Abstract
Background:
There is growing evidence suggesting efficacy of endovascular therapy for M2 occlusions of the middle cerebral artery. More than one recanalization attempt is often required to achieve successful reperfusion in M2 occlusions, associated with general concerns about the safety of multiple maneuvers in these medium vessel occlusions.
Aim:
The aim of this study was to investigate the association between the number of recanalization attempts and functional outcomes in M2 occlusions in comparison with large vessel occlusions (LVO).
Methods:
Retrospective multicenter cohort study of patients who underwent endovascular therapy for primary M2 occlusions. Patients were enrolled in the German Stroke Registry at 1 of 25 comprehensive stroke centers between 2015 and 2021. The study cohort was subdivided into patients with unsuccessful reperfusion (mTICI 0–2a) and successful reperfusion (mTICI 2b–3) at first, second, third, fourth, or ⩾fifth recanalization attempt. Primary outcome was 90-day functional independence defined as modified Rankin Scale score of 0–2. Safety outcome was the occurrence of symptomatic intracranial hemorrhage. Internal carotid artery or M1 occlusions were defined as LVO and served as comparison group.
Results:
A total of 1078 patients with M2 occlusion were included. Successful reperfusion was observed in 87.1% and 90-day functional independence in 51.9%. The rate of functional independence decreased gradually with increasing number of recanalization attempts (p < 0.001). In both M2 occlusions and LVO, successful reperfusion within three attempts was associated with greater odds of functional independence, while success at ⩾fourth attempt was not. Patients with ⩾4 attempts exhibited higher rates of symptomatic intracranial hemorrhage in M2 occlusions (6.5% vs 2.7%, p = 0.02) and LVO (7.2% vs 3.5%, p < 0.001).
Conclusion:
This study suggests a clinical benefit of successful reperfusion within three recanalization attempts in endovascular therapy for M2 occlusions, which was similar in LVO. Our findings reduce concerns about the risk–benefit ratio of multiple attempts in M2 medium vessel occlusions.
Data access statement:
The data that support the findings of this study are available on reasonable request after approval of the German Stroke Registry (GSR) steering committee.
Clinical Trial Registration Information:
ClinicalTrials.gov Identifier: NCT03356392
Keywords: Cerebral infarction, infarction, ischemic stroke, stroke, thrombectomy
Introduction
Landmark thrombectomy trials have demonstrated that endovascular therapy is more effective in reducing long-term disability than best medical treatment alone in patients with ischemic stroke due to anterior circulation large vessel occlusion (LVO). 1 Importantly, these trials primarily investigated occlusions of the internal carotid artery (ICA) or of the M1 segment of the middle cerebral artery. Patients with M2 segment occlusions, commonly considered as medium vessel occlusions (MeVO),2–4 were either excluded or underrepresented in these studies. The HERMES collaboration and other meta-analyses strongly suggest, but lack study design and statistical power to finally confirm efficacy and safety of endovascular therapy for both proximal and distal M2 occlusions.5,6 While awaiting supporting data from pending trials, such as DISTAL and ESCAPE-MeVO, 7 retrospective studies might identify prognostic factors, aiming to improve outcome prediction and treatment decision-making in patients with M2 occlusion.
Prior studies introduced the “first-pass effect,” indicating complete reperfusion at first thrombectomy attempt as a significant predictor of long-term functional independence.8,9 However, successful mechanical reperfusion often requires more than one retrieval maneuver. Beyond the first pass, it has been demonstrated that the number of recanalization attempts is associated with periprocedural safety measures, and, ultimately, with functional outcomes.10–14 More specifically, successful mechanical reperfusion within three recanalization attempts was associated with superior clinical outcomes by several studies, which were mostly including patients with LVO.11,12 The question remains whether these cut-off points explicitly apply for M2 MeVO with smaller-diameter arteries and increased vessel tortuosity compared with LVO.
This study sought to provide an in-depth comparison of the number of recanalization attempts and its prognostic value in anterior circulation MeVO and LVO. We hypothesized that multiple recanalization attempts diminish the clinical benefit of successful reperfusion and might harm patients with M2 occlusion at a certain threshold.
Materials and methods
Study design and participating centers
We conducted a retrospective multicenter cohort study to investigate the association between the number of recanalization attempts and clinical outcomes in endovascular therapy for M2 middle cerebral artery occlusions. Eligibility was assessed in patients who were enrolled in the German Stroke Registry—Endovascular Treatment (GSR) between May 1, 2015 and December 31, 2021. The GSR is an ongoing, prospective, open-label, multicenter registry including patients who underwent endovascular therapy at 1 of 25 comprehensive stroke centers in Germany (ClinicalTrials.gov identifier: NCT03356392). 15 The GSR was approved by the responsible ethics committee of the Ludwig Maximilian University, Munich, Germany (689-15). The local ethics committee of each participating center gave approval to contribute fully anonymized data to the GSR. Informed consent for this study was waived after review of the central ethics committee. This study was reported using the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) reporting guideline. 16
Study cohort
Inclusion criteria were defined as follows: (1) prestroke modified Rankin Scale (mRS) score of 0–2; (2) acute ischemic stroke in the anterior circulation due to primary and isolated occlusion of the M2 segment of the middle cerebral artery, defined as anterior circulation MeVO; (3) small-to-moderate baseline infarction, defined as an Alberta Stroke Program Early CT Score (ASPECTS) of 6–10; (4) treatment with endovascular therapy; (5) available data on the admission National Institutes of Health Stroke Scale (NIHSS) score; final modified Thrombolysis in Cerebral Infarction (mTICI) grade, number of recanalization attempts, and mRS score at 90 days. Exclusion criteria were defined as follows: (1) multiple vascular occlusion sites in the anterior and posterior circulation and (2) concomitant stenting therapy. Patients with isolated occlusion of the intracranial ICA or of the proximal M1 segment of the middle cerebral artery were defined as LVO and served as comparison group. Supplemental Figure S1 provides a detailed flowchart of the inclusion and exclusion criteria.
Clinical and radiologic assessment
Patient characteristics, radiologic findings, and clinical outcomes were retrieved from the GSR database. Baseline imaging (computed tomography in 95.6% and magnetic resonance imaging in 7.2% of patients), digital subtraction angiograms, and follow-up imaging were assessed by local investigators at the respective participating center. Middle cerebral artery occlusions were subclassified into proximal M1, distal M1, and M2 occlusions by the local investigator. The number of recanalization attempts included both maneuvers with stent-retriever devices and maneuvers with aspiration catheters. A final mTICI grade of 0, 1, or 2a was defined as unsuccessful reperfusion and a final mTICI grade of 2b or 3 as successful reperfusion. 17 Symptomatic intracranial hemorrhage (sICH) was defined as any intracranial hemorrhage on follow-up imaging together with a neurological deterioration of ⩾4 points on the NIHSS according to ECASS II. 18 Clinical assessments were conducted at baseline and at 90 days using the NIHSS and the mRS.
Outcomes and safety measures
Primary outcome was functional independence at 90 days defined as mRS score of 0–2 according to previous studies on M2 occlusions.6,19 Safety outcome was the occurrence of sICH within 24 h.
Statistical analysis
Descriptive statistics were used to describe the study cohort subdivided into patients with unsuccessful reperfusion and successful reperfusion at first, second, third, or ⩾fourth recanalization attempt, respectively (Table 1). Categorical variables were reported as counts plus percentages. Continuous variables were reported as median and interquartile range (IQR). Kolmogorov–Smirnov tests were used to test data distributions for normality. Statistical tests between subgroups including post hoc comparisons were conducted using non-parametrical Kruskal–Wallis one-way analysis of variance test for continuous variables and Pearson’s chi-square test for categorical variables (Table 1 and Supplemental Table S1).
Table 1.
Baseline, imaging, and treatment characteristics compared by number of recanalization attempts and reperfusion status in M2 occlusions.
| mTICI 0–2a (n = 139) |
mTICI 2b–3 First attempt (n = 494) |
mTICI 2b–3 Second attempt (n = 224) |
mTICI 2b–3 Third attempt (n = 111) |
mTICI 2b–3 ⩾Fourth attempt (n = 110) |
p † | |
|---|---|---|---|---|---|---|
| Baseline patient characteristics | ||||||
| Age (years) | 76 (68–82) | 77 (68–83) | 75 (67–82) | 76 (68–81) | 73 (62–82) | 0.14 a |
| Sex | 0.72 b | |||||
| Male | 74 (53.2) | 252 (51.0) | 111 (49.6) | 50 (45.0) | 58 (52.7) | |
| Female | 65 (46.8) | 242 (49.0) | 113 (50.4) | 61 (55.0) | 52 (47.3) | |
| Arterial hypertension | 108 (77.7) | 395 (80.1) | 173 (77.2) | 79 (71.2) | 74 (67.3) | 0.15 b |
| Missing | 0 (0) | 1 (0.2) | 0 (0) | 0 (0) | 0 (0) | |
| Atrial fibrillation | 59 (42.4) | 228 (46.2) | 94 (42.2) | 49 (44.1) | 40 (36.4) | 0.70 b |
| Missing | 0 (0) | 1 (0.2) | 1 (0.4) | 0 (0) | 0 (0) | |
| Admission NIHSS score, median (IQR) | 11 (7–16) | 9 (5–14) | 10 (6–14) | 9 (5–15) | 9 (6–14) | 0.21 a |
| Stroke etiology | ||||||
| Cardioembolism | 74 (53.2) | 310 (62.8) | 120 (53.6) | 61 (55.0) | 60 (54.5) | 0.30 b |
| Large-artery atherosclerosis | 26 (18.7) | 59 (11.9) | 37 (16.5) | 18 (16.2) | 18 (16.4) | |
| Other determined etiology | 11 (7.9) | 24 (4.9) | 15 (6.7) | 5 (4.5) | 10 (9.1) | |
| Undetermined etiology | 28 (20.1) | 101 (20.4) | 52 (23.2) | 27 (24.3) | 22 (20.0) | |
| Imaging characteristics | ||||||
| Left occlusion side | 86 (61.9) | 276 (55.9) | 128 (57.1) | 67 (60.4) | 65 (59.1) | 0.72 b |
| Baseline ASPECTS, median (IQR) | 9 (8–10) | 10 (8–10) | 9 (8–10) | 9 (8–10) | 9 (8–10) | 0.02 a |
| Workflow times | ||||||
| Symptom onset or last known well to admission (min), median (IQR) | 198 (77–310) | 135 (66–328) | 150 (70–325) | 165 (68–397) | 150 (71–344) | 0.60 a |
| Missing | 21 (15.1) | 36 (7.3) | 12 (5.4) | 8 (7.2) | 19 (17.3) | |
| Symptom onset or last known well to admission ⩽ 360 min | 96 (81.4) | 352 (76.9) | 164 (77.4) | 74 (71.8) | 69 (75.8) | 0.58 b |
| Missing | 21 (15.1) | 36 (7.3) | 12 (5.4) | 8 (7.2) | 19 (17.3) | |
| Procedure time (min), median (IQR) | 55 (40–77) | 30 (21–44) | 40 (30–53) | 58 (40–81) | 79 (61–106) | <0.001 a |
| Missing | 69 (49.6) | 8 (1.6) | 5 (2.2) | 3 (2.7) | 6 (5.5) | |
| Treatment characteristics | ||||||
| Administration of IVT | 66 (47.5) | 256 (51.8) | 117 (52.2) | 53 (47.7) | 37 (33.6) | 0.01 b |
| General anesthesia | 81 (58.3) | 336 (68.0) | 165 (73.7) | 76 (68.5) | 85 (77.3) | 0.009 b |
| Recanalization attempts, median (IQR) | 2 (1–4) | 1 (1–1) | 2 (2–2) | 3 (3–3) | 5 (4–5) | NA |
| Outcome measures | ||||||
| 90-day mRS score, median (IQR) | 4 (3–6) | 2 (1–4) | 2 (1–4) | 2 (1–5) | 3 (2–6) | <0.001 a |
| 90-day mRS score 0–2 | 34 (24.5) | 302 (61.1) | 132 (58.9) | 57 (51.4) | 35 (31.8) | <0.001 b |
| 90-day mRS score 0–1 | 23 (16.5) | 204 (41.3) | 98 (43.8) | 35 (31.5) | 23 (20.9) | <0.001 b |
| Safety measures | ||||||
| sICH within 24 h | 13 (9.6) | 8 (1.6) | 4 (1.8) | 3 (2.8) | 7 (6.4) | <0.001 b |
| Missing | 3 (2.2) | 2 (0.4) | 1 (0.4) | 3 (2.7) | 1 (0.9) | |
| Death within 90 days | 48 (34.5) | 71 (14.4) | 29 (12.9) | 22 (19.8) | 30 (27.3) | <0.001 b |
Results are reported as n (%) unless otherwise stated.
Characteristics were compared between TICI 0–2a, TICI 2b–3 at first, second, third, and ⩾fourth attempt with the use of either (a) Kruskal–Wallis test for continuous variables or (b) Pearson’s chi-square test for categorical variables.
Abbreviations: mTICI, modified Thrombolysis in cerebral infarction; IQR, interquartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; ASPECTS, Alberta Stroke Program Early CT Score; IVT, intravenous thrombolysis; sICH, symptomatic intracranial hemorrhage.
Logistic regression analysis was used to identify factors associated with functional independence at 90 days (Model A) and sICH (Model B). Unadjusted and adjusted odds ratios (aOR) were reported with 95% confidence intervals (CI). For multivariable regression analysis, independent variables were selected a priori and based on the results of the descriptive statistics (threshold p < 0.05, Table 1). The following independent variables were included in Model A: Age, sex, time from symptom onset or last known well to admission, admission NIHSS, baseline ASPECTS, treatment with intravenous thrombolysis, general anesthesia, successful reperfusion at first, second, third, fourth, or ⩾fifth attempt (treated as factor variable with unsuccessful reperfusion as reference level), procedure time, and occurrence of sICH (Supplemental Table S2). 12 In Model B, backward elimination was used to reduce the number of independent variables and thereby the possibility of overfitting given the small number of patients with sICH (n = 35 cases). Please refer to the final and full Model B in Supplemental Tables S2 and S3 for more detailed information. As sensitivity analyses, we performed regression Model A adjusting for potential differences between participating centers (Supplemental Table S4) and in patients with intracranial ICA or proximal M1 occlusion for comparison between MeVO and LVO (Supplemental Table S5). Complete-case analysis was performed for all regression models. Patients with missing values are specified in Supplemental Figure S1.
A two-tailed p value of less than 0.05 was considered significant for all statistical tests. All analyses were performed using R statistical software (version 4.1.2, R Project for Statistical Computing) and RStudio statistical software (version 2021.09.1 + 372, Rstudio).
Results
Patient characteristics
A total of 13,082 patients were assessed for eligibility. Of those, 1078 patients with M2 occlusion from 22 participating centers met the inclusion criteria (Supplemental Figure S1). Across all patients with M2 occlusion, the median age was 76 years (IQR, 67–82) and 49.4% were female. The median admission NIHSS score was 10 points (IQR, 6–14) and the median baseline ASPECTS was 9 points (IQR, 8–10). Intravenous thrombolysis was administered in 1 out of 2 patients (49.1%). Successful reperfusion was achieved in 87.1% of patients with a median number of 2 recanalization attempts (IQR, 1–3). More than one recanalization attempt was performed in 50.5% of patients. The overall rate of sICH within 24 h was 3.3%. At 3 months after stroke, functional independence was observed in 51.9% and death in 18.6% of patients.
Patient characteristics stratified by number of recanalization attempts
For descriptive statistics, the study cohort was subdivided into patients with unsuccessful reperfusion (mTICI 0–2a) and successful reperfusion (mTICI 2b–3) at first, second, third, or ⩾ fourth attempt, respectively. In M2 occlusions, successful reperfusion was achieved in 45.8% of patients at first attempt, in 20.8% at second attempt, in 10.3% at third attempt, and in 10.2% at ⩾ fourth attempt. Among patients with unsuccessful reperfusion (12.9%), a median number of 2 recanalization attempts (IQR, 1–4) was performed. Baseline patient characteristics were balanced between subgroups. Initial ASPECTS, procedure time, the rate of intravenous thrombolysis, the use of general anesthesia, and final mTICI grade differed between subgroups. Please refer to Table 1 for more detailed information.
Primary outcome
The percentage of functional independence at 90 days was 61.1% when successful reperfusion was achieved at first attempt, decreased gradually with each additional attempt to 31.8% at ⩾fourth attempt, and reached the lowest level at 24.5% in patients with M2 occlusion and unsuccessful reperfusion (Pearson’s chi-square test, p < 0.001; please note Figure 1 and pairwise post hoc comparisons in Supplemental Table S1).
Figure 1.
Association between number of recanalization attempts, successful mechanical reperfusion, and functional outcomes in M2 segment occlusions. (a) Cumulative rates of successful reperfusion (mTICI 2b–3; black line) and functional independence at 90 days (mRS score 0–2; blue line) stratified by the number of recanalization attempts. The cumulative rate of functional independence at 90 days did not increase substantially with four or more attempts. (b) Distribution of mRS scores at 90 days stratified by the number of recanalization attempts to achieve successful reperfusion. The rate of functional independence decreased gradually when successful reperfusion was achieved with an increasing number of recanalization attempts (dotted line) and was the lowest in patients with unsuccessful reperfusion (mTICI 0–2a).
In multivariable regression analysis, older age, higher admission NIHSS, lower baseline ASPECTS, missing treatment with intravenous thrombolysis and the occurrence of sICH were associated with a lower likelihood of functional independence at 90 days (Supplemental Table S2). Compared with unsuccessful reperfusion as reference, successful reperfusion at first attempt (aOR, 3.23 (95% CI, 1.69–6.33); p < 0.001), second attempt (aOR, 2.74 (95% CI, 1.37–5.58); p = 0.005), or third attempt (aOR, 2.20 (95% CI, 1.03–4.80); p = 0.04) increased the odds of achieving 90-day mRS scores of 0–2, whereas successful reperfusion at fourth attempt or ⩾fifth attempt did not show a significant association. Notably, the point estimates of the odds ratios for successful reperfusion at fourth attempt (aOR, 0.88 (95% CI, 0.33–2.30); p = 0.79) and ⩾fifth attempt (aOR, 0.69 (95% CI, 0.26–1.80); p = 0.45) were less than 1, but without reaching statistical significance. Results were comparable after adjusting for potential center effects (Supplemental Table S4). The predicted probabilities of functional independence at 90 days stratified by the number of recanalization attempts required for successful reperfusion are shown in Figure 2(a).
Figure 2.
Predicted probabilities of functional independence at 90 days from multivariable logistic regression analyses. Model-based estimates of averaged marginal probabilities from the multivariable logistic regression models to predict functional independence at 90 days for (a) M2 occlusions and (b) for intracranial ICA/proximal M1 occlusions. A higher number of recanalization attempts required for successful mTICI 2b–3 reperfusion decreased the predicted probability of functional independence at 90 days in both ICA/M1 and M2 occlusions. In both regression models, only successful reperfusion within three attempts was associated with greater odds of achieving functional independence at 90 days compared with unsuccessful mTICI 0–2a reperfusion (indicated by asterisks; see Supplemental Tables S2 and S5). Please note that compared with unsuccessful reperfusion, successful reperfusion at fourth or ⩾fifth attempt showed smaller point estimates in M2 occlusions, but greater point estimates in ICA/M1 occlusions (red dotted line). Results were adjusted for age, sex, admission NIHSS, baseline ASPECTS, treatment with intravenous thrombolysis, general anesthesia, procedure time, and occurrence of sICH. Error bars indicate the 95% CI.
For comparison between anterior circulation MeVO and LVO, we investigated the association between the number of recanalization attempts and functional independence at 90 days in patients with intracranial ICA or proximal M1 occlusion (n = 2721 cases). Only successful reperfusion at first, second, or third attempt increased the odds of achieving 90-day mRS scores of 0–2, with lower predicted probabilities of functional independence compared with M2 occlusions (Figure 2(b) and Supplemental Table S5).
Safety measure
We investigated the safety profiles of multiple recanalization attempts in endovascular therapy for M2 occlusions. Irrespective of the final mTICI grade, the rate of sICH increased gradually with an increasing number of recanalization attempts (Pearson’s chi-square test, p < 0.001; please note pairwise post hoc comparisons in Supplemental Table S1). After dichotomization, the rate of sICH was higher when more than three attempts were performed in M2 occlusions (2.7% vs 6.5%; p = 0.02), which was similar in ICA/M1 occlusions (3.5% vs 7.2%; p < 0.001) (Figure 3). In multivariable regression analysis, unsuccessful reperfusion (aOR, 3.76 (95% CI, 1.29–9.59); p = 0.008) and more than three recanalization attempts (aOR, 3.17 (95% CI, 1.16–7.77); p < 0.02) were independently associated with higher odds of sICH in M2 occlusions (Supplemental Table S2).
Figure 3.
Occurrence of sICH stratified by the number of recanalization attempts. Frequency of sICH stratified by occlusion location and the number of recanalization attempts irrespective of the final mTICI grade. The rates of sICH increased gradually with an increasing number of recanalization attempts and were compared between M2 and ICA/M1 occlusions. Consistently, the rate of sICH was significantly higher in patients with more than three attempts during endovascular therapy in M2 occlusions (2.7% vs 6.5%; p = 0.02) and ICA/M1 occlusions (3.5% vs 7.2%; p < 0.001).
Discussion
This retrospective multicenter cohort study provides an in-depth analysis on the relationship between the number of recanalization attempts and functional outcomes in endovascular therapy for M2 occlusions. Successful reperfusion at first, second, and third attempt was associated with a higher likelihood of achieving mRS scores of 0–2 at 90 days, while success at ⩾ fourth attempt was not. In patients with M2 occlusions, the rate of sICH was significantly higher when more than three attempts were performed. The number of beneficial recanalization attempts and the rates of sICH were comparable between MeVO and LVO. Our findings provide new insights into endovascular therapy for M2 occlusions and emphasize the prognostic value of the number of recanalization attempts in proximal anterior circulation MeVO.
Previous studies demonstrated the inverse association between the number of recanalization attempts and functional outcomes, mostly including patients with LVO.10–12,14 It has been hypothesized that vessel wall injury with endothelial dysfunction,20–22 and clot fragmentation,23,24 might mediate the association between multiple recanalization attempts and poorer functional outcomes. In comparison with LVO, multiple recanalization attempts in MeVO could induce relatively greater vessel wall injury and clot fragmentation due to increased vessel tortuosity25,26 and smaller vessel diameters, ranging from 1.1 to 2.4 mm in the M2 segment. 2 Both of these pathophysiological concepts might lower the cut-off point for beneficial recanalization attempts in anterior circulation MeVO compared with LVO.
This study, however, found a benefit of successful reperfusion at first, second, and third attempt and higher rates of sICH after more than three attempts in M2 occlusions. These cut-off points are in line with previous studies largely including LVO10–12,14 and were validated by our control analysis in patients with intracranial ICA or proximal M1 occlusion. Thus, an interaction effect of the ICA/M1/M2 vessel diameter on the relationship between recanalization attempts and functional outcomes seems to be unlikely. Accordingly, a recent study in middle cerebral artery strokes could not identify the vessel diameter as a significant predictor of functional independence and mortality. 27 The development and use of new techniques and thrombectomy devices tailored to endovascular therapy in smaller arteries might add to the comparable risk–benefit profiles of multiple recanalization attempts in anterior circulation MeVO and LVO.28–30
There has been debate whether the association between recanalization attempts and clinical outcomes is primarily spurious due to confounding variables. 9 Prolonged procedure time, leading to later flow restoration, could represent such a confounder. We adjusted the main findings for the procedure time, which should reduce the risk of bias by this parameter. Finally, the influence of known or unknown confounders on the results cannot be fully excluded. However, despite the potential impact of confounding factors, the number of recanalization attempts remains an easy collectable parameter in endovascular therapy for anterior circulation strokes, which has significant prognostic value for interventionalists and neurologists in daily clinical practice.
The here presented findings raise the question whether endovascular therapy for M2 occlusions should be stopped after three recanalization attempts and persistent vessel occlusion. Successful reperfusion at ⩾ fourth attempt was neither significantly associated with greater nor with lower odds of functional independence at 90 days, but showed point estimates with a tendency toward worse disability scores compared with unsuccessful reperfusion. Importantly, these non-significant point estimates do not justify to always stop endovascular therapy after three attempts. In the authors’ opinion, it is virtually impossible to establish a fixed stopping rule with a maximum number of recanalization attempts during endovascular therapy. Such a fixed stopping rule would require a randomized controlled trial, facing major concerns about balancing of patient characteristics and clinical equipoise. Nevertheless, this study provides added value by highlighting the prognostic value of the number of recanalization attempts in endovascular therapy for M2 occlusions. The number of recanalization attempts might be used to support intraprocedural risk–benefit assessment, to guide postprocedural clinical monitoring and to improve long-term outcome prediction in patients with anterior circulation MeVO.
This study has certain limitations. First, the retrospective and nonrandomized study design might introduce selection bias and reduce the generalizability of the findings. Second, the main inclusion criterion was the presence of primary M2 occlusion. The definition of M2 occlusion, however, was not explicitly specified according to vessel anatomy or diameter in the GSR database, and subsumed several subtypes, including proximal, distal, dominant, and non-dominant M2 occlusions. A further subdivision would be preferable, and at the same time difficult to integrate into the in-depth, stepwise analysis of the number of recanalization attempts in anterior circulation MeVO. The highly heterogenous angioarchitecture of the M2 segment would result in various subtypes, insufficient group sizes, and issues with statistical power. Third, the vascular occlusion site, the number of recanalization attempts, and the final mTICI grade were assessed by local investigators at each study center, which is prone to interrater variability and cluster effects. Fourth, the GSR database did not differentiate between retrieval and aspiration attempts. Previous studies found similar functional outcomes in patients with first-line stent retriever and aspiration technique, for both anterior circulation and posterior circulation MeVO.31,32 In contrast, a recent meta-analysis suggested superior functional outcomes for combined stent retriever and aspiration techniques in MeVO. 33 Fifth, there was no information about the vessel diameter of the occluded vessel, sudden or stepwise reperfusion, reasons for early termination of endovascular therapy, and additional intra-arterial thrombolysis, all of which might influence the main findings. Sixth, the GSR database does not provide detailed information about perfusion imaging, commonly used to identify salvageable parenchyma and to select patients for endovascular therapy. In summary, future studies are warranted to dissect different subtypes of M2 occlusions and the importance of thrombectomy techniques and mismatch profiles in anterior circulation MeVO.
Conclusion
This study provides new insights into endovascular therapy for M2 occlusions, suggesting that its clinical benefit is associated with the number of recanalization attempts required for successful reperfusion. Our results encourage to perform at least three recanalization attempts to seek for successful reperfusion in endovascular therapy for M2 occlusions. These findings are highly comparable with those in LVO, thereby reducing general safety concerns about multiple recanalization attempts in endovascular therapy for proximal anterior circulation MeVO. Upcoming randomized controlled trials will address the efficacy and safety of endovascular therapy for different subtypes of M2 occlusions and, beyond that, for more distal occlusions of the M3/M4 segment.
Supplemental Material
Supplemental material, sj-docx-1-wso-10.1177_17474930231214769 for Prognostic value of recanalization attempts in endovascular therapy for M2 segment middle cerebral artery occlusions by Laurens Winkelmeier, Christian Heitkamp, Tobias D Faizy, Gabriel Broocks, Helge Kniep, Lukas Meyer, Maxim Bester, Caspar Brekenfeld, Maximilian Schell, Uta Hanning, Götz Thomalla, Jens Fiehler and Fabian Flottmann in International Journal of Stroke
Acknowledgments
The authors thank the GSR investigators and the GSR steering committee (Supplemental Table S6).
Footnotes
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.W., C.H., M.B., C.B., and M.S. reported no disclosure. T.D.F. reported grants from the German Research Foundation (DFG; Project No. 411621970). G.B. and L.M. reported receiving compensation as a speaker from Balt and personal fees from Eppdata GmbH outside the submitted work. H.K. reported an ownership stake in Eppdata GmbH and compensation from Eppdata GmbH for consultant services outside the submitted work. U.H. reported receiving personal fees from Eppdata GmbH outside the submitted work. G.T. reported receiving personal fees from Acandis, Alexion, Amarin, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Portola, and Stryker outside the submitted work. J.F. reported compensation from Acandis, Cerenovus, MicroVention, Medtronic, Penumbra, Phenox, Roche, Stryker, Tonbridge, and stock holdings in Eppdata GmbH and Tegus Medical outside the submitted work. F.F. reported receiving personal fees from Eppdata GmbH outside the submitted work.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Data Availability: The data that support the findings of this study are available on reasonable request after approval of the GSR steering committee.
ORCID iDs: Laurens Winkelmeier 
https://orcid.org/0000-0002-9103-5983
Christian Heitkamp
https://orcid.org/0000-0002-8988-0918
Tobias D Faizy
https://orcid.org/0000-0002-1631-2020
Gabriel Broocks
https://orcid.org/0000-0002-7575-9850
Fabian Flottmann
https://orcid.org/0000-0001-8358-8089
Supplemental material: Supplemental material for this article is available online.
References
- 1. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387: 1723–1731. [DOI] [PubMed] [Google Scholar]
- 2. Goyal M, Ospel JM, Menon BK, Hill MD. MeVO: the next frontier? J Neurointerv Surg 2020; 12: 545–547. [DOI] [PubMed] [Google Scholar]
- 3. Goyal M, Kappelhof M, McDonough R, Ospel JM. Secondary medium vessel occlusions. Stroke 2021; 52: 1147–1153. [DOI] [PubMed] [Google Scholar]
- 4. Cimflova P, Kappelhof M, Singh N, et al. Factors influencing thrombectomy decision making for primary medium vessel occlusion stroke. J Neurointerv Surg 2022; 14: 350–355. [DOI] [PubMed] [Google Scholar]
- 5. Sarraj A, Parsons M, Bivard A, et al. Endovascular thrombectomy versus medical management in isolated M2 occlusions: pooled patient-level analysis from the EXTEND-IA trials, INSPIRE, and SELECT studies. Ann Neurol 2022; 91: 629–639. [DOI] [PubMed] [Google Scholar]
- 6. Menon BK, Hill MD, Davalos A, et al. Efficacy of endovascular thrombectomy in patients with M2 segment middle cerebral artery occlusions: meta-analysis of data from the HERMES Collaboration. J Neurointerv Surg 2019; 11: 1065–1069. [DOI] [PubMed] [Google Scholar]
- 7. Fiehler J, Nawka MT, Meyer L. Persistent challenges in endovascular treatment decision-making for acute ischaemic stroke. Curr Opin Neurol 2022; 35: 18–23. [DOI] [PubMed] [Google Scholar]
- 8. Zaidat OO, Castonguay AC, Linfante I, et al. First pass effect: a new measure for stroke thrombectomy devices. Stroke 2018; 49: 660–666. [DOI] [PubMed] [Google Scholar]
- 9. Nikoubashman O, Dekeyzer S, Riabikin A, Keulers A, Reich A, Mpotsaris A, Wiesmann M. True first-pass effect. Stroke 2019; 50: 2140–2146. [DOI] [PubMed] [Google Scholar]
- 10. Bourcier R, Saleme S, Labreuche J, et al. More than three passes of stent retriever is an independent predictor of parenchymal hematoma in acute ischemic stroke. J Neurointerv Surg 2019; 11: 625–629. [DOI] [PubMed] [Google Scholar]
- 11. Bai Y, Pu J, Wang H, et al. Impact of retriever passes on efficacy and safety outcomes of acute ischemic stroke treated with mechanical thrombectomy. Cardiovasc Intervent Radiol 2018; 41: 1909–1916. [DOI] [PubMed] [Google Scholar]
- 12. Flottmann F, Brekenfeld C, Broocks G, et al. Good clinical outcome decreases with number of retrieval attempts in stroke thrombectomy: beyond the first-pass effect. Stroke 2021; 52: 482–490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Winkelmeier L, Faizy TD, Broocks G, et al. Association between recanalization attempts and functional outcome after thrombectomy for large ischemic stroke. Stroke 2023; 54: 2304–2312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Maros ME, Brekenfeld C, Broocks G, et al. Number of retrieval attempts rather than procedure time is associated with risk of symptomatic intracranial hemorrhage. Stroke 2021; 52: 1580–1588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Alegiani AC, Dorn F, Herzberg M, et al. Systematic evaluation of stroke thrombectomy in clinical practice: the German stroke registry endovascular treatment. Int J Stroke 2019; 14: 372–380. [DOI] [PubMed] [Google Scholar]
- 16. Simera I, Moher D, Hoey J, Schulz KF, Altman DG. A catalogue of reporting guidelines for health research. Eur J Clin Invest 2010; 40: 35–53. [DOI] [PubMed] [Google Scholar]
- 17. Tomsick T, Broderick J, Carrozella J, Khatri P, Hill M, Palesch Y, Khoury J. Revascularization results in the interventional management of stroke II trial. AJNR Am J Neuroradiol 2008; 29: 582–587. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998; 352: 1245–1251. [DOI] [PubMed] [Google Scholar]
- 19. Kniep H, Meyer L, Broocks G, et al. Thrombectomy in M2 occlusion compared to M1 occlusion: treatment effects of Thrombolysis In Cerebral Infarction (TICI) 2b and TICI 3 recanalization on functional outcome. J Neurointerv Surg 2023; 2023: 19898. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Mereuta OM, Abbasi M, Fitzgerald S, et al. Histological evaluation of acute ischemic stroke thrombi may indicate the occurrence of vessel wall injury during mechanical thrombectomy. J Neurointerv Surg 2022; 14: 356–361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Renú A, Laredo C, Lopez-Rueda A, et al. Vessel wall enhancement and blood-cerebrospinal fluid barrier disruption after mechanical thrombectomy in acute ischemic stroke. Stroke 2017; 48: 651–657. [DOI] [PubMed] [Google Scholar]
- 22. Arai D, Ishii A, Chihara H, Ikeda H, Miyamoto S. Histological examination of vascular damage caused by stent retriever thrombectomy devices. J Neurointerv Surg 2016; 8: 992–995. [DOI] [PubMed] [Google Scholar]
- 23. Bala F, Kappelhof M, Ospel JM, et al. Distal embolization in relation to radiological thrombus characteristics, treatment details, and functional outcome. Stroke 2023; 54: 448–456. [DOI] [PubMed] [Google Scholar]
- 24. Chueh JY, Kühn AL, Puri AS, Wilson SD, Wakhloo AK, Gounis MJ. Reduction in distal emboli with proximal flow control during mechanical thrombectomy: a quantitative in vitro study. Stroke 2013; 44: 1396–1401. [DOI] [PubMed] [Google Scholar]
- 25. Kaneko N, Komuro Y, Yokota H, Tateshima S. Stent retrievers with segmented design improve the efficacy of thrombectomy in tortuous vessels. J Neurointerv Surg 2019; 11: 119–122. [DOI] [PubMed] [Google Scholar]
- 26. Bala F, Cimflova P, Singh N, et al. Impact of vessel tortuosity and radiological thrombus characteristics on the choice of first-line thrombectomy strategy: results from the ESCAPE-NA1 trial. Eur Stroke J 2023; 8: 675–683. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Mönch S, Boeckh-Behrens T, Maegerlein C, Berndt M, Wunderlich S, Zimmer C, Friedrich B. Mechanical thrombectomy of the middle cerebral artery—neither segment nor diameter matter. J Stroke Cerebrovasc Dis 2020; 29: 104542. [DOI] [PubMed] [Google Scholar]
- 28. Guenego A, Mine B, Bonnet T, et al. Thrombectomy for distal medium vessel occlusion with a new generation of Stentretriever (Tigertriever 13). Interv Neuroradiol 2022; 28: 444–454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Psychogios MN, Tsogkas I, Blackham K, et al. The Quattro technique for medium distal vessel occlusion stroke. Clin Neuroradiol 2024; 34: 257–262. [DOI] [PubMed] [Google Scholar]
- 30. Kurre W, Aguilar-Pérez M, Martinez-Moreno R, Schmid E, Bäzner H, Henkes H. Stent retriever thrombectomy of small caliber intracranial vessels using pREset LITE: safety and efficacy. Clin Neuroradiol 2017; 27: 351–360. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Siegler JE, Shaikh H, Khalife J, et al. Aspiration versus stent-retriever as first-line endovascular therapy technique for primary medium and distal intracranial occlusions: a propensity-score matched multicenter analysis. Stroke Vasc Interv Neurol 2023; 123: e000931. [Google Scholar]
- 32. Meyer L, Stracke P, Wallocha M, et al. Aspiration versus stent retriever thrombectomy for distal, medium vessel occlusion stroke in the posterior circulation: a subanalysis of the TOPMOST study. Stroke 2022; 53: 2449–2457. [DOI] [PubMed] [Google Scholar]
- 33. Bilgin C, Hardy N, Hutchison K, et al. First-line thrombectomy strategy for distal and medium vessel occlusions: a systematic review. J Neurointerv Surg 2023; 15: 539–546. [DOI] [PubMed] [Google Scholar]
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-wso-10.1177_17474930231214769 for Prognostic value of recanalization attempts in endovascular therapy for M2 segment middle cerebral artery occlusions by Laurens Winkelmeier, Christian Heitkamp, Tobias D Faizy, Gabriel Broocks, Helge Kniep, Lukas Meyer, Maxim Bester, Caspar Brekenfeld, Maximilian Schell, Uta Hanning, Götz Thomalla, Jens Fiehler and Fabian Flottmann in International Journal of Stroke