Comparing the Efficacy and Safety of Endovascular Therapy Versus Best Medical Treatment in Acute Ischemic Stroke Patients With Distal Medium Vessel Occlusion: A Systematic Review and Meta-Analysis

Abstract

Introduction

Distal Medium Vessel Occlusions (DMVOs) represent a significant subset of Acute Ischemic Stroke (AIS), with unique treatment challenges due to vessel size and location. While Endovascular Therapy (EVT) shows promise, its efficacy compared to Best Medical Treatment (BMT) remains unclear.

Methods

PubMed, Cochrane Central, and ScienceDirect were searched from inception till May 2025. Categorical data were pooled as risk ratios (RRs) along with 95% Confidence intervals (CIs) using the Review Manager software. Quality was assessed using the Cochrane Risk of Bias tool and the Newcastle Ottawa Scale.

Results

Thirty-seven studies pooling a total of 9,505 patients were included in this meta-analysis. The excellent functional outcome (modified Rankin Scale (mRS) 0-1) was comparable between both the EVT and BMT arms (RR= 1.04; 95% CI: [0.96, 1.13]; p= 0.34; I²= 59%). Similarly, the functional independence (mRS 0-2) showed no significant difference between the two groups (RR= 1.00; 95% CI: [0.94, 1.06]; p= 0.99; I²= 64%). The 90-day mortality (RR= 1.21; 95% CI: [0.97, 1.52]; p= 0.09; I²= 46%) and neurological deterioration (RR= 1.39; 95% CI: [0.65, 2.95]; p= 0.40; I²= 82%) were also comparable between the two arms. EVT showed a statistically significant increase in early neurological improvement (RR= 1.38; 95% CI: [1.05, 1.82]; p= 0.02; I²= 53%) although it was associated with a high risk of symptomatic intracranial hemorrhage (sICH) (RR= 1.56; 95% CI: [1.15, 2.13]; p= 0.005; I²= 39%).

Conclusion

EVT was associated with a significant increase in the early neurological improvement, although the risk of sICH was high in it. Other safety and efficacy outcomes were comparable. Further high-powered randomized trials are needed to confirm these findings.

Keywords

endovascular thrombectomy mechanical thrombectomy distal medium vessel occlusions acute ischemic stroke systematic review meta-analysis

Introduction

Acute Ischemic Stroke (AIS) ranks as a primary source of chronic disability among adults and is the second most common cause of death worldwide.¹ Endovascular therapy (EVT) has been recognized as the gold-standard treatment for patients with Large Vessel Occlusion (LVO), encompassing the Internal Carotid Artery (ICA), the first segment of the middle cerebral artery (MCA) (M1), and the Basilar artery. The robustness of this approach has been corroborated by multiple randomized controlled trials and meta-analyses over time.^2-7 However, an alarming count of patients presents with occlusions in medium and distal cerebral vessels, such as the anterior cerebral artery (ACA), M2–M4 segments of the MCA, posterior cerebral artery (PCA), posterior inferior cerebellar artery (PICA), anterior inferior cerebellar artery (AICA), and superior cerebellar artery (SCA) (5). Distal Medium Vessel Occlusions (DMVOs) are a subset of AIS and account for a substantial percentage of ischemic strokes, ranging from 25% to 40%.⁸ These occlusion sites pose distinctive challenges owing to the narrower diameter, heightened tortuosity, and peripheral placement of the vessels, obscuring thrombectomy procedures and elevating the chance of complications, such as vessel perforation and distal embolization.⁹

Conventionally, Best Medical Treatment (BMT), comprising antiplatelets, anticoagulants, and supportive care, has served as the standard of care for DMVOs, although this approach has yielded less favorable outcomes.¹⁰ While EVT is well-established for LVOs, its use in DMVOs remains unclear. Recent advancements in thrombectomy devices, like low-profile stent retrievers and distal aspiration catheters, have made EVT more viable for distal occlusions. Studies by Sun et al. and Anadani et al. have demonstrated that EVT for distal occlusions is relatively achievable, offering beneficial clinical outcomes.^11,12 However, inconsistent patient selection, occlusion locations, and device choices have led to variable results, underscoring the need for further evidence to establish EVT’s role in DMVO treatment. A meta-analysis by Loh et al. (2023) discovered that EVT for DMVO can lead to favorable functional outcomes and minimal complication rates, supporting this approach as a feasible treatment option.¹³ Conversely, Wang et al. (2025) found no clinical superiority of EVT over BMT in major outcomes.¹⁴ This discrepancy highlights the potential risks of EVT and reinforces the continuing uncertainty regarding its role in treating DMVO.

Hence, our study aimed to provide an updated meta-analysis comparing EVT and BMT in DMVO-related AIS. This meta-analysis utilized recent clinical data, building upon the work of Wang et al.,¹⁴ which included recently published high-quality trials^15,16 and rigorous methods to address gaps in the literature. This approach explored the evolving procedural strategy for DMVO.

Methods

This meta-analysis was conducted according to the guidelines laid down by the Preferred Reporting of Items in Systematic Review and Meta Analysis [PRISMA] guidelines¹⁷ and followed the Cochrane Handbook for Systematic Reviews of Interventions.¹⁸ This review’s protocol was registered on PROSPERO under the ID: CRD420251088113.

Search Strategy

A search was conducted across PubMed, Cochrane Central, and ScienceDirect from inception through May 2025. A robust search strategy was formulated with the use of relevant keywords, which comprised, but were not limited to, “Endovascular Thrombectomy”, “Distal, Medium Vessel Occlusions”, and “Ischemic Stroke”, in combination with Boolean operators such as “OR” and “AND”. The detailed search strategies used for each of the above databases are listed in Supplemental Table 1.

Study Selection and Eligibility Criteria

All the articles retrieved in our search were imported into EndNote version 20.5, and any duplicates found were removed. Two authors (B.S. and Z.U.A.) independently assessed the articles based on their titles and abstracts during the primary screening process. During secondary screening, the full texts of the articles identified in primary screening are assessed against a predetermined eligibility criterion. Any conflicts during the screening process were resolved by discussion through a third author (M.H.W.).

Inclusion criteria consisted of Randomized Controlled Trials (RCTs) and observational studies, which comprised adult patients > 18 years with AIS caused by DMVO (occlusion at ACA, MCA M2-M4 segment, PCA, PICA, AICA, and SCA); Intervention groups consisted of EVT therapy, which included mechanical thrombectomy (MT), intra-arterial thrombolysis, or bridging therapy. Control groups consisted of BMT patients receiving either conservative treatment or intravenous thrombolysis alone.

Data Extraction

Two independent authors (Z.U.A. and M.A.) performed data extraction from the eligible studies into an Excel sheet. Extracted baseline characteristics comprised: Author name, year of study, location, data collection period, study design, sample size, occlusion site, arms compared, mean age, sex, male%, NIHSS score on admission, and clinically relevant outcomes reported. Primary outcomes included excellent functional outcome and functional independence at 90 days. Secondary endpoints included symptomatic intracranial hemorrhage (sICH), 90-day mortality, early neurological improvement, and neurological deterioration.

Endpoints Definitions

The excellent functional outcome is defined as the modified Rankin Scale (mRS) score of 0-1, whereas the functional independence is determined by an mRS score of 0-2. sICH definitions used by the included studies are provided in the Supplemental Table 2.

Early neurological improvement is defined as a decrease of 4 or more points in the National Institutes of Health Stroke Scale (NIHSS) score, or a score of 0 on the earliest NIHSS after 24 hours but before discharge. Alternatively, neurological deterioration is defined as an increase in NIHSS score of ≥4 points 24 hours after admission.

Risk of Bias Assessment

The Cochrane Risk of Bias tool for randomized controlled trials (RoB 2.0)¹⁹ was employed by two authors (E.Z. and H.K.) to evaluate the quality of the included RCTs, whereas the Newcastle-Ottawa Scale (NOS)²⁰ was used to evaluate the observational cohorts included. The studies were divided into the following quality categories based on the NOS: high (8-9 score), medium (5-7 score), and low (<5 score). RoB 2.0 is divided into five domains: (1) bias from the randomization process, (2) bias from deviations from planned interventions, (3) bias due to missing outcome data, (4) bias in outcome measurement, and (5) bias in selecting reported results. Meanwhile, the NOS evaluates studies based on three domains: selection, comparability, and outcome.

Statistical Analysis

Statistical Analysis was performed using Review Manager (RevMan) Version 5.4.1, and the data were presented as forest plots. Categorical data were pooled as risk ratios (RRs) with 95% confidence intervals (CIs) employing the Mantel-Haenszel random effects model. Subgrouping was performed based on occlusion sites, including the ACA, MCA M2-4, PCA, and the unspecified DMVO subgroup, in which the occlusion site in DMVO is not specified. Heterogeneity was evaluated using Higgins I² statistics²¹ and a p-value of <0.05 was deemed statistically significant. With outcomes showing heterogeneity >50%, we assessed the source of heterogeneity using leave-one-out sensitivity analysis. Publication bias was evaluated visually through funnel plots and statistically via Egger’s regression test. To determine the certainty of evidence, the GRADE assessment was done using the GRADEpro GDT.²²

Results

Study Selection

After an initial detailed search across PubMed, Cochrane Central, and ScienceDirect, a total of 4,321 articles were identified. After removing duplicates (n = 2,808), the remaining articles (n = 1,513) were passed through the primary title and abstract screening, thus yielding a total of 152 articles. These filtered articles were passed through the full-text secondary screening, yielding 37 articles^15,16,23-57 which were included in the final quantitative synthesis. The study selection process is depicted in the PRISMA flowchart in Figure 1.

Figure 1.

PRISMA flowchart of the study selection process

Study and Patient Characteristics

A total of 9,505 patients with DMVO from 37 studies^15,16,23-57 were included in this meta-analysis. Vascular occlusions most frequently involve the M2 segment of the MCA, with several studies also reporting on occlusions of the M3, M4 segments, ACA, and PCA. The included cohorts were drawn from diverse clinical settings and displayed substantial variability in patient demographics, including age, sex, and baseline stroke severity. The included studies were conducted at different locations, including the USA,^{41,43,47,50,52} Japan,²⁴ Portugal,²⁵ Germany,^38,52 France,^27,32,48 Switzerland,^26,33,49 Italy,^23,53,55 Israel,²⁸ Britan,³¹ China⁵¹ and the rest of the studies are multicenter. The mean age across both arms ranged from 60 to 80 years. The admission NIHSS score ranged from 3 to 17. Comprehensive study-level characteristics and patient demographics are detailed in Table 1.

Table 1.

The Baseline Characteristics of Included Studies

Author ID	Location	Data collection	Study design	Sample size	Occlusion site	Study arms	Mean age (y)	Sex (male %)	NIHSS	Clinical outcomes
Rai et al. 2013	USA	—	Prospective	71	M2	EVT	68.6 ±16.4	59(47.9)	16.1 ±7.3	90-day mRS0-1, mRS0-2
Rai et al. 2013	USA	—	Prospective	71	M2	BMM	76.1 ±12.7	39(39)	16.1 ±8	90-day mRS0-1, mRS0-2
Urra et al. 2014	USA	2009-2012	Retrospective	23	M2	EVT	—	—	—	90-day mRS0-1, mRS0-2
Urra et al. 2014	USA	2009-2012	Retrospective	23	M2	BMM	—	—	—	90-day mRS0-1, mRS0-2
Qureshi et al. 2017	—	—	Randomized	51	M2	EVT:34	71 (23–81)**	16(47.1)	16 (7–25)*	90-day mRS0-1, mRS0-2, mortality, sICH, END
Qureshi et al. 2017	—	—	Randomized	51	M2	BMM:17	73 (53–81)**	12(70.6)	14 (8–24)*	90-day mRS0-1, mRS0-2, mortality, sICH, END
Sarraj et al. 2016	USA	2012-2015	Retrospective	522	M2	EVT	68 (56–78)*	144 (50)	16 (11–20)*	90-day mRS0-1, mRS0-2,
Sarraj et al. 2016	USA	2012-2015	Retrospective	522	M2	BMM	73 (60–81)*	112 (47.9)	15 (11–20)*	90-day mRS0-1, mRS0-2,
Sarraj et al. 2018	—	2012-2017	Retrospective	92	Distal M2 (M2+M3/M4/ACA)	EVT:35	—	—	—	90-day mRS0-1, mRS0-2, mortality
Sarraj et al. 2018	—	2012-2017	Retrospective	92	Distal M2 (M2+M3/M4/ACA)	MM:57	—	—	—	90-day mRS0-1, mRS0-2, mortality
Menon et al. 2019	International	—	Randomized	131	Proximate M2	EVT:67	66.0 ± 13.7	31(46.3)	14.4 ± 5.1	90-day mRS0-1, mRS0-2, mortality, sICH
Menon et al. 2019	International	—	Randomized	131	Proximate M2	Control: 64	65.2 ± 12.0	34(53.1)	15.4 ± 6.0	90-day mRS0-1, mRS0-2, mortality, sICH
Miura et al. 2019	—	—	Retrospective	372	M2	EVT: 184	73 ±10	110 (60)	15(9–19)*	90-day mRS0-1, mRS0-2, mortality, sICH
Miura et al. 2019	—	—	Retrospective	372	M2	No-EVT:188	74 ±11	109 (58)	10 (5–16)*	90-day mRS0-1, mRS0-2, mortality, sICH
Goyal et al. 2019	International	2013-2017	Retrospective	78	M2	MT: 34	—	—	—	90-day mRS0-1, mRS0-2, mortality, sICH
Goyal et al. 2019	International	2013-2017	Retrospective	78	M2	BMM: 44	—	—	—	90-day mRS0-1, mRS0-2, mortality, sICH
Aoki et al. 2020	Japan	2011-2019	Retrospective	121	M2	EVT only: 38	78 (72–83)*	21 (55)	17 (12−20)*	90-day mRS0-2, sICH
						IVT only:55	79 (73–85)*	29 (53)	13 (6–18)*
						both: 28	76 (67–85)*	19 (68)	11 (4–19)*
Cunha et al. 2020	Portugal	2015-2019	Retrospective	38	P1-P3	MT: 25	80.2 (73.8–83.4)*	16(64.0)	10 (6.0–14.5)*	90-day mRS0-1, mRS0-2, mortality, sICH
Cunha et al. 2020	Portugal	2015-2019	Retrospective	38	P1-P3	IVT only: 13	74.9 (68.9–82.5)*	7 (53.8)	8 (5.5–10.0)*	90-day mRS0-1, mRS0-2, mortality, sICH
Nagel et al. 2020	Germany	2002-2019	Retrospective	94	DMVO	EVT ± IVT: 30	69.4 ± 14.1	15 (50)	3 (0–5)**	90-day mRS0-1, mRS0-2, mortality
Nagel et al. 2020	Germany	2002-2019	Retrospective	94	DMVO	IVT: 64	70.8 ± 13.5	35 (57.8)	4 (0–5)**	90-day mRS0-1, mRS0-2, mortality
Seners et al. 2020	France	2006-2018	Retrospective	346	M2	BT: 87	—	—	—	90-day mRS0-1, mRS0-2
Seners et al. 2020	France	2006-2018	Retrospective	346	M2	IVT only: 259	—	—	—	90-day mRS0-1, mRS0-2
Strambo et al. 2020	Switzerland	2003-2018	Retrospective	106	P1-P2	EVT: 21	71 (64–78)*	8 (38.1)	7 (5–8.3)*	90-day mRS0-1, mortality, sICH
Strambo et al. 2020	Switzerland	2003-2018	Retrospective	106	P1-P2	BMM: 85	76.6 (68.–83)*	48 (56.5)	7 (4–12)*	90-day mRS0-1, mortality, sICH
Dobrocky et al. 2021	Switzerland	2005-2020	Retrospective	169	M2	EVT ± IVT: 85	71 (30.–97)**	52(62.2)	3 (0–5)**	90-day mRS0-1, mRS0-2, mortality, sICH
Dobrocky et al. 2021	Switzerland	2005-2020	Retrospective	169	M2	IVT only: 84	67 (18–94)**	52(61.9)	3 (0–5)**	90-day mRS0-1, mRS0-2, mortality, sICH
Herweh et al. 2021	International	2012-2020	Retrospective	130	P1-P2	BMM + EVT:23	70 ± 13.3	14(60.9)	9 (1–20)**	90-day mRS0-1, mRS0-2, mortality, sICH, ENI
Herweh et al. 2021	International	2012-2020	Retrospective	130	P1-P2	BMM:107	74 ± 13.1	56(52.3)	7 (1–38)**	90-day mRS0-1, mRS0-2, mortality, sICH, ENI
Meyer et al. 2021	International	2010-2020	Retrospective	243	P2-P3	MT:143	75 (62–81)*	79(55.2)	7 (4–11)*	90-day mRS0-1, mRS0-2, mortality, sICH, ENI
Meyer et al. 2021	International	2010-2020	Retrospective	243	P2-P3	BMM: 100	75 (62–81)*	50 (50.0)	5 (2–10)*	90-day mRS0-1, mRS0-2, mortality, sICH, ENI
Alexandre et al. 2022	Italy	2016-2020	Retrospective	388	Proximate M2	eMT: 180	70 ±13.9	93(51.7)	4 (2–5)*	90-day mRS0-1, mRS0-2, mortality, sICH
Alexandre et al. 2022	Italy	2016-2020	Retrospective	388	Proximate M2	BMM/rMT: 208	70.2 ±11.9	106(51)	3 (2–5)*	90-day mRS0-1, mRS0-2, mortality, sICH
Elhorany et al. 2022	France	2016-2022	Retrospective	80	DMVO	MT + BMT: 44	78 (64–85)*	25(56.8)	11 (7–21)*	90-day mRS0-1, mRS0-2, mortality, sICH, ENI
Elhorany et al. 2022	France	2016-2022	Retrospective	80	DMVO	BMT: 36	70 (57–78)*	24(66.7)	6 (3–10)*	90-day mRS0-1, mRS0-2, mortality, sICH, ENI
Flioglo et al. 2022	Israel	2015-2020	Retrospective	92	A1-A3	EVT:37	—	—	—	90-day mRS0-2, mortality, sICH
Flioglo et al. 2022	Israel	2015-2020	Retrospective	92	A1-A3	IVT:55	—	—	—	90-day mRS0-2, mortality, sICH
Kuhn et al. 2022	Britain	2018-2021	Retrospective	64	DMVO	MT:27	65	18(66.6)	5 (3–5)**	90-day mRS0-2, mortality
Kuhn et al. 2022	Britain	2018-2021	Retrospective	64	DMVO	MM:37	68	20(54)	4 (2–5)**	90-day mRS0-2, mortality
Marchal et al. 2022	France	2017-2020	Retrospective	171	Distal M2	EVT:96	68.7 ± 15.8	45 (46.9)	12.9 ± 7.2	90-day mRS0-1, mRS0-2, mortality, sICH, ENI
Marchal et al. 2022	France	2017-2020	Retrospective	171	Distal M2	No-EVT:75	73.9 ± 13.1	33 (44.0)	12.5 ± 6.3	90-day mRS0-1, mRS0-2, mortality, sICH, ENI
Saber et al. 2022	US	2015-2019	Retrospective	286	DMVO	EVT:156	66.7 ± 13.7	90 (57.6)	13.9 ± 6.8	90-day mRS0-1, mRS0-2, mortality, sICH
Saber et al. 2022	US	2015-2019	Retrospective	286	DMVO	MM:130	69.8 ± 14.9	62 (47.7)	9.4 ± 7.2	90-day mRS0-1, mRS0-2, mortality, sICH
Sarraj et al. 2022	—	—	Retrospective	207	M2	EVT:80	—	—	—	90-day mRS0-2, mortality, sICH,
Sarraj et al. 2022	—	—	Retrospective	207	M2	MM:127	—	—	—	90-day mRS0-2, mortality, sICH,
Sarraj et al. 2022	—	2010-2020	Retrospective	517	M2	EVT:195	71.0 (62.0–79.0)*	98(50.3)	13.0 (8.0–19.0)*	90-day mRS0-1, mRS0-2, mortality,
Sarraj et al. 2022	—	2010-2020	Retrospective	517	M2	MM:322	75.0 (65.0–83.0)*	173(53.9)	10.0 (6.0–15.0)*	90-day mRS0-1, mRS0-2, mortality,
Maulucci et al. 2023	Switzerland	2014-2020	Retrospective	268	P1-P2	EVT: 119	72.2 (62.1–80.0)*	77 (64.7)	7 (5–13)*	90-day mRS0-2, mortality, sICH
Maulucci et al. 2023	Switzerland	2014-2020	Retrospective	268	P1-P2	IVT:149	75.7 (66.5–83.6)*	81 (54.4)	5 (3–8)*	90-day mRS0-2, mortality, sICH
Meyer et al.2023	Europe, US, Asia (global)	2013-2021	Retrospective	154	ACA	MT:94	76 (67–84)*	52(55)	10 (7–13)*	90-day mRS0-1, mRS0-2, mortality, sICH
Meyer et al.2023	Europe, US, Asia (global)	2013-2021	Retrospective	154	ACA	BMT: 60	78 (64–84)*	28(47)	6.5 (4–15)*	90-day mRS0-1, mRS0-2, mortality, sICH
Nguyen et al. 2023	Europe and North America	2015-2022	Retrospective	1023	P1-P4	EVT:378	74 (64–82)*	216 (57.1)	8 (5–12)*	90-day mRS0-1, mRS0-2, mortality, sICH
Nguyen et al. 2023	Europe and North America	2015-2022	Retrospective	1023	P1-P4	MM:645	75 (64–82)*	373 (57.8)	5 (2–9)*	90-day mRS0-1, mRS0-2, mortality, sICH
Sabben et al. 2023	France, Switzerland, US	2003-2022	Retrospective	752	P1-P2	BMM + EVT:167	72 (62–82)*	88(52.7)	8 (5–11)*	90-day mRS0-1, mRS0-2, sICH, END
Sabben et al. 2023	France, Switzerland, US	2003-2022	Retrospective	752	P1-P2	BMM only:585	74 (63–83)*	335(57.3)	6 (3–10)*	90-day mRS0-1, mRS0-2, sICH, END
Xu et al. 2023	China	2018-2020	Retrospective	109	M2	EVT: 42	67.4 ± 13.0	19 (45.2)	13.1 ±3.9	90-day mRS0-1, mRS0-2, sICH
						IVT: 45	68.7 ± 10.9	21 (46.7)	11.7 ± 3.2
						BMM: 22	74.71 ± 8.3	9 (40.9)	13.1 ± 2.7
Nedelcu et al. 2023	US	2018-2021	Retrospective	80	DMVO	EVT:39	65 (58–78)*	22 (56.4)	4 (3–5)*	90-day mRS0-1,mRS0-2,mortality,sICH
Nedelcu et al. 2023	US	2018-2021	Retrospective	80	DMVO	BMT:41	68 (60–80)*	20 (48.8)	4 (2–4.5)*	90-day mRS0-1,mRS0-2,mortality,sICH
Rizzo et al. 2023	Italy	2019-2021	Prospective	180	DMVO	BT:83	72 ± 14.9	36(43.4)	9.1 ± 5.8	90-day mRS0-2,mortality,sICH
						EVT:38	76.1 ±11.5	17(44.7)	12.1 ± 6.4
						BMT:59	80.2 ± 9.4	23(39)	6 ± 3.7
Salim et al. 2024	Global	2017-2023	Retrospective	177	P1, P2, and P3	EVT:89	74 (61, 82)*	57 (64)	8.0 (6.0, 14.0)*	90-day mRS0-2, mortality, sICH
Salim et al. 2024	Global	2017-2023	Retrospective	177	P1, P2, and P3	MM:88	68 (60, 75)*	60 (68)	6.0 (3.8, 10.0)*	90-day mRS0-2, mortality, sICH
Salsano et al. 2024	Italy	2019-2023	Retrospective	114	DMVO	IVT:64	80 (74,84)*	29(45.3)	8.44 ± 5.40	90-day mRS0-1,mRS0-2,ENI at 1 day after treatment.
Salsano et al. 2024	Italy	2019-2023	Retrospective	114	DMVO	EVT+-IVT:50	78 (72,83.7)*	32(64)	11.02 ± 4.92	90-day mRS0-1,mRS0-2,ENI at 1 day after treatment.
Mohammaden et al. 2024	US+1 Europe	2017-2021	Retrospective	321	DMVO	EVT:179	69.4±13	61(34.1)	10 (7–16)*	90-day (mRS 0–2)(mRS, 0–1),sICH,90-day mortality.
Mohammaden et al. 2024	US+1 Europe	2017-2021	Retrospective	321	DMVO	MM:142	66.4±13.5	58(40.8)	6 (3–11)*	90-day (mRS 0–2)(mRS, 0–1),sICH,90-day mortality.
Goyal et al. 2025	5 countries	2022-2024	RCT	530	DMVO	EVT+Usual Care:255	74(63–82)*	137 (53.7)	8(6–11)*	90 days mRS ranging from 0 (no disability) to 6 (death).
Goyal et al. 2025	5 countries	2022-2024	RCT	530	DMVO	Usual Care:274	76(65–83)*	147 (53.6)	7(5–11)*	90 days mRS ranging from 0 (no disability) to 6 (death).
Psychogios et al. 2025	11 countries	2021- 2024	RCT	543	DMVO	EVT+BMT	77 (68–83)*	155(57.2)	6 (5–9)*	The level of disability in performing daily activities at 90 days, mRS 0–1, sICH, mortility
Psychogios et al. 2025	11 countries	2021- 2024	RCT	543	DMVO	BMT	77.5 (68–84)*	149(54.8)	6 (5–9)*
Salim et al. 2024	North America, Asia, and Europe	2017-2023	Retrospective	782	M2, M3 and M4	EVT:391	77 (65–83)*	191 (49)	8 (5–15)*	90 days (mRS 0–2),(mRS 0–1),mortality, sICH
Salim et al. 2024	North America, Asia, and Europe	2017-2023	Retrospective	782	M2, M3 and M4	BMM:391	77 (66–84)*	192 (49)	7 (4–15)*	90 days (mRS 0–2),(mRS 0–1),mortality, sICH

Note. All values are reported as Mean +− Standard deviation. * Median (Inter Quartile), **Median (Range).

A1, A2, A3 = A1, A2, A3 segment of the Anterior cerebral artery respectively; EVT: endovascular treatment; IV, intravenous; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Rankin scale; M1 = M1 segment of the middle cerebral artery; M2 = M2 segment of the middle cerebral artery; M3=M3 segment of the middle cerebral artery; M4=M4 segment of the middle cerebral artery; sICH = symptomatic intracranial hemorrhage. P1=P1 segment of Posterior communicating artery, P2=P2 segment of Posterior communicating artery; P3=P3 segment of Posterior communicating artery; IVT: intravenous thrombolysis; MM: medical management; BMM: Best Medical Management; BMT: Best medical treatment; DMVO: distal and medium vessel occlusions; BT: bridging therapy; MT: Mechanical thrombectomy; ACA: Anterior cerebral artery; ENI: early neurologic improvement; eMT: early mechanical thrombectomy; rMT: rescue mechanical thrombectomy; RCT: Randomized controlled trial; END: Early neurological deterioration.

Outcomes

The summary of the pooled effect sizes of different endpoints included in this meta-analysis is shown in Table 2.

Table 2.

Summary of Meta-Analysis

Outcome	Number of studies	Number of patients	Effect size (RR)	95% CI	P value	Heterogeneity (I²)	Egger’s test P- value
Excellent Functional Outcome	31	8,832	1.04	0.96-1.13	0.34	59%	0.35614
Functional Independence	36	9,149	1.00	0.94-1.06	0.99	64%	0.82511
Symptomatic Intracranial Hemorrhage	31	8,505	1.56	1.15-2.13	0.005	39%	0.30330
90 days Mortality	31	7,265	1.21	0.97-1.52	0.09	46%	0.59933
Early Neurological Improvement	7	821	1.38	1.05-1.82	0.02	53%	0.12594
Neurological Deterioration	6	2,035	1.39	0.65-2.95	0.40	82%	0.69338

Note. RR: Risk ratio; CI: Confidence interval.

Excellent Functional Outcome

Thirty-one studies comprising 8,832 patients (EVT: 3,872 vs BMT: 4,960) were included in the analysis of excellent functional outcome. Pooled analysis using a random-effects model showed no significant difference between EVT and BMT (RR = 1.04; 95% CI: [0.96,1.13]; p = 0.34). Heterogeneity was moderate (I² = 59%) (Figure 2).

Figure 2.

Excellent functional outcome forest plot

Functional Independence

A total of 36 studies, including 9,149 patients (EVT: 4,024; BMT: 5,125), reported on functional independence. The pooled analysis demonstrated no statistically significant difference between EVT and BMT (RR = 1.00; 95% CI: [0.94-1.06]; p = 0.99). Moderate heterogeneity was observed (I² = 64%) (Figure 3).

Figure 3.

Functional independence forest plot

Symptomatic Intracranial Hemorrhage

Thirty-one studies involving 8,505 patients (EVT: 3,694; BMT: 4,811) reported the incidence of sICH. EVT was associated with a significantly increased risk of sICH compared to BMT (RR = 1.56; 95% CI: [1.15, 2.13]; p = 0.005). Heterogeneity was moderate (I² = 39%) (Figure 4).

Figure 4.

Symptomatic intracranial hemorrhage forest plot

90-Day Mortality

Mortality at 90 days was reported in 31 studies encompassing 7,265 patients (EVT: 3,308; BMT: 3,957). The pooled analysis revealed no significant difference in mortality between the two groups (RR = 1.21; 95% CI: [0.97, 1.52]; p = 0.09). Heterogeneity was moderate (I² = 46 %) (Figure 5).

Figure 5.

90 days mortality forest plot

Early Neurological Improvement

Seven studies involving 821 patients (EVT: 381; BMT: 440) assessed early neurological improvement. EVT was associated with a significantly higher likelihood of improvement compared to BMT (RR = 1.38; 95% CI: [1.05, 1.82]; p = 0.02). Heterogeneity was moderate (I² = 53%) (Figure 6).

Figure 6.

Early neurological improvement forest plot

Neurological Deterioration

Six studies, including 2,035 patients (EVT: 778, BMT: 1,257), reported on neurological deterioration. The meta-analysis showed no significant difference between EVT and BMT (RR = 1.39; 95% CI: [0.65, 2.95]; p = 0.40). However, heterogeneity was substantial (I² = 82%) (Supplemental Figure 1).

Subgroup Analysis Based on Occlusion Site

MCA

On the subgroup analysis based on the MCA M2-M4 occlusion sites, all the efficacy outcomes including the excellent functional outcome (p = 0.24), and functional independence (p = 0.12), and the safety outcomes including the sICH (p = 0.25), and 90 days mortality (p = 0.93), became statistically insignificant (Figures 7-10).

Figure 7.

Excellent functional outcome subgroup analysis based on the occlusion sites

Figure 8.

Functional independence subgroup analysis based on the occlusion sites

Figure 9.

Symptomatic intracranial hemorrhage subgroup analysis based on the occlusion sites

Figure 10.

90 days mortality forest plot subgroup analysis based on the occlusion sites

ACA

On subgrouping based on the ACA occlusion sites, the endpoints including excellent functional outcome (p = 0.41), sICH (p = 0.74), and 90 days mortality (p = 0.67) became insignificant except for the functional independence which showed a statistically significant decrease in the EVT (RR= 0.75; 95% CI: [0.56, 0.99]; p= 0.05; I²= 0%) (Figures 7-10).

PCA

Subgrouping based on the PCA occlusion sites showed insignificant results regarding the excellent functional outcome (p = 0.23), functional independence (p = 0.35), and sICH (p = 0.16) whereas the mortality was significantly increased (RR= 1.50; 95% CI: [1.08, 2.07]; p= 0.01; I²= 0%) (Figures 7-10).

DMVO

Subgroup analysis based on the unspecified occlusion site in DMVO; showed no significant difference in excellent functional outcome (p = 0.62) and the functional independence (p = 0.20) whereas both the sICH (RR= 1.55; 95% CI: [1.10, 2.18 ]; p= 0.01; I²= 0%) and the 90 days mortality (RR= 1.39; 95% CI: [1.10, 1.76]; p= 0.005; I²= 1%) were significantly increased in the EVT (Figures 7-10).

Risk of Bias Assessment

Risk of bias for randomized studies was evaluated using the RoB 2.0 tool.¹⁹ Four studies^15,16,34,40 were assessed. All the studies exhibited some concerns in Domain 5 (selection of the reported result), whereas both Menon et al. and Qureshi et al. also showed some concerns in Domain 2 (deviations from the intended interventions), as shown in RoB 2.0 traffic light plot Supplemental Figure 2.

For non-randomized studies, quality was assessed using NOS.²⁰ All studies scored between 7 and 9, indicating high methodological quality. Most studies reported robust performance across the selection, comparability, and outcome assessment domains, as shown in Supplemental Table 3.

Sensitivity Analysis and Publication Bias

For outcomes having heterogeneity > 50% we performed a leave-one-out sensitivity analysis to investigate the cause of this heterogeneity. On removing the study by Sarraj et al. 2016,⁴⁷ the heterogeneity falls to 46% and 45% for the excellent functional outcome and functional independence, respectively (Supplemental Figures 3-4). Likewise, on removing the studies by Menon et al.³⁴ and Marchal et al.,³² the heterogeneity decreased to 41% and 39% for the outcome of early neurological improvement, respectively (Supplemental Figures 5-6).

Publication bias was assessed visually using funnel plots and statistically via Egger’s regression test. On visual inspection of funnel plots, no asymmetry was found, suggesting insignificant publication bias which was further confirmed using Egger’s regression test (Supplemental Figures 7-12) and Table 2.

GRADE Assessment

GRADE assessment was done to assess the certainty of evidence for each endpoint. The detailed summary of findings is given in Table 3.

Table 3.

GRADE Summary of Findings Table

EVT compared to BMT for DMVO
Patient or population: DMVO
Intervention: EVT
Comparison: BMT

Outcomes	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with IVT	Risk with EVT	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Excellent functional outcome	424 per 1,000	441 per 1,000 (407 to 479)	RR 1.04 (0.96 to 1.13)	8832 (31 studies)	⨁◯◯◯
Excellent functional outcome	424 per 1,000	441 per 1,000 (407 to 479)	RR 1.04 (0.96 to 1.13)	8832 (31 studies)	Very low^a
Functional independence	607 per 1,000	607 per 1,000 (571 to 643)	RR 1.00 (0.94 to 1.06)	9149 (36 studies)	⨁◯◯◯
Functional independence	607 per 1,000	607 per 1,000 (571 to 643)	RR 1.00 (0.94 to 1.06)	9149 (36 studies)	Very low^a,b
sICH	32 per 1,000	49 per 1,000 (36 to 67)	RR 1.56 (1.15 to 2.13)	8505 (32 studies)	⨁⨁◯◯
sICH	32 per 1,000	49 per 1,000 (36 to 67)	RR 1.56 (1.15 to 2.13)	8505 (32 studies)	Low
90 days Mortality	86 per 1,000	104 per 1,000 (83 to 131)	RR 1.21 (0.97 to 1.52)	7265 (31 studies)	⨁◯◯◯
90 days Mortality	86 per 1,000	104 per 1,000 (83 to 131)	RR 1.21 (0.97 to 1.52)	7265 (31 studies)	Very low^a
Early neurological improvement	336 per 1,000	464 per 1,000 (353 to 612)	RR 1.38 (1.05 to 1.82)	821 (7 studies)	⨁⨁◯◯
Early neurological improvement	336 per 1,000	464 per 1,000 (353 to 612)	RR 1.38 (1.05 to 1.82)	821 (7 studies)	Low
Neurological deterioration	75 per 1,000	104 per 1,000 (49 to 221)	RR 1.39 (0.65 to 2.95)	2035 (6 studies)	⨁◯◯◯
Neurological deterioration	75 per 1,000	104 per 1,000 (49 to 221)	RR 1.39 (0.65 to 2.95)	2035 (6 studies)	Very low^a,b

Note. CI: confidence interval; RR: risk ratio; a. The 95% confidence interval is crossing 1; b. The heterogeneity (I²) is more than 60%; DMVO: Distal and medium vessel occlusion; EVT: Endovascular thrombectomy; BMT: Best medical treatment; sICH : Symptomatic intracranial hemorrhage

Discussion

In this systematic review and meta-analysis of 37 studies comparing EVT with BMT in patients with DMVO, we assessed both efficacy and safety outcomes. The pooled analysis revealed no significant differences between EVT and BMT in achieving excellent functional outcome, functional independence, 90-day mortality, or rates of neurological deterioration. EVT was associated with significantly greater early neurological improvement compared to BMT; however, it also demonstrated a higher risk of sICH.

This meta-analysis sets itself apart from prior studies by using a larger sample size of 9,505 patients, compared to Wang et al.’s¹⁴ 6,826 patients and Loh et al.’s¹³ 2,469 patients. It also includes recent high-impact trials like ESCAPE-MeVO¹⁵ and DISTAL,¹⁶ which were not part of earlier analyses. Our findings regarding comparable excellent functional outcomes, functional independence, 90-day mortality, and rates of neurological deterioration, along with increased early neurological improvement and a higher risk of sICH, were consistent with those of Wang et al.¹⁴ However, Loh et al.¹³ reported a significant increase in functional independence in the EVT group. Moreover, we employed the GRADE assessment to evaluate the certainty of the evidence, which further enhances the methodology compared to previous reviews.

Current guidelines strongly endorse EVT for AIS due to proximal large-vessel occlusion (LVO). The 2018 AHA/ASA guidelines recommend MT with a stent retriever for patients with intracranial ICA or proximal MCA occlusions within 6 hours of onset.⁵⁸ European stroke guidelines similarly endorse EVT for LVO (including M2 MCA occlusions), but note that M3/ACA/PCA occlusions were underrepresented in trials and have uncertain benefit.⁵⁹ By contrast, EVT was not initially applied to DMVOs for several reasons. Early trials and subsequent meta-analyses largely excluded patients with small distal vessel occlusions, and those enrolled with M2, or more distal occlusions, represented only a small subset. Consequently, there was no robust randomized evidence to guide the use of EVT in this population. Additionally, the technical complexity of navigating smaller, tortuous distal vessels raised concerns about procedural safety, including risks of vessel injury, dissection, or perforation.⁶⁰ Furthermore, DMVO strokes often present with lower NIHSS scores and milder deficits, leading to a preference for intravenous thrombolysis (IVT) or conservative management.⁶⁰ Despite accounting for approximately 25 to 40% of all ischemic strokes, optimal treatment strategies for DMVO remain undefined.^8,61 Recent advancements in low-profile thrombectomy devices and perfusion-based imaging have enhanced the feasibility and safety of EVT in this setting, and an increasing number of observational studies and RCTs are now evaluating its role in DMVO.

Our pooled analysis demonstrated that EVT did not confer a significant advantage over BMT in achieving either excellent functional outcome or functional independence at 90 days. Our findings build upon and expand upon previous meta-analyses by Loh et al.¹³ and Wang et al.¹⁴ Loh et al.¹³ reported that EVT was associated with improved functional independence compared to BMT, only after statistical correction. Similarly, Wang et al.¹⁴ found no significant overall difference in functional outcomes. However, both studies were limited by smaller sample sizes and lacked the most recent data. By incorporating a larger number of studies and more recent evidence, our analysis offers an updated and more comprehensive evaluation of EVT in DMVO. The recent ESCAPE-MeVO randomized trial similarly found no benefit of EVT on excellent functional outcome.¹⁵ The trial investigators noted several factors that may have contributed to the lack of benefit, including longer workflow times, incomplete reperfusion in a substantial proportion of patients, and a higher incidence of sICH and other adverse events in the EVT group. Moreover, approximately 15% of EVT-assigned patients showed spontaneous recanalization prior to thrombectomy, often following IVT, further diluting any potential EVT effect. Consistent with these findings, data from large observational registries have similarly shown no significant differences in functional outcomes between EVT and BMT.^23,57 The consistency of these results suggests that EVT does not clearly improve functional outcomes in the overall population of patients with DMVO. Moderate heterogeneity was observed in these outcomes, possibly reflecting differences in baseline stroke severity (e.g., NIHSS score), affected vessel segments (e.g., dominant vs. non-dominant M2, PCA, ACA), and use of IVT. It is plausible that EVT offers benefit in specific subgroups (e.g., dominant M2 occlusions), which may be offset by neutral or even harmful effects in others. Wang et al. further explored this and reported that, for M2 segment MCA occlusions, EVT was associated with significantly higher odds of achieving excellent functional outcomes compared to BMT.¹⁴ They also observed reduced functional independence in individuals with ACA occlusion, which aligns with the findings of our subgroup analysis. A pooled meta-analysis of EVT-treated ACA strokes found that approximately only 41% achieved 3-month functional independence, and roughly 20% died by 3 months.⁶² These rates are substantially lower than those reported for proximal MCA strokes or other LVOs.

We observed no significant difference in rates of neurological deterioration between EVT and BMT. Early deterioration was generally uncommon in both groups across studies. This implies that EVT did not meaningfully prevent early worsening any more than medical therapy. Prior literature on DMVO has not emphasized neurological decline, but available data are consistent with our findings. A post-hoc analysis of the HERMES study found that the incidence of unexplained early neurological deterioration (UnEND) was similar between the EVT and medical management arms, and patient-related factors did not increase the risk of UnEND with EVT compared to medical management.⁶³ This is broadly consistent with non-DMVO stroke data, where early NIHSS fluctuations often depend on infarct growth and edema, factors not entirely prevented by EVT.⁶⁴ We also observed significant heterogeneity in the pooled analysis of neurological deterioration, suggesting variability in outcome definitions, assessment time points, or patient selection across studies, which may limit the generalizability of this finding. However, while EVT did not appear to reduce early neurological deterioration, our analysis revealed a significant advantage in terms of early neurological improvement. This effect was consistently observed across studies and was statistically significant in our pooled estimates. Among the included studies, Marchal et al. (2022), which contributed the highest weight to our analysis, reported a greater improvement in NIHSS scores at discharge among EVT-treated patients compared to those who received medical management alone.³² This finding is biologically plausible, as successful recanalization in smaller, distal vessels can promptly restore perfusion to penumbral tissue, leading to rapid clinical improvement. Similar associations between early reperfusion and neurological recovery have been well established in the context of proximal LVOs.⁶⁵ Nonetheless, the observed early improvement did not translate into superior long-term functional outcomes. This discrepancy may be attributable to the relatively small infarct volumes typically associated with DMVO, where early symptom resolution may have limited impact on eventual disability or independence. Alternatively, the higher rate of sICH and other complications with EVT might negate the early gains by 90 days.

Our analysis found a significantly higher rate of sICH in the EVT group, consistent with the previous meta-analysis.¹⁴ This elevated risk may reflect the inherent procedural challenges of thrombectomy in smaller, more fragile distal vessels, which are prone to injury during catheter navigation or device deployment. Moreover, patients with DMVO often have lower baseline NIHSS scores and smaller infarct cores, potentially reducing the margin of benefit from EVT and increasing the relative impact of procedure-related complications.^66,67 Loh et al. also observed a numerical increase in sICH with EVT, though it did not reach statistical significance in their smaller sample.¹³ Notably, a meta-analysis by Chen et al. focusing on EVT in large LVO among patients with mild stroke also found a higher incidence of sICH in the EVT group compared to those treated with medical management, suggesting that lower stroke severity may be associated with a less favorable risk-benefit profile for EVT.⁶⁸ Taken together, the available evidence indicates that EVT for DMVO does increase the risk of symptomatic bleeding, and this risk should be carefully weighed against the uncertain clinical benefit.

Our subgroup analysis of the MCA, including M2, M3, and M4 occlusion sites, found no significant differences in efficacy or safety between EVT and BMT. It’s important to note that these results apply to a broad grouping of MCA occlusions rather than isolated M2 occlusions, where EVT might show benefits due to larger vessel size and favorable anatomy. However, the absence of significant benefits across the overall MCA subgroups highlights the need for more detailed analysis of specific vessel segments to identify which MCA occlusion patients truly benefit from EVT. Additionally, the increased mortality seen in the EVT group within the PCA subgroup suggests that EVT may not be suitable for this patient population. A multicenter cohort of 752 patients with isolated PCA occlusion found that EVT doubled the risk of sICH and early neurological deterioration.⁴² They concluded that EVT should not be routinely recommended for PCA strokes outside trials. Similarly, a pooled meta-analysis of 7 studies reported no difference in functional outcomes for isolated PCA occlusions but a significantly higher mortality in the EVT arm.⁶⁹ The evidence consistently shows that EVT for isolated PCA occlusions appears less beneficial and potentially harmful. Additional high-quality randomized trials focused on specific occlusion sites are needed to verify these results and identify which patients with specific occlusion locations are likely to benefit from EVT treatment.

Lastly, we found no significant difference in 90-day all-cause mortality between patients with DMVO stroke treated with EVT versus BMT, a result consistent with earlier analyses.^13,14 The available data do not indicate a clear mortality benefit of EVT over BMT in this patient population, emphasizing the need for larger prospective randomized trials to assess the impact of EVT on survival definitively. In contrast, EVT has been shown to reduce mortality in patients with LVO stroke. A systematic review of 18 trials reported significantly lower 90-day mortality with EVT compared to BMT.⁷⁰ However, a more recent meta-analysis of 22 studies found a higher risk of 90-day mortality with EVT, suggesting that outcomes may vary based on patient selection, timing, and complication rates.⁷¹ Given that DMVO strokes generally carry a lower baseline risk of death than LVO strokes, any intervention must be exceptionally safe to confer a mortality benefit. Our findings suggest that neither EVT nor BMT alone improves survival in DMVO, possibly due to a balance between potential life-saving reperfusion benefits and the procedural or hemorrhagic risks associated with thrombectomy. Notably, even in LVO stroke, the mortality benefits from EVT have been modest, making the neutral result in DMVO a consistent and expected extension of current evidence.

The observed findings indicate that although EVT may lead to early neurological improvement, these do not necessarily translate into long-term functional benefits. Clinicians should carefully weigh the potential for early recovery against the higher risk of sICH associated with EVT. Given the high heterogeneity and low certainty of current evidence, further high-quality randomized trials are essential to confirm the long-term advantages and risks of EVT for patients with AIS caused by DMVO before it can be broadly recommended for this group.

Limitations

This meta-analysis has certain limitations. First, the analysis was conducted at the study level rather than using individual patient data, limiting the ability to adjust for patient-level confounders. Secondly, many included studies were observational registries or non-randomized cohorts, which are prone to selection bias and residual confounding. For instance, patients selected for EVT often had more severe strokes or showed early deterioration under medical care. In contrast, those who did well with IVT alone were not taken for intervention. Such confounding can affect the apparent treatment effect sizes. Additionally, there was variability in treatment protocols, including intervention time windows, use of bridging IVT, imaging selection criteria (such as non-contrast CT and CTA versus perfusion imaging), thrombectomy techniques (device type, number of passes, adjunctive intra-arterial therapy), vessel occlusion sites like ACA, MCA, and PCA in DMVO stroke, study designs including observational studies and RCTs, and initial stroke severity indicated by NIHSS scores, which may contribute to heterogeneity. Additionally, differences in how sICH is defined can lead to heterogeneity; hence, future research should aim to standardize these definitions to minimize variability. A key limitation of this study is the high heterogeneity and low certainty in some outcomes, which highlights uncertainty in the pooled estimates and limits their generalizability. These limitations emphasize the need for large-scale, prospective RCTs to more definitively establish the safety and efficacy of EVT in patients with DMVO.

Conclusion

This systematic review and meta-analysis found no significant differences between EVT and BMT in terms of excellent functional outcome, functional independence, 90-day mortality, or neurological deterioration in patients with DMVO. However, EVT was associated with greater early neurological improvement, suggesting potential early clinical benefits that did not translate into superior long-term outcomes. Notably, EVT was also linked to a higher risk of sICH. Subgroup analysis revealed no significant advantage of EVT in MCA occlusion, suggesting that EVT’s benefit in this subgroup remains uncertain. In contrast, it was associated with a higher risk of mortality in the PCA subgroup. However, due to high heterogeneity and low certainty evidence, current findings cannot definitively establish equivalence between EVT and BMT. Instead, they indicate ongoing uncertainty about the relative effects of these treatments. More randomized trials are needed to confirm these results and offer clearer insights.

Supplemental Material

Supplemental Material - Comparing the Efficacy and Safety of Endovascular Therapy versus Best Medical Treatment in Acute Ischemic Stroke Patients With Distal Medium Vessel Occlusion: A Systematic Review and Meta-Analysis

Supplemental Material for Comparing the Efficacy and Safety of Endovascular Therapy versus Best Medical Treatment in Acute Ischemic Stroke Patients With Distal Medium Vessel Occlusion: A Systematic Review and Meta-Analysis by Muhammad Hassan Waseem, Zain ul Abideen, Eeshal Zulfiqar, Barka Sajid, Aisha Kakakhail, Haider Kashif, Muhammad Ansab, Muhammad Wajih Ansari, Rowaid Ahmad, Zara Fahim, Pawan Kumar Thada, and Brandon Lucke-Wold in Journal of Central Nervous System Disease.

Footnotes

ORCID iD

Pawan Kumar Thada

Author Contributions

Study concept and design: MHW and ZUA; acquisition of data: ZUA, BS, HK and MA; analysis and interpretation of data: ZUA, EZ, and AK; drafting of the manuscript: RA, ZF, MWA, and PKT; critical revision of the manuscript: MHW and BLW.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data will be made available upon reasonable request to the authors.*

Supplemental Material

Supplemental material for this article is available online.

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