Abstract
Background
Acute ischaemic stroke due to distal medium vessel occlusion (AIS-DMVO) causes significant morbidity. Endovascular thrombectomy advancement has made treating AIS-DMVO with stent retrievers (SR) and aspiration catheters (AC) possible, however the optimal technique remains unknown. We performed a systematic review and meta-analysis to investigate the efficacy and safety of SR use compared to purely AC use in patients with AIS-DMVO.
Methods
We systematically searched PubMed, Cochrane Library and EMBASE, from inception to 2nd September 2022, for studies comparing SR or primary combined (SR/PC) against AC in AIS-DMVO. We adopted the Distal Thrombectomy Summit Group’s definition of DMVO. Efficacy outcomes were functional independence (modified Rankin Scale (mRS) 0–2 at 90 days), first pass effect (modified Thrombolysis in Cerebral Infarction scale (mTICI) 2c-3 or expanded Thrombolysis in Cerebral Infarction scale (eTICI) 2c-3 at first pass), successful final recanalisation (mTICI or eTICI 2b-3), and excellent final recanalisation (mTICI or eTICI 2c-3). Safety outcomes were symptomatic intracranial haemorrhage (sICH) and 90-day mortality.
Results
12 cohort studies and 1 randomised-controlled trial were included, involving 1881 patients with 1274 receiving SR/PC and 607 receiving AC only. SR/PC achieved higher odds of functional independence (odds ratio (OR) 1.33, 95% confidence interval (CI) 1.06–1.67) and lower odds of mortality (OR 0.69, 95% CI 0.50–0.94) than AC. Odds of successful/excellent recanalisation and sICH were similar between both groups. Stratified to compare only SR and only AC, the use of only SR, achieved significantly higher odds of successful recanalisation as compared to only AC (OR 1.80, 95% CI 1.17–2.78).
Conclusion
There is potential for efficacy and safety benefits in SR/PC use as compared to AC only in AIS-DMVO. Further trials are necessary to validate the efficacy and safety of SR use in AIS-DMVO.
Keywords: Ischaemic stroke, distal medium vessel occlusion, thrombectomy, stent retriever, aspiration
Introduction
Endovascular thrombectomy (EVT) has been demonstrated to be the standard of care for acute ischaemic stroke (AIS) due to proximal large vessel occlusions (PLVOs). However, EVT for distal medium vessel occlusions (DMVOs), which account for 25–40% of all AIS cases, have yet to be proven in randomised trials. DMVOs are defined by the Distal Thrombectomy Summit Group consensus statement as thromboembolic occlusion of the anterior cerebral artery, M2–M4 middle cerebral artery (MCA), posterior cerebral artery (PCA), posterior inferior cerebellar artery, anterior inferior cerebellar artery or superior cerebellar artery. 1 These vessels have longer, more tortuous access routes and thinner arterial walls, potentially increasing the risks of dissection, perforation and vasospasm upon mechanical manipulation. This needs to be balanced against the lower potential reperfusion benefit due to smaller at-risk tissue volumes as compared to PLVOs. 1
DMVOs are common and can result in poor functional outcomes despite medical therapy,2,3 with only half of patients with M2 occlusions achieving a good functional outcome at 90 days. 4 Based on increasing evidence for the efficacy and safety of EVT in M2 occlusions, DMVOs have been proposed as the next frontier for EVT.1,5 Recent advances in stent retriever and aspiration catheter technology have enabled devices to reach more distal vessels, with a good efficacy and safety profile. 6 Defining the efficacy and safety profiles of the various techniques is of importance in avoiding further complications in this subgroup of patients.
Despite these iterative advances in EVT technology, procedural evidence remains limited. For M2 occlusions, the randomised controlled trial (RCT) ASTER (Contact Aspiration Versus Stent Retriever for Successful Revascularization) enrolled 79 patients with M2 occlusions but was generally underpowered and found only a nominal non-significant difference in reperfusion rates and functional outcome between the two techniques. 7 Evidence for other DMVOs has been limited to case series and cohort studies; however, these studies have demonstrated promising results in both reperfusion and functional outcomes.6,8,9 Given a lack of conclusive evidence regarding the efficacy and safety profiles of stent retriever versus aspiration techniques in DMVOs, we aimed to perform a systematic review and meta-analysis of the literature comparing stent retriever (SR) use versus aspiration catheter (AC) only, to investigate their efficacy and safety in treatment of AIS patients with DMVO (AIS-DMVO).
Methods
A systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A protocol delineating the aims and strategy was established in consensus with all authors prior to the start of the study and registered on PROSPERO (registration number: CRD42022367860).
Search methods and selection criteria
A comprehensive literature search was performed of the PubMed, EMBASE and Cochrane library from inception until 2nd September 2022. The complete search strategy is available in Supplemental Table S1. Manual search in the reference lists of included articles and relevant review articles was further conducted and relevant articles included.
Inclusion criteria were: (1) included at least 10 AIS-DMVO patients as defined in the consensus statement; (2) compared two treatment arms of either SR, PC or both with AC use and (3) presented sufficient information to calculate the odds ratio of at least one efficacy or safety outcome. Exclusion criteria were: (1) only abstract available and (2) review articles.
Two reviewers independently screened the titles and abstracts to identify articles that potentially met the inclusion criteria, following which two reviewers independently reviewed the full text of the resulting articles to arrive at the final inclusion decision. The reference lists of the included studies and relevant review articles were also screened for appropriate articles. Any disagreements were resolved by discussion.
Outcomes
The efficacy outcomes were functional independence, defined as modified Rankin scale (mRS) score of 0–2 at 90 days after AIS, first pass effect (FPE; modified Thrombolysis in Cerebral Infarction scale (mTICI) or expanded Thrombolysis in Cerebral Infarction scale (eTICI) 2c-3 at first pass), successful final recanalisation (mTICI or eTICI 2b-3), and excellent final recanalisation (mTICI or eTICI 2c-3). Safety outcomes were defined as 90-day mortality and occurrence of symptomatic intracranial haemorrhage (sICH).
Data extraction and quality assessment
Data were independently extracted from included studies by two reviewers using a standardised data collection form. Data extracted included the efficacy and safety outcomes, in addition to patient characteristics including study year, design, size of cohort, age, sex, medical co-morbidities, National Institutes of Health Stroke Scale (NIHSS) score at admission, stroke onset to treatment time, site of occlusion, number of passes and procedure time.
Study quality and risk of bias was independently assessed by two reviewers using Cochrane’s revised tool (RoB 2) for randomised controlled trials and the Newcastle–Ottawa scale (NOS) for cohort studies. Two authors independently graded studies as having a high (<5 score), moderate (5–7 score) or low (8–9 score) risk of bias as per the NOS grading in prior studies.
Of the 13 included studies, 4 studies10–13 reported adjusted ORs, and the remaining 9 reported summary data for each intervention group without adjustment, which were then processed to obtain unadjusted ORs. A comparison of the ORs is available in Supplemental Table S2. Of the four studies that reported adjusted ORs, the adjusted effect sizes were similar to the unadjusted effect sizes, and therefore only unadjusted ORs were used for the purposes of this meta-analysis.
Statistical analysis
All statistical analyses were performed using RStudio Version 4.2.1, with statistical methods and plots provided by the meta package. Analyses were performed in accordance with general approaches laid out by the Cochrane Handbook. Pooled odds ratios (OR) and associated 95% confidence intervals (CI) were calculated for all outcomes where data was available.
Variance between individual studies was estimated using the method of restricted maximum-likelihood (REML). Heterogeneity was assessed via the Cochran’s Q test and quantified by the I 2 statistic, with ranges of 12–30%, 30–60% and >60% indicating low, moderate and substantial heterogeneity, respectively. Prediction intervals give the range of expected effect sizes within which the results of a future study might lie. Funnel plots were constructed for analyses involving 10 or more studies, and visually inspected to identify any publication biases or small studies effects.
Results
Systematic search
The search yielded a total of 2854 records, from which 537 duplicates were removed. Following title and abstract screening, 2240 articles were excluded. Of the 77 full texts assessed for eligibility, 65 were excluded. An additional study was identified from the reference lists of other articles. Finally, 13 eligible studies7,10–21 were included in this meta-analysis (Figure 1).
Figure 1.
PRISMA flow diagram depicting the systematic review process.
Study characteristics
A total of 1881 patients were included across 13 studies, of which 12 were cohort studies and one 7 was an RCT. The characteristics of the included studies are summarised in Table 1.
Table 1.
Descriptive summary of included studies.
| Study | Alawieh et al. 14 | Atchaneeyasakul et al. 10 | Baig et al. 15 | Bernsen et al. 11 | Brehm et al. 12 | de Castro Afonso et al. 16 | Gory et al. 7 |
|---|---|---|---|---|---|---|---|
| Location | International | USA | USA | Netherlands | Germany | Brazil | France |
| Design | Retrospective cohort | Retrospective cohort | Retrospective cohort | Prospective cohort | Retrospective cohort | Prospective cohort | RCT |
| Study period | – | Oct 1999–Jun 2016 | Jan 2015–Jul 2020 | Mar 2016–Nov 2017 | Jan 2014–Sep 2017 | Nov 2012–May 2018 | Oct 2015–Oct 2016 |
| Type of occlusion | Only primary DMVO | Only primary DMVO | Only primary DMVO | Only primary DMVO | Only primary DMVO | Only primary DMVO | Only primary DMVO |
| Occlusion site(s) | M3/4, A2/3, P2/3 | M2 | P1/P2 | M2 | M2 | M2 | M2 |
| NOS, total (S, C, E) | 9 (4,2,3) | 7 (3,2,2) | 9 (4,2,3) | 9 (4,2,3) | 8 (3,2,3) | 9 (4,2,3) | – |
| SR/PC | |||||||
| No. treated (%) @ | 64 (5.02) | 120 (9.42) | 12 (0.942) | 327 (25.67) | 12 (0.942) | 25 (1.96) | 31 (2.43) |
| Pri Treatment | SR/PC | SR/PC | SR/PC | SR/PC | Combined | SR | SR |
| Device(s) used | – | – | – | – | GC: 8F Mach1, 8F Vista Brite Tip, NeuronMAX 088; SR: Trevo XP ProVue, pRESET, APERIO, 3D Separator | Solitaire FR (Medtronic), TREVO (Stryker) | SOLITAIRE FR, Trevo, Embotrap, Embolys 5 × 21, Catch 3 × 15, ERIC, Phenox, REVIVE |
| Use of IVT (%) | 30 (46.87) | 66 (55.2) | 4 (33.33) | – | – | 16 (64.00) | 23 (74.19) |
| Use of GA (%) | – | – | – | – | – | – | 4 (12.9) |
| Age, yrs^ | 67 ± 15 | 68.6 ± 13.1 | 70.5 (57.5–78.25) | – | – | – | 70.2 ± 13.4 |
| NIHSS^ | 11 ± 6 | 15 (11–20) | 9 (4.75–11) | – | – | 15 (13–22) | 13.7 ± 6.5 |
| ASPECTS^ | –* | 9 (7.5–9.5) | – | – | – | 9 (7–10) | 7 (6–9) |
| Time to groin, min^ | 336 ± 418 | 280 (209–443) | 186 (105–205) | 254 (199–326) # | – | – | 228 (190–271) |
| No. of passes^ | 1.9 ± 1.1 | – | 2 (1–2) | – | – | – | 2 (1–3) |
| Procedure time, min^ | 49 ± 46 | – | – | 62 (45–85) | – | 60 (35–97) | 50 (33–70) |
| Study | Haussen et al. 17 | Hulscher et al. 18 | Kim et al. 20 | Meyer et al. 19 | Mokin et al. 21 | Renieri et al. 13 | |
| Location | USA | Belgium | South Korea | International | USA | North America and Europe | |
| Design | Retrospective cohort | Retrospective cohort | Retrospective cohort | Retrospective cohort | Retrospective cohort | Retrospective cohort | |
| Study period | Jan 2014–Jul 2018 | Jan 2018–Jan 2021 | Jan 2011–Jun 2015 | Jan 2014–Jun 2020 | Mar 2012–Mar 2016 | Jan 2017–May 2020 | |
| Type of occlusion | Primary DMVO, ENT, EST$ | Only primary DMVO | Only primary DMVO | Only primary DMVO | Only primary DMVO | Only primary DMVO | |
| Occlusion site(s) | A1/A2/A3, M2/M3, P1/P2 | A2/A3, P1/P2, M2/M3 | P1/P2 | P2/P3 | M2 | M2 | |
| NOS, total (S, C, E) | 8 (3,2,3) | 9 (4,2,3) | 9 (4,2,3) | 8 (4,2,2) | 7 (3,1,3) | 9 (4,2,3) | |
| SR/PC | |||||||
| No. treated (%) @ | 92 (7.22) | 41 (3.22) | 16 (1.26) | 100 (7.85) | 62 (4.87) | 372 (29.20) | |
| Pri Treatment | SR | SR | SR | SR | SR | SR | |
| Device(s) used | 3 mm TREVO | – | Solitaire AB/FR, TrevoProVue/XP, 0.04 inch microguidewire, 0.021 inch microcatheter | – | – | – | |
| Use of IVT (%) | 36 (39.13) | – | 7 (43.75) | 41 (41.00) | – | 69 (51.88) | |
| Use of GA (%) | – | – | – | 37 (37.8) | – | – | |
| Age, yrs^ | 66 (55–74) | – | 76.5 (65.5–82) | 74.5 (62–82) | – | SR: 71.73 ± 15.16; PC: 71.11 ± 14.56 | |
| NIHSS^ | 16 (11–23) | – | 10.5 (6–17) | 7 (4–10) | – | – | |
| ASPECTS^ | 9 (7–10) | – | 7 (6.75–9.0) | 9 (9–10) | – | – | |
| Time to groin, min^ | 474 (222–726) | – | 98 (66.5–123.25) | 200 (151–256) | – | SR: 195.5 (150–283.5); PC: 262 (180–453) | |
| No. of passes^ | 1 (1–2) | – | – | 1.5 (1–2) | – | 1.7 ± 1.0 | |
| Procedure time, min^ | – | – | 38.5 (31.5–57.25) | 38.5 (22–64.5) | 45 | – | |
| Study | Alawieh et al. 14 | Atchaneeyasakul et al. 10 | Baig et al. 15 | Bernsen et al. 11 | Brehm et al. 12 | de Castro Afonso et al. 16 | Gory et al. 7 |
| Aspiration only | |||||||
| No. treated (%) @ | 32 (5.27) | 77 (12.69) | 9 (1.48) | 144 (23.72) | 10 (1.65) | 5 (8.24) | 48 (7.91) |
| Pri Treatment | Aspiration | Aspiration | Aspiration | Aspiration | Aspiration | Aspiration | Aspiration |
| Device(s) used | – | Penumbra 4MAX, Penumbra 5MAX, DAC, Navien, etc. | – | – | GC: 8F Mach1, 8F Vista Brite Tip, NeuronMAX 088; AC: SOFIA 6F, SOFIA plus, SOFIA 5F, CATALYST 6, 5MAX ACE, ACE 68, 5MAX, 4 MAX, CATALYST 5, ACE 64 | ACE64, 3MAX | ACE64, ACE60, ACE68, 3MAX, 4MAX, 5MAX, SOFIA, ARC 6F |
| Use of IVT (%) | 10 (31.25) | 28 (36.36) | 4 (44.44) | – | – | 3 (60.00) | 31 (64.58) |
| Use of GA (%) | – | – | – | – | – | – | 5 (10.4) |
| Age, yrs^ | 66 ± 15 | 67.7 ± 13.4 | 69 (68–82) | – | – | – | 69.3 ± 14.9 |
| NIHSS^ | 9 ± 5 | 17 (12–20) | 8 (7–17) | – | – | 16 (9–18) | 13.2 ± 6.1 |
| ASPECTS^ | –,* | 9 (7–10) | – | – | – | 9 (8–10) | 8 (6–9) |
| Time to groin, min^ | 441 ± 318 | 276.5 (173.75–425) | 236 (181.25–482.25) | 235 (197–300) # | – | – | 240 (161–270) |
| No. of passes^ | 2.6 ± 1.7 | – | 2 (1–2) | – | – | – | 2 (1–4) |
| Procedure time, min^ | 42 ± 34 | – | – | 48 (35–70) | – | 45 (43–74) | 41 (25–57) |
| Study | Haussen et al. 17 | Hulscher et al. 18 | Kim et al. 20 | Meyer et al. 19 | Mokin et al. 21 | Renieri et al. 13 | |
| Aspiration only | |||||||
| No. treated (%) @ | 52 (8.57) | 20 (3.29) | 25 (4.12) | 41 (6.75) | 51 (8.40) | 93 (15.32) | |
| Pri Treatment | Aspiration | Aspiration | Aspiration | Aspiration | Aspiration | Aspiration | |
| Device(s) used | 3MAX | – | Penumbra 041/4Max, 0.014 inch microguidewire (Synchro-14/Traxcess 14), 0.021 inch microcatheter (Prowler Select Plus) | – | – | – | |
| Use of IVT (%) | 24 (46.15) | – | 13 (52.00) | 15 (36.6) | – | 42 (45.16) | |
| Use of GA (%) | – | – | – | 23 (56.1) | – | – | |
| Age, yrs^ | 65 (49–75) | – | 71 (60.5–75) | 75 (59.5–80) | – | 72.07 ± 12.34 | |
| NIHSS^ | 18 (12–21) | – | 15 (8–17) | 6 (3–11.5) | – | – | |
| ASPECTS^ | 8 (7–9) | – | 8 (7.5–9) | 10 (9–10) | – | – | |
| Time to groin, min^ | 282 (198–684) | – | 99 (82.5–120.5) | 190 (140–362.5) | – | 262 (194–385) | |
| No. of passes^ | – | – | – | 1 (1–2) | – | 1.3 ± 0.6 | |
| Procedure time, min^ | – | – | 53 (41–74) | 35 (24–50) | 40 | – | |
ASPECTS: Alberta stroke program early CT score; DMVO: distal medium vessel occlusion; ENT: emboli to new territory; EST: emboli to same territory; GA: general anaesthesia; GC: guide catheter; IQR: interquartile range; IVT: intravenous thrombolysis; NIHSS: National Institutes of Health Stroke Scale; NOS: Newcastle–Ottawa Scale; PC: primary combined; S,C,E: selection, comparability and exposure domains of the NOS; RCT: randomised controlled trial; SD: standard deviation; SR: stent retriever; USA: United States of America.
In terms of type of occlusion, Haussen et al. 17 reported 75 patients (52.1%) with primary DMVO, 10 patients (6.94%) with emboli to new territory, 60 patients (41.7%) with emboli to same territory.
The no treated are each presented as a percentage of the total meta-analysis for that arm of the meta-analysis. All other percentages represent the original study population.
^Figures are either mean ± SD or median (IQR).
Alawieh et al. 14 reported 63 patients (98%) in the SR/Combined arm with ASPECTS>6, and 29 (91%) in the Aspiration arm with ASPECTS>6.
Bernsen et al. 11 reported as time from onset to reperfusion/last contrast bolus.
The pooled sample comprised 50.84% (602 of 1184) males. Most studies reported vascular risk factors, including hypertension (70.51%, 507 of 719), dyslipidaemia (34.57%, 215 of 622), diabetes mellitus (26.43%, 190 of 719), coronary artery disease (17.73%, 25 of 141), atrial fibrillation (36.09%, 231 of 640), as well as prior histories of stroke (15.0%, 18 of 120) and smoking (24.91%, 142 of 570).
Overall, the SR/PC thrombectomy group included 1274 patients (67.73%), while 607 patients (32.27%) were treated with AC only. The SR only group included 462 patients (24.56%). Good recanalisation was achieved in 964 of 1233 patients (78.18%) in the SR/PC group, and 444 of 585 patients (75.90%) in the AC only group. Pooled patient characteristics are shown in Table 2, and individual study patient characteristics are shown in Supplemental Table S3.
Table 2.
Pooled clinical characteristics of available data from included studies.
| Study arm | Male (%) | HTN (%) | DYS (%) | DM (%) | Prior stroke (%) | IHD/CAD (%) | AF (%) | Smoker (%) | mTICI/eTICI 2b-3 a (%) |
|---|---|---|---|---|---|---|---|---|---|
| SR/combined | 401/807 (49.69) | 317/435 (72.87) | 123/370 (33.24) | 116/435 (26.67) | 6/47 (12.77) | 10/59 (16.95) | 145/404 (35.89) | 101/413 (24.46) | 964/1233 (78.18) |
| Aspiration | 201/377 (53.32) | 190/284 (66.90) | 92/252 (36.51) | 74/284 (26.06) | 12/73 (16.44) | 15/82 (18.29) | 86/236 (36.44) | 41/157 (26.11) | 444/585 (75.90) |
| Overall | 602/1184 (50.84) | 507/719 (70.51) | 215/622 (34.57) | 190/719 (26.43) | 18/120 (15.00) | 25/141 (17.73) | 231/640 (36.09) | 142/570 (24.91) | 1408/1818 (77.45) |
AF: atrial fibrillation; CAD: coronary artery disease; DM: diabetes mellitus; DYS: dyslipidaemia; eTICI: expanded Treatment in Cerebral Ischemia score; HTN: hypertension; IHD: ischemic heart disease; mTICI: Modified Treatment in Cerebral Ischemia score; SR: stent retriever.
Technical outcomes
In total, 12 studies were included in the analysis of successful recanalization comprising 1818 patients. Successful recanalisation was achieved in 78.18% (964 of 1233) of patients treated with SR/PC, and in 75.90% (444 of 585) of patients treated with AC only. Successful recanalization was similar between the two groups, with substantial heterogeneity (OR 1.33, 95% CI 0.86–2.08, p = 0.2019, I 2 = 63%, Figure 2). Visual inspection of a funnel plot of the technical outcomes revealed a low likelihood of publication bias (Data Supplement, Figure S1).
Figure 2.
Forest plots comparing efficacy outcomes of SR/PC versus AC in terms of: (a) successful recanalisation (mTICI 2b-3/eTICI 2b-3); (b) excellent recanalisation (mTICI 2c-3/eTICI 2c-3); (c) functional independence (mRS 0–2 at 90 days); safety outcomes of SR/PC versus AC in terms of: (d) sICH incidence; (e) mortality at 90 days.
AC: aspiration catheter; SR: stent retriever; PC: primary combined; mTICI: modified Thrombolysis in Cerebral Infarction scale; eTICI: expanded Thrombolysis in Cerebral Infarction scale; mRS: modified Rankin Scale; sICH: symptomatic intracranial haemorrhage; OR: odds ratio; CI: confidence interval.
In total, six studies were included in the analysis of excellent recanalisation comprising 759 patients. Excellent recanalisation was achieved in 50.20% (252 of 502) of patients treated with SR/PC, and in 53.31% (137 of 257) of patients treated with AC only. Excellent recanalisation was similar between the two groups, with no heterogeneity (OR 0.85, 95% CI 0.62–1.17, p = 0.3140, I 2 = 0%, Figure 2).
In total, two studies presented data on FPE comprising 220 patients. FPE was achieved in 42.75% (56 of 131) of patients treated with SR/PC, and in 48.31% (43 of 89) of patients treated with AC only.
Functional outcomes
In total, nine studies were included in the analysis of functional outcomes comprising 1486 patients. Functional independence was achieved in 54.01% of patients treated with SR/PC (546 of 1011) and in 47.79% of patients treated with AC only (227 of 475). Patients treated with SR/PC had higher odds of achieving functional independence, with no heterogeneity (OR 1.33, 95% CI 1.06–1.67, p = 0.0155, I 2 = 0%, Figure 2).
Safety outcomes
In total, eight studies were included in the analysis of sICH between the two treatment arms comprising 1051 patients. The incidence of sICH was 5.06% of patients treated with SR/PC (35 of 692) and 9.19% of patients treated with AC only (33 of 359). There was no significant difference in the odds of sICH between SR/PC and AC only, with moderate heterogeneity (OR 0.49, 95% CI 0.23–1.02, p = 0.058, I 2 = 13%, Figure 2).
In total, eight studies were included in the analysis of 90-day mortality between the two treatment arms comprising 1152 patients. The incidence of mortality was 17.73% in patients treated with SR/PC (128 of 722) and 21.63% in patients treated with AC only (93 of 430). Patients treated with SR/PC, compared to AC, had lower odds of mortality, with low heterogeneity (OR 0.69, 95% CI 0.50–0.94, p = 0.0191, I 2 = 8%, Figure 2).
Subgroup analysis comparing purely SR against purely AC techniques
In total, of the 13 included studies, 9 studies reported data for patients treated with SR only and AC only. A subgroup analysis was performed on these 9 studies to investigate the outcomes of patients treated with SR only and patients treated with AC only, without stratification for occlusion site.
In terms of technical outcomes, patients treated with SR only had higher odds of achieving successful recanalisation as compared to patients treated with AC only, with no heterogeneity (OR 1.80, 95% CI 1.17–2.78, p = 0.0075, I 2 = 0%, Figure 3(a)).
Figure 3.
Forest plots comparing (a) SR only versus AC only in terms of successful recanalisation (mTICI 2b-3/eTICI 2b-3); (b) SR/PC versus AC, stratified by occlusion site, in terms of functional independence (mRS 0–2 at 90 days); (c) SR/PC versus AC, stratified by occlusion site, in terms of sICH incidence; SR/PC versus AC, for cohort studies only, in terms of (d) functional independence (mRS 0–2) at 90 days) and (e) mortality at 90 days.
AC: aspiration catheter; SR: stent retriever; PC: primary combined; mTICI: modified Thrombolysis in Cerebral Infarction scale; eTICI: expanded Thrombolysis in Cerebral Infarction scale; mRS: modified Rankin Scale; sICH: symptomatic intracranial haemorrhage; OR: odds ratio; CI: confidence interval.
No significant difference was noted in the odds of functional independence in patients treated with SR only as compared to patients treated with AC only (Supplemental Figure S2). In terms of safety outcomes, no significant difference was noted in the odds of sICH incidence and incidence of mortality between patients treated with SR only as compared to patients treated with AC only (Supplemental Figure S2).
Subgroup analysis of M2 occlusions and other DMVOs
In total, of the 13 included studies, 8 studies reported data for patients with only M2 occlusions. A subgroup analysis was performed on these 8 studies to investigate the outcomes of patients with M2 occlusions who were treated with SR/PC and patients who were treated with AC only.
In terms of functional outcomes, patients with M2 occlusions who were treated with SR/PC had higher odds of achieving functional independence as compared to patients treated with AC only, with no heterogeneity (OR 1.39, 95% CI 1.09–1.78, p = 0.0074, I 2 = 0%, Figure 3(b)).
No significant difference was noted in the odds of successful recanalisation between patients with M2 occlusions treated with SR/PC and patients treated with AC only (Supplemental Figure S3).
In terms of safety outcomes, a lower odds of sICH was observed in patients with M2 occlusions who were treated with SR/PC as compared to patients treated with AC only, with low heterogeneity (OR 0.36, 95% CI 0.16–0.85, p = 0.0190, I 2 = 2%, Figure 3(c)). No significant difference was noted in the odds of 90-day mortality incidence between the two treatment arms in patients with M2 occlusions (Supplemental Figure S3).
In total, of the 13 included studies, 3 studies reported data for patients with other DMVOs excluding M2 occlusions. A subgroup analysis was performed on these three studies investigating outcomes of patients with other DMVOs besides M2 occlusions who were treated with SR/PC and AC only. No significant difference was noted in the odds of successful recanalisation or sICH incidence between patients with other DMVOs excluding M2 occlusions treated with SR/PC and AC only (Supplemental Figure S4).
Subgroup analysis of only cohort studies
In total, of the 13 included studies, 12 were cohort studies. A subgroup analysis was performed on these 12 studies to account for differing weights of the studies in the meta-analysis, due to the lower risk of bias in RCTs.
In total, 11 cohort studies were included in the analysis of successful recanalization comprising 1739 patients. Successful recanalization was achieved in 78.03% (938 of 1202) of patients treated with SR/PC, and in 74.67% (401 of 537) of patients treated with AC only. Successful recanalization was similar between the two groups, with substantial heterogeneity (OR 1.42, 95% CI 0.89–2.24, p = 0.140, I 2 = 65%, Supplemental Figure S5). In this analysis, the heterogeneity increased from 63% in the main analysis to 65%, with no statistical significance.
In total, eight studies were included in the analysis of functional outcomes comprising 1410 patients. Functional independence was achieved in 54.13% of patients treated with SR/PC (531 of 981) and in 47.09% of patients treated with AC only (202 of 429). Patients treated with SR/PC had higher odds of achieving functional independence, with no heterogeneity (OR 1.37, 95% CI 1.08–1.73, p = 0.0095, I 2 = 0%, Figure 3). In this analysis, the heterogeneity remained the same at 0% compared to the main analysis, and the odds of achieving functional independence remained statistically significant with similar effect size.
In total, seven cohort studies were included in the analysis of sICH between the two treatment arms comprising 989 patients. The incidence of sICH was 5.14% of patients treated with SR/PC (34 of 661) and 9.15% of patients treated with AC only (30 of 328). There was no significant difference in the odds of sICH between SR/PC and AC only, with moderate heterogeneity (OR 0.51, 95% CI 0.22–1.17, p = 0.1129, I 2 = 23%, Supplemental Figure S5). In this analysis, the heterogeneity increased from 13% in the main analysis including the RCT, to 23%. The odds of sICH between SR/PC and AC only, however, remained statistically insignificant.
In total, seven cohort studies were included in the analysis of 90-day mortality between the two treatment arms comprising 1076 patients. The incidence of mortality was 18.35% in patients treated with SR/PC (127 of 692) and 21.88% in patients treated with AC only (84 of 384). Patients treated with SR/PC, compared to AC, had lower odds of mortality, with no heterogeneity (OR 0.71, 95% CI 0.52–0.98, p = 0.0359, I 2 = 0%, Figure 3). In this analysis, the heterogeneity decreased from 8% in the main analysis including the RCT, to 0%, but the odds of mortality remained statistically significant with similar effect size.
Discussion
In our pair-wise systematic review and meta-analysis of 1881 patients, we observed that the use of an SR in the EVT method is associated with higher successful recanalisation rates, improved functional outcomes and a better safety profile, as compared to only AC. These findings were consistent for the subgroup of M2 occlusions. In our analysis, the majority of pooled studies showed low heterogeneity and low likelihood of publication bias. Furthermore, studies included in the analysis were of high quality as assessed by the Cochrane RoB 2 tool for randomised controlled trials and the NOS for cohort studies.
Recent RCTs in PLVO suggest that SR and AC are non-inferior to one another.22,23 However, our study suggests that in AIS-DMVO, SR use in combination with an AC may result in better outcomes than AC alone. This may be attributed to the use of newer EVT devices such as the third-generation stent retrievers like the EmboTrap reperfusion device (Neuravi/Cerenovus) or the manually deployable Tigertriever 13 device (Rapid Medical, Yoqneam, Israel). 24 Several of the included studies7,12 employed the use of these newer, more advanced devices, which may account for the observed superiority of techniques employing SR as opposed to AC only in terms of recanalisation and functional outcomes.
Distal medium vessels tend to be more tortuous, smaller in calibre and have thinner walls, and are hence more prone to vessel injury. 1 In animal studies, the use of SR devices has been found to cause more damage to the endothelium compared to ACs,25–27 largely due to the continuous outward radial force 28 exerted by the device. A post-hoc analysis of the STRATIS registry also identified a higher risk of post-thrombectomy SAH with more distal occlusions. 29 Interestingly, our study found that SR use was associated with significantly lower incidence of sICH in patients with M2 occlusions, as compared to patients treated with AC only, though this association did not extend to patients with occlusions of other DMVO locations. This may be because the M2 branch of the MCA possesses a highly heterogeneous angioarchitecture, and an M2 MCA occlusion may occur in dominant segments similar to an M1 branch in size, or in nondominant segments similar to an M3 branch in size. 30 This large variation in M2 calibre may therefore account for the improved safety outcomes when limited to M2 patients only, especially if there is a bias towards treating larger M2 vessels with bigger neurological deficits.
There is evidence that AC is a fast, efficient and safe approach to EVT, 31 demonstrated to have a faster puncture-to-recanalisation time coupled with a lower cost as compared to SR. 32 However, our study found that the use of SR had a better safety profile than AC only in AIS-DMVO, with the SR/PC group reporting lower 90-day mortality than the AC only patients. Combined SR and AC techniques have the potential to reduce vascular injury in more distal vessels as they redirect the ‘line-of-force’ when withdrawing the stent retriever, potentially reducing avulsion injuries to the surrounding perforator vessels.14,33 In addition, the flexibility of concomitant ACs eliminates the challenge of navigating the stiffer stent retrievers through more tortuous vasculature. 34 AC use is also potentially associated with a risk of emboli breaking off distally during catheter withdrawal, therefore requiring bail-out techniques and possibly causing emboli to distal or new territories. This risk has been demonstrated in an in vitro model 35 to be significantly higher as compared to SR thrombectomy.
Overall, our study has demonstrated the relative efficacy and safety of SR as compared to AC use in AIS-DMVO patients. With judicious patient selection and use of newer, more advanced SR devices more suited for distal vasculature, there is promise for improved efficacy and safety outcomes in EVT for AIS-DMVO. However, given that our data was mostly limited to observational studies, further trials should be performed to better establish the relative efficacy and safety of a combined SR/PC technique compared to AC only in AIS-DMVO.
Study limitations
The findings of this meta-analysis should be interpreted with consideration of the study’s limitations. First, most of the included studies were observational studies and therefore prone to selection and reporting bias. Second, more than half of the included studies involved only patients with M2 occlusions, and thus DMVOs of other vessels may be under-represented. Furthermore, as the M2 vascular bed angioarchitecture has high heterogeneity, M2 occlusions present as a wide clinical spectrum based on the type and site of branch occluded, length of clot and collateral status. 16 The data were not presented and thus could not be accounted for. Therefore, the ability to generalise efficacy and safety outcomes of the EVT techniques for M2 occlusions may be limited, and more detailed studies regarding this subgroup of DMVOs are warranted. Third, reports of AC performed for DMVOs distal to M2 occlusions are very rare, as interventionalists opt for SR use over AC in these patients owing to commonly available ACs being too large for these distal vessels, 36 which may explain the relatively smaller number of AC patients in the pooled sample of this meta-analysis. Fourth, SR and AC techniques face different technical difficulties, as distal occlusions or small branches cannot be easily reached with an AC. Thus, the choice of the technique employed is always biased by the anatomical considerations and occlusion site in the angiographic imaging findings as assessed by the neurointerventionist. Lastly, our meta-analysis was based on the first-line EVT method employed. However, the methodology of most of the included studies employed the use of a rescue manoeuvre in event of primary technique failure. This may have skewed the analysis of the efficacy and safety outcomes, which were based on post-hoc data after the entire thrombectomy procedure, inclusive of rescue if performed. While we also sought to meta-analyse the FPE and successful recanalisation after the primary first pass, this was not performed as only two studies presented this data.
Conclusion
There is promise for SR use for AIS-DMVO, with a suggestion of benefit with the usage of SR/PC methodology in AIS-DMVO as compared to AC only, possibly improving the efficacy and safety of EVT in AIS-DMVO patients. Further trials are necessary to evaluate the efficacy and safety profile for specific EVT methods in AIS-DMVO patients.
Supplemental Material
Supplemental material, sj-docx-1-eso-10.1177_23969873231151262 for Distal medium vessel occlusions in acute ischaemic stroke – Stent retriever versus direct aspiration: A systematic review and meta-analysis by Keith Zhi Xian Toh, Ming Yi Koh, Enver De Wei Loh, Gabriel Yi Ren Kwok, Yao Hao Teo, Yao Neng Teo, Claire Xin Yi Goh, Nicholas Li Xun Syn, Andrew Fu Wah Ho, Ching-Hui Sia, Patrick A Brouwer, Tommy Andersson, Lukas Meyer, Jens Fiehler, Pervinder Bhogal, Vijay K Sharma, Benjamin YQ Tan and Leonard L L Yeo in European Stroke Journal
Supplemental material, sj-docx-2-eso-10.1177_23969873231151262 for Distal medium vessel occlusions in acute ischaemic stroke – Stent retriever versus direct aspiration: A systematic review and meta-analysis by Keith Zhi Xian Toh, Ming Yi Koh, Enver De Wei Loh, Gabriel Yi Ren Kwok, Yao Hao Teo, Yao Neng Teo, Claire Xin Yi Goh, Nicholas Li Xun Syn, Andrew Fu Wah Ho, Ching-Hui Sia, Patrick A Brouwer, Tommy Andersson, Lukas Meyer, Jens Fiehler, Pervinder Bhogal, Vijay K Sharma, Benjamin YQ Tan and Leonard L L Yeo in European Stroke Journal
Supplemental material, sj-docx-3-eso-10.1177_23969873231151262 for Distal medium vessel occlusions in acute ischaemic stroke – Stent retriever versus direct aspiration: A systematic review and meta-analysis by Keith Zhi Xian Toh, Ming Yi Koh, Enver De Wei Loh, Gabriel Yi Ren Kwok, Yao Hao Teo, Yao Neng Teo, Claire Xin Yi Goh, Nicholas Li Xun Syn, Andrew Fu Wah Ho, Ching-Hui Sia, Patrick A Brouwer, Tommy Andersson, Lukas Meyer, Jens Fiehler, Pervinder Bhogal, Vijay K Sharma, Benjamin YQ Tan and Leonard L L Yeo in European Stroke Journal
Acknowledgments
We have no acknowledgments to disclose.
Footnotes
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Patrick A Brouwer is the Head of Medical Affairs, CERENOVUS.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Benjamin YQ Tan was supported by the MOH Healthcare Research Scholarship, National Medical Research Council, Singapore and the ExxonMobil-NUS Research Fellowship for Clinicians.
Leonard LL Yeo was supported by the National Medical Research Council, Singapore (NMRC/MOH-TA91Nov-0003).
Informed consent: No informed consent is required given the nature of the study as a systematic review and meta-analysis.
Ethical approval: No ethical approval is required given the nature of the study as a systematic review and meta-analysis.
Guarantor: LLLY
Contributorship: KZXT, MYK, EDWL, GYRK, YHT, YNT, CXYG and NLXS contributed to data collection, data curation and data analysis. KZXT, MYK, EDWL and GYRK contributed to writing original draft. AFWH, CHS, PAB, TA, LM, JF, PB, VKS, BYQT and LLLY contributed to study conceptualisation, editing manuscript and supervision of study.
ORCID iDs: Keith Zhi Xian Toh 
https://orcid.org/0000-0002-7609-3632
Gabriel Yi Ren Kwok https://orcid.org/0000-0001-6849-6098
Data availability statement: The data that support the findings of this study are available within the article. These data were derived from resources available in the public domain and have been referenced.
Supplemental material: Supplemental material for this article is available online.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material, sj-docx-1-eso-10.1177_23969873231151262 for Distal medium vessel occlusions in acute ischaemic stroke – Stent retriever versus direct aspiration: A systematic review and meta-analysis by Keith Zhi Xian Toh, Ming Yi Koh, Enver De Wei Loh, Gabriel Yi Ren Kwok, Yao Hao Teo, Yao Neng Teo, Claire Xin Yi Goh, Nicholas Li Xun Syn, Andrew Fu Wah Ho, Ching-Hui Sia, Patrick A Brouwer, Tommy Andersson, Lukas Meyer, Jens Fiehler, Pervinder Bhogal, Vijay K Sharma, Benjamin YQ Tan and Leonard L L Yeo in European Stroke Journal
Supplemental material, sj-docx-2-eso-10.1177_23969873231151262 for Distal medium vessel occlusions in acute ischaemic stroke – Stent retriever versus direct aspiration: A systematic review and meta-analysis by Keith Zhi Xian Toh, Ming Yi Koh, Enver De Wei Loh, Gabriel Yi Ren Kwok, Yao Hao Teo, Yao Neng Teo, Claire Xin Yi Goh, Nicholas Li Xun Syn, Andrew Fu Wah Ho, Ching-Hui Sia, Patrick A Brouwer, Tommy Andersson, Lukas Meyer, Jens Fiehler, Pervinder Bhogal, Vijay K Sharma, Benjamin YQ Tan and Leonard L L Yeo in European Stroke Journal
Supplemental material, sj-docx-3-eso-10.1177_23969873231151262 for Distal medium vessel occlusions in acute ischaemic stroke – Stent retriever versus direct aspiration: A systematic review and meta-analysis by Keith Zhi Xian Toh, Ming Yi Koh, Enver De Wei Loh, Gabriel Yi Ren Kwok, Yao Hao Teo, Yao Neng Teo, Claire Xin Yi Goh, Nicholas Li Xun Syn, Andrew Fu Wah Ho, Ching-Hui Sia, Patrick A Brouwer, Tommy Andersson, Lukas Meyer, Jens Fiehler, Pervinder Bhogal, Vijay K Sharma, Benjamin YQ Tan and Leonard L L Yeo in European Stroke Journal