Chaidari, Athens, Greece 12462. Email tsivgoulisgiorg@yahoo.gr

Disclosures
Dr Aguiar de Sousa declares receiving fees from AstraZeneca, Bayer; Fundação Bial, Organon & Co, and University of British Columbia. Dr Ahmed declares receiving fees from Boehringer Ingelheim. Dr Sarraj declares receiving fees from AstraZeneca and Stryker. Dr Szikora declares receiving fees from Medtronic Vascular Inc, MicroVention Inc, and Stryker. Dr Safouris has received a stipendium from the Hellenic Neurological Society for training in Interventional Neurology that is unrelated to the article. Dr Strbian is a member of the Data and Safety Monitoring Board of the ENDOLOW trial Endovascular Therapy for Low NIHSS Ischemic Strokes). The other authors report no conflicts.