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Endovascular Therapy of Anterior Circulation Tandem Occlusions

Pooled Analysis From the TITAN and ETIS Registries
and for the TITAN and ETIS Registry Investigators
Originally publishedhttps://doi.org/10.1161/STROKEAHA.120.033032Stroke. 2021;52:3097–3105

Abstract

Background and Purpose:

Endovascular therapy for tandem occlusion strokes of the anterior circulation is an effective and safe treatment. The best treatment approach for the cervical internal carotid artery (ICA) lesion is still unknown. In this study, we aimed to compare the functional and safety outcomes between different treatment approaches for the cervical ICA lesion during endovascular therapy for acute ischemic strokes due to tandem occlusion in current clinical practice.

Methods:

Individual patients’ data were pooled from the French prospective multicenter observational ETIS (Endovascular Treatment in Ischemic Stroke) and the international TITAN (Thrombectomy in Tandem Lesions) registries. TITAN enrolled patients from January 2012 to September 2016, and ETIS from January 2013 to July 2019. Patients with acute ischemic stroke due to anterior circulation tandem occlusion who were treated with endovascular therapy were included. Patients were divided based on the cervical ICA lesion treatment into stent and no-stent groups. Outcomes were compared between the two treatment groups using propensity score methods.

Results:

A total of 603 patients were included, of whom 341 were treated with acute cervical ICA stenting. In unadjusted analysis, the stent group had higher rate of favorable outcome (90-day modified Rankin Scale score, 0–2; 57% versus 45%) and excellent outcome (90-day modified Rankin Scale score, 0–1; 40% versus 27%) compared with the no-stent group. In inverse probability of treatment weighting propensity score–adjusted analyses, stent group had higher odds of favorable outcome (adjusted odds ratio, 1.09 [95% CI, 1.01–1.19]; P=0.036) and successful reperfusion (modified Thrombolysis in Cerebral Ischemia score, 2b-3; adjusted odds ratio, 1.19 [95% CI, 1.11–1.27]; P<0.001). However, stent group had higher odds of any intracerebral hemorrhage (adjusted odds ratio, 1.10 [95%, 1.02–1.19]; P=0.017) but not higher rate of symptomatic intracerebral hemorrhage or parenchymal hemorrhage type 2. Subgroup analysis demonstrated heterogeneity according to the lesion type (atherosclerosis versus dissection; P for heterogeneity, 0.01), and the benefit from acute carotid stenting was only observed for patients with atherosclerosis.

Conclusions:

Patients treated with acute cervical ICA stenting for tandem occlusion strokes had higher odds of 90-day favorable outcome, despite higher odds of intracerebral hemorrhage; however, most of the intracerebral hemorrhages were asymptomatic.

See related article, p 3106

Tandem occlusions, that is concurrent intracranial and extracranial occlusions, constitute 10% to 20% of all large vessel occlusion strokes.1,2 Endovascular therapy (EVT) has been proven to be safe and effective in acute ischemic strokes due to anterior tandem occlusions and is associated with higher odds of favorable functional outcome compared with medical therapy alone.3,4 The presence of a cervical internal carotid artery (ICA) steno-occlusion lesion poses a technical challenge that operators face treating tandem occlusions with EVT. The treatment of cervical ICA varies from no intervention to acute stenting with and without angioplasty. Meta-analyses of the previous observational studies comparing different treatment strategies reported conflicting results, while one meta-analysis reported better outcome with cervical ICA stenting,5 one reported no difference in functional outcome,6 and another reported a higher complication rate and longer procedure time with cervical ICA stenting.7 Based on the available evidence, the American Heart Association/American Stroke Association considered the treatment of cervical ICA during EVT as reasonable (level IIb evidence).8 The lack of randomized trials and the conflicting results from the observational studies created a state of uncertainty that was highlighted in a recent international survey regarding acute treatment options of tandem occlusions.9

In view of these considerations, we sought to compare different treatment strategies for cervical ICA lesion in patients receiving EVT for acute ischemic stroke due to tandem occlusion using 2 large multicenter prospective registries.

Methods

Data for this study are available upon a reasonable request from the corresponding author.

Cohort

This is a pooled analysis of the TITAN (Thrombectomy in Tandem Lesions) and ETIS (Endovascular Treatment in Ischemic Stroke; https://www.clinicaltrials.gov; unique identifier: NCT03776877) registries. All adult patients with anterior circulation tandem occlusion due to atherosclerosis or dissection treated with EVT using modern-generation devices such as stent retriever or contact aspiration were included (Figure 1). Details regarding the ETIS10 and TITAN11,12 registries were reported before. In brief, TITAN pooled individual patients with tandem occlusion treated with EVT from 18 comprehensive stroke centers across Europe and the United States. In TITAN, tandem occlusion was defined as a proximal intracranial occlusion (distal intracranial ICA or M1-M2 segment of the middle cerebral artery) and a cervical ICA lesion (complete occlusion or stenosis ≥90% North American Symptomatic Carotid Endarterectomy Trial). ETIS is an ongoing prospective multicenter registry that enrolls all patients treated with EVT at 6 large comprehensive stroke centers in France. In ETIS, tandem occlusion was defined as a proximal intracranial occlusion (distal intracranial ICA or M1-M2 segment of the middle cerebral artery) and a cervical ICA lesion (complete occlusion or high-grade stenosis).

Figure 1.

Figure 1. Flowchart. ETIS indicates Endovascular Treatment in Ischemic Stroke; and TITAN, Thrombectomy in Tandem Lesions.

All patients received mechanical thrombectomy of the intracranial occlusion with and without cervical ICA lesion intervention. The cervical ICA treatment approach was based on the operator’s preference and included cervical ICA stenting with and without angioplasty (stent group) or EVT without cervical ICA stenting (no stent). No-stent group included patients who either did not receive any EVT for cervical ICA lesion or were treated with carotid angioplasty alone. Both intracranial and extracranial occlusions were treated emergently at the same EVT session. There was no standardized selection protocol for EVT treatment, and patients were selected for EVT based on the participating center’s protocol. Data collection and analyses were approved by the local institutional review boards. In the ETIS registry, written informed consent was obtained from all the patients or their legal representatives. In the TITAN registry, requirement of consent was waived due to the retrospective design. This study followed the STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology).

Outcomes

The primary outcome is the 90-day modified Rankin Scale score of 0 to 2, which was termed favorable outcome. Approximately 90 days after the acute event, functional outcome was assessed by board-certified vascular neurologists during a routinely scheduled clinical visit or by a study nurse certified in administering the modified Rankin Scale during a standardized telephone interview if the patient was unable to attend. The secondary outcomes were excellent outcome (90-day modified Rankin Scale score, 0–1), efficacy outcomes, safety outcomes, infarct extension, and National Institutes of Health Stroke Scale (NIHSS) shift. Efficacy outcomes included successful reperfusion, which was defined as a modified Thrombolysis in Cerebral Ischemia score of 2b-3, and complete reperfusion (modified Thrombolysis in Cerebral Ischemia score, 3). Safety outcomes included any intracerebral hemorrhage (ICH), parenchymal hemorrhage type 2 (PH2), and symptomatic ICH (sICH). PH and sICH were defined according to the European Collaborative Acute Stroke Study classifications.13,14 To assess infarct extension, we calculated the Alberta Stroke Program Early CT Score 24-hour shift.

Statistical Analysis

Continuous variables are expressed as mean (SD) in the case of normal distribution or medians (interquartile range) otherwise. Categorical variables are expressed as n (%). Normality of distributions was assessed using histograms and the Shapiro-Wilk test. Baseline characteristics were described according to the treatment groups, stent (±angioplasty) versus no stent, and the magnitude of the between-group differences was assessed by calculating the absolute standardized difference; an absolute standardized difference >10% was interpreted as a meaningful difference.15

We assessed the impact of stent treatment on outcomes before and after taking into account the potential confounding factors by using prespecified propensity score methods.16 As the primary analysis, we used the inverse probability of treatment weighting (IPTW) approach using stabilized inverse propensity score as weights into regression models, and as secondary analysis, we used the propensity score matching method to assemble a well-balanced treatment group. The propensity score was estimated using a nonparsimonious multivariable logistic regression model, with the treatment group as the dependent variable and all of the characteristics listed in Table 1 as covariates. We included all variables in Table 1 in the propensity score estimation because we considered all variables as potential confounders. To evaluate bias reduction using the propensity score methods, absolute standardized differences were calculated after weighting or matching. For matched propensity score method, patients treated by cervical ICA stenting (±angioplasty) were matched with a 1:1 ratio to patients treated without cervical ICA stenting according to propensity score using the greedy nearest neighbor matching algorithm with a caliper width of 0.2 SD of logit of propensity score.17,18

Table 1. Baseline Characteristics According to the Use of Cervical Internal Carotid Artery Stent in the Overall Cohort

Overall (main analysis)
No stent (n=262)Stent (n=341)
Age, y; mean (SD)62.3±13.763.4±12.9
Men182 (69.5)226 (66.2)
Medical history
 Hypertension127 (48.5)195 (57.1)
 Diabetes40 (15.4)44 (13.0)
 Hypercholesterolemia77 (29.4)116 (34.1)
 Current smoking92 (35.2)113 (33.2)
Stroke event
 NIHSS score, median (IQR)16 (12–19)16 (11–20)
 ASPECTS score, median (IQR)7 (6–8)8 (6–9)
 Etiology
  Atherosclerosis175 (66.8)264 (77.4)
  Dissection87 (33.2)77 (22.6)
EVT characteristics
 Intravenous thrombolysis166 (63.4)214 (62.9)
 General anesthesia79 (30.2)176 (51.7)
 First-line strategy
  ADAPT108 (41.0)70 (20.6)
  Stent retriever126 (48.2)236 (69.3)
  ADAPT+stent retriever28 (10.8)35 (10.1)
Workflow
 Onset-to-puncture time, min; median (IQR)258 (180–331)226 (170–312)
 Onset-to-imaging time, min; median (IQR)113 (86–193)110 (77–165)
 Imaging-to-puncture time, min; median (IQR)104 (62–158)99 (65–156)

Values are expressed as n (%) unless otherwise indicated. Values were calculated after handling missing data using multiple imputation procedure. ADAPT indicates A Direct Aspiration First Pass Technique; ASPECTS, Alberta Stroke Program Early CT Score; EVT, endovascular therapy; IQR, interquartile range; and NIHSS, National Institutes of Health Stroke Scale.

Because of missing baseline data, we estimated the treatment effect sizes adjusted using propensity score methods after handling missing covariates values by multiple imputation using a regression switching approach (chained equations with m=10).19 Imputation procedure was performed under the missing-at-random assumption using all variables listed in Table 1 with a predictive mean matching method for continuous variables and multinomial or binary logistic regression model for categorical variables. Baseline characteristics before imputation are reported in Tables I and II in the Data Supplement. In each imputed data set, we calculated the propensity score and the weighted and matched treatment effect sizes. Then, we combined effect sizes from each imputed data set using Rubin rules.

In the IPTW cohort, the effect size of stent treatment (±angioplasty) on outcomes was estimated using weighted logistic (binary outcomes: favorable, excellent, death, any ICH, sICH, PH2, successful and complete reperfusion, and procedural complications) or linear regression models (continuous outcomes: 24-hour NIHSS shift, 24-hour Alberta Stroke Program Early CT Score shift) with use of stabilized inverse propensity score as weights. In propensity score–matched cohort, comparisons were done using a generalized linear mixed model (binomial distribution, logit function) for binary outcomes and a linear mixed model for continuous outcomes with the matched sets as random effect to account the matched design. Using the no-stent group as a reference, we derived from these regression models treatment effect size measures with their 95% CIs (odds ratios [ORs]) for binary outcomes and mean differences for continuous outcomes.

We further investigated the heterogeneity in treatment effect sizes for prespecified primary outcome (90-day favorable outcome) according to the following subgroups: prior intravenous thrombolysis, etiology (atherosclerosis versus dissection), use of procedural antiplatelet, age (<75 and ≥75 years), initial NIHSS (<10 and ≥10), initial Alberta Stroke Program Early CT Score (<8 and 8–10), delay between onset to puncture (<180 and ≥180 minutes), and study group (ETIS versus TITAN) by introducing the corresponding multiplicative term into regression models. Regarding the issue of multiple testing and low statistical power to test heterogeneity, heterogeneity in treatment effect was interpreted as meaningful regarding the direction, values, and 95% CIs of effect sizes estimated in each subgroup.

Statistical testing was conducted at the 2-tailed α-level of 0.05. Data were analyzed using the SAS Software, version 9·4 (SAS Institute, Cary, NC).

Results

We included 603 of 760 patients in the final analysis (Figure 1). Of the included patients, 341 were treated with acute cervical ICA stenting. Baseline characteristics and outcomes per study are reported in Table I in the Data Supplement. Both the stent and no-stent groups had a comparable age (63.4 versus 62.3 years) and median NIHSS (16 for both groups). More patients in the stent group had atherosclerosis (77.4% versus 66.8%), treated with stent retriever (69.3% versus 48.2%) and received general anesthesia (51.7% versus 30.2%; Table 1; Table II in the Data Supplement). All baseline between-group differences were reduced after IPTW adjustment (Figure I in the Data Supplement), as well as after propensity score matching (Figure II in the Data Supplement).

Compared with the no-stent group, the stent group had a higher rate of favorable outcome (57% versus 45%) and excellent outcome (40% versus 27%) in unadjusted analysis. In IPTW adjusted analyses, the stent group had higher odds of favorable outcome (adjusted OR, 1.09 [95% CI, 1.01–1.19]; Table 2; Figure 2). Similar results were found with excellent outcome although the difference did not reach statistical significance (adjusted OR, 1.08 [95% CI, 0.99–1.17]; Table 2). In unadjusted analyses, the rate of any ICH was higher in the stent group (48.1% versus 43.0%), likewise the rate of sICH (8.2% versus 6.4%) and PH2 (6.7% versus 5.2%). In IPTW adjusted analyses, the stent group had higher odds of any ICH (adjusted OR, 1.10 [95% CI, 1.02–1.19]) compared with the no-stent group (Table 2). In contrast, there was no significant association between cervical ICA stenting and sICH or PH2 in IPTW adjusted analyses (Table 2). With respect to angiographic outcome, the stent group had higher odds of successful reperfusion (OR, 1.19 [95% CI, 1.11–1.27]). Baseline characteristics and outcomes of both groups after propensity score matching are shown in Tables III and IV in the Data Supplement. The results of the propensity score matching analysis were generally similar to IPTW analyses.

Table 2. Comparisons in Clinical and Procedural Outcomes According to Use of Cervical Internal Carotid Artery Stent Before and After IPTW in the Overall Study Sample (Main Analysis)

Before IPTWAfter IPTW¶
No stent (n=262)Stent (n=341)Effect size (95% CI)P valueEffect size (95% CI)P value
Clinical outcomes
 Favorable outcome*118 (45.0)194 (57.0)1.61 (1.15 to 2.25)0.0051.09 (1.01 to 1.19)0.036
 Excellent outcome71 (27.0)137 (40.2)1.82 (1.26 to 2.61)0.0011.08 (0.99 to 1.17)0.061
 90-d mortality35 (13.5)40 (11.6)0.84 (0.51 to 1.38)0.490.99 (0.93 to 1.04)0.63
 Hemorrhagic complications
  Any ICH113 (43.0)164 (48.1)1.23 (0.88 to 1.70)0.221.10 (1.02 to 1.19)0.017
  sICH17 (6.4)28 (8.2)1.30 (0.68 to 2.50)0.421.05 (0.99 to 1.09)0.069
  PH214 (5.2)23 (6.7)1.31 (0.64 to 2.68)0.461.03 (0.99 to 1.06)0.20
 Change in NIHSS at 24 h, median (IQR)−2 (−8 to 2)−3 (−8 to 0)−0.89 (−2.49 to 0.60)0.24−0.20 (−1.72 to 1.33)0.80
 Change in ASPECTS at 24 h, median (IQR)−1 (−3 to 0)−1 (−3 to 0)−0.23 (−0.64 to 0.17)0.250.09 (−0.30 to 0.49)0.65
Procedural outcomes
 Successful reperfusion§172 (65.6)285 (83.6)2.67 (1.82 to 3.91)<0.0011.19 (1.11 to 1.27)<0.001
 Excellent reperfusion62 (23.7)110 (32.3)1.53 (1.07 to 2.21)0.0211.06 (0.97 to 1.14)0.12
 Procedural complications39 (15.0)38 (11.1)0.71 (0.44 to 1.14)0.160.97 (0.92 to 1.02)0.28

Values are expressed in n (%) unless otherwise indicated. ASPECTS indicates Alberta Stroke Program Early CT Score; ICH, intracerebral hemorrhage; IPTW, inverse probability of treatment weighting; IQR, interquartile range; mRS, modified Rankin Scale; mTICI, modified Thrombolysis in Cerebral Ischemia; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; PH2, parenchymal hemorrhage type 2; and sICH, symptomatic intracerebral hemorrhage.

* Prespecified primary outcome defined as a 90-d mRS score of 0 to 2 or equal to prestroke mRS score.

† Defined as a 90-d mRS score of 0 to 1 or equal to prestroke mRS score.

‡ Defined as an mTICI score of 2b/3.

§ Mean difference estimated from the linear regression model.

∥ Defined as an mTICI score of 3. Descriptive parameters and effect sizes (OR or mean difference) were calculated after handling missing values for variables included in the propensity score using a multiple imputation procedure.

¶Propensity score was calculated with all parameters in Table 1.

Figure 2.

Figure 2. Distribution of the modified Rankin Scale according to the treatment of the cervical carotid lesion (stenting vs no stenting).

For subgroup analyses, there was evidence of heterogeneity across baseline NIHSS (<10 versus ≥10) and etiology of cervical ICA lesion (atherosclerosis versus dissection), with a stronger benefice of stent treatment on favorable outcome in lower NIHSS and atherosclerosis subgroups (Figure 3; Figure III in the Data Supplement).

Figure 3.

Figure 3. Comparisons in favorable outcome (90-d modified Rankin Scale score, 0–2) rate according to the use of cervical internal carotid artery stent and key subgroups before and after inverse probability treatment weighting (IPTW). Odds ratios (ORs) were calculated after handling missing values for variables included in the propensity score using a multiple imputation procedure. ASPECTS indicates Alberta Stroke Program Early CT Score; ETIS, Endovascular Treatment in Ischemic Stroke; IVT, intravenous thrombolysis; NIHSS, National Institutes of Health Stroke Scale; p-het, P of heterogeneity; and TITAN, Thrombectomy in Tandem Lesions. *Propensity score was calculated with all parameters in Table 1.

Discussion

In this large, multicenter study, we compared different EVT approaches for anterior tandem occlusion strokes. The main findings of this study are as follows: (1) treatment with acute cervical ICA stenting is associated with higher odds of successful reperfusion and favorable outcome compared with no cervical ICA stenting; (2) there is higher odds of any hemorrhagic complications after acute cervical ICA stenting compared with no stenting but without higher odds of sICH and PH2; (3) there is evidence of heterogeneity across cervical ICA lesion etiology with stronger benefit in patients with atherosclerosis and lower NIHSS at admission.

This study adds to the growing evidence, suggesting a clinical benefit of acute cervical ICA stenting in association to thrombectomy in tandem occlusions.2,20 Cervical ICA stenting in this subgroup of patients provides more definitive treatment for the cervical ICA lesion than conservative treatment with higher successful reperfusion rate, as shown in our study, and likely better overall cerebral perfusion. Moreover, cervical ICA stenting of atherosclerotic lesion may decrease the risk of recurrent strokes from unstable atherosclerotic plaque embolization21 and subsequently improving 90-day functional outcome. However, cervical ICA stenting requires at least 1 antiplatelet agent administration, which may increase the risk of hemorrhagic complications when administrated early after stroke, especially after intravenous thrombolysis.22,23 In this study, we observed a higher risk of hemorrhagic complications in the stent group than in the no-stent group. This finding differs from previous analysis of the TITAN registry.20 The difference is likely secondary to difference in sample size, study design, and statistical analysis. In this study, the rate of any hemorrhagic complications was similar between the two groups, and the difference was not significant in unadjusted analysis. However, when propensity score analysis was performed, the difference became statistically significant. Despite the higher rate of hemorrhagic complications, the functional outcome was better in the stent group, which is likely due to the fact that the difference in hemorrhagic complications was mainly driven by the difference in asymptomatic hemorrhage. In fact, there was no difference in the rate of sICH and PH2 between the two groups. Nonetheless, this finding highlights the importance of weighting the benefit from cervical ICA stenting and antiplatelet treatment administration against the potential risk of hemorrhagic complications.

Etiology of the cervical ICA lesion should be considered while planning EVT for acute ischemic stroke due to tandem occlusion. Tandem occlusions due to dissection, which is the second major cause of tandem occlusion, constituted 27% of our cohort. There was an interaction between cervical ICA etiology and the effect of cervical ICA stenting. Cervical ICA stenting was associated with favorable outcome in the atherosclerosis group but not in the dissection group. This finding is likely due to the fact that tandem occlusions secondary to cervical ICA dissection tend to have better functional outcome, higher rate of spontaneous recanalization, and lower rate of recurrent strokes compared with tandem occlusions secondary to cervical ICA atherosclerosis.24–26 Our findings are consistent with a recently published study that showed no difference in the functional outcome between carotid artery stenting and conservative treatment in tandem occlusion due to dissection.27 Therefore, we believe that conservative treatment should be considered first in patients with dissection and cervical ICA stenting should be reserved for selected cases.

Antithrombotic treatment is needed after cervical ICA stenting, which may increase the risk of hemorrhagic complications, especially in the subgroup of patients who receive intravenous thrombolysis before intervention. In this study, there was no evidence of heterogeneity according to thrombolysis treatment. In addition, previous analysis of TITAN found a comparable rate of hemorrhagic complications in patients treated with cervical ICA stenting with and without thrombolysis.12 Our study, along with the previous study, suggests that cervical ICA stenting can be used safely in patients treated with prior thrombolysis.

Literature regarding cervical ICA stenting for secondary stroke prevention suggested that age modifies the effect of cervical ICA stenting on the outcome with higher risk of adverse events with increasing age.28 To examine the effect to age on the outcome of cervical ICA stenting, we performed sensitivity analysis according to age (<75 versus ≥75 years) and found no evidence of heterogeneity across age groups.

Taken all together, our study along with previous studies suggests that acute cervical ICA stenting is an effective and safe treatment for tandem occlusion strokes pending the results of the ongoing randomized controlled TITAN trial.29 However, we encourage caution while interpreting our results for multiple reasons. First, our study enrolled patients from high-volume centers, and most procedures were done with experienced operators. Therefore, our results may not apply to small-volume centers. Second, our patients had relatively small infarct volume with median Alberta Stroke Program Early CT Score of 7 and 8 in the no-stent and stent groups, respectively. Therefore, our results may not apply for patients with large core infarct.

Limitations

Limitations to this study are inherent to its nonrandomized design. The present findings are derived from observational analyses, which are subject to well-known limitations. The first is the potential for confounding by measured or unmeasured variables, which cannot be ruled out, even after propensity score matching or adjustment. A second limitation is the presence of missing data in some covariates, including in the propensity score calculation, as well as in outcomes. Although we used multiple imputations to handle missing data as appropriate, we cannot exclude that missing data could have introduced a bias in estimates in unpredictable manner. Perioperative antithrombotic protocols were also not standardized. Third, all outcome measures were reported by local operators, which may have resulted in reporting bias, except for the 90-day modified Rankin Scale assessment. Finally, the order of treatment (intracranial first or cervical first) was not available from the ETIS registry; therefore, we cannot comment on the effect of treatment order on the outcome. However, a previous analysis of the TITAN registry and previous meta-analysis did not demonstrate a difference in functional outcome according to treatment order.6,30

Conclusions

Acute cervical ICA stenting is associated with higher odds of favorable outcome and successful reperfusion in patients with ischemic strokes due to tandem occlusions. However, cervical ICA stenting is also associated with higher risk of hemorrhagic complications but not with sICH and PH2. Therefore, the choice of EVT type for cervical ICA in tandem occlusion should be selected after careful risk-benefit assessment considering multiple factors such as etiology and severity. The results of the ongoing TITAN randomized trial will hopefully determine the best EVT approach for acute anterior tandem occlusions.

Nonstandard Abbreviations and Acronyms

EVT

endovascular therapy

ETIS

Endovascular Treatment in Ischemic Stroke

ICA

internal carotid artery

ICH

intracerebral hemorrhage

IPTW

inverse probability of treatment weighting

NIHSS

National Institutes of Health Stroke Scale

PH2

parenchymal hemorrhage type 2

sICH

symptomatic intracerebral hemorrhage

TITAN

Thrombectomy in Tandem Lesions

Supplemental Materials

Online Tables I–IV

Online Figures I–III

APPENDIX

TITAN (Thrombectomy in Tandem Lesions) investigators: Francis Turjman, Michel Piotin, Henrik Steglich-Arnholm, Markus Holtmannspötter, Christian Taschner, Sebastian Eiden, Diogo C. Haussen, Maria Boutchakova, Franziska Dorn, Monika Killer-Oberpfalzer, Salvatore Mangiafico, Marios N. Psychogios, Marc-Antoine Labeyrie, Alessandra Biondi, Serge Bracard, Jonathan Andrew Grossberg, Adrien Guenego, Julien Darcourt, Isabelle Vukasinovic, Elisa Pomero, Jason Davies, Leonardo Renieri, Corentin Hecker, Maria Muchada Muchada, Arturo Consoli, Georges Rodesch, Emmanuel Houdart, Johanna Lockau, Andreas Kastrup, Hocine Redjem, Daniel Behme, Hussain Shallwani, Maurer Christopher, Gioia Mione, Lisa Humbertjean, Nolwenn Riou-Comte, François Zhu, Anne-Laure Derelle, Liang Liao. ETIS (Endovascular Treatment in Ischemic Stroke) investigators: Fondation Adolphe de Rothschild: Michel Piotin, Raphael Blanc, Hocine Redjem, Simon Escalard, Benjamin Maïer, Jean-Philippe Desilles, Gabriele Ciccio, Stanislas Smajda, Mikael Mazighi, Mikael Obadia, Candice Sabben, Ovide Corabianu, Thomas de Broucker, Didier Smadja, Sonia Alamowitch, Olivier Ille, Eric Manchon, Pierre-Yves Garcia, Guillaume Taylor, Malek Ben Maacha; Hôpital Foch: Adrien Wang, Serge Evrard, Maya Tchikviladze, Nadia Ajili, Bertrand Lapergue, David Weisenburger, Lucas Gorza, Oguzhan Coskun, Arturo Consoli, Federico Di Maria, Georges Rodesh, Morgan Leguen, Julie Gratieux, Fernando Pico, Haja Rakotoharinandrasana, Philippe Tassan, Roxanna Poll, Sylvie Marinier; CHU Bordeaux: Gaultier Marnat, Florent Gariel, Xavier Barreau, Jérôme Berge, Louis Veunac, Patrice Menegon, Igor Sibon, Ludovic Lucas, Stéphane Olindo, Pauline Renou, Sharmila Sagnier, Mathilde Poli, Sabrina Debruxelles, Thomas Tourdias, Jean-Sebastien Liegey; CHU Nantes: Romain Bourcier, Lili Detraz, Benjamin Daumas-Duport, Pierre-Louis Alexandre, Monica Roy, Cédric Lenoble, Vincent L’allinec, Jean-Baptiste Girot, Hubert Desal; CHRU-Nancy: Benjamin Gory , Fatiha Bechiri, Serge Bracard, René Anxionnat, Marc Braun, Anne-Laure Derelle, Romain Tonnelet, Liang Liao, François Zhu, Emmanuelle Schmitt, Sophie Planel, Sébastien Richard, Lisa Humbertjean, Gioia Mione, Jean-Christophe Lacour, Gabriela Hossu, Marine Beaumont, Mitchelle Bailang, Gérard Audibert , Marie Reitter, Agnès Masson, Lionel Alb, Adriana Tabarna, Marcela Voicu, Iona Podar, Madalina Brezeanu, Sarah Guy; CHU Montpellier: Vincent Costalat, Caroline Arquizan, Cyril Dargazanli, Grégory Gascou, Pierre-Henri Lefèvre, Imad Derraz, Carlos Riquelme, Nicolas Gaillard, Isabelle Mourand, Lucas Corti.

Disclosures Dr Spiotta reports support from Penumbra, Stryker, and Medtronic and consulting fees from Terumo, Stryker, Penumbra, and Siemens. Dr Lapergue reports grants from Stryker, Penumbra, and Microvention. Dr Mazighi reports personal fees from Acticor Biotech, Air Liquide, Amgen, and Boehringer. Dr Nogueira is a principal investigator for Stryker Neurovascular (DAWN trial [no compensation] and Trevo-2 trial) and Cerenovus/Neuravi (ENDOLOW trial [no compensation]); consultant to Stryker Neurovascular; steering committee member for Stryker Neurovascular (no compensation), Medtronic (SWIFT trial and SWIFT Prime trial [no compensation]), and Cerenovus/Neuravi (ARISE-2 trial [no compensation]); belongs to the angiographic core laboratory at Medtronic (STAR trial); executive committee member at Penumbra (no compensation); and belongs to the physician advisory board at Cerenovus/Neuravi, Phenox, Anaconda, Genentech, Biogen, Prolong Pharmaceuticals, Allm, Inc (no compensation), and Viz-AI (stock options). Dr Siddiqui reports financial interest/investor/stock options/ownership at Amnis Therapeutics, Apama Medical, BlinkTBI, Inc, Buffalo Technology Partners, Inc, Cardinal Health, Cerebrotech Medical Systems, Inc, Claret Medical, Cognition Medical, Endostream Medical, Ltd, Imperative Care, International Medical Distribution Partners, Rebound Therapeutics Corp, Silk Road Medical, StimMed, Synchron, Three Rivers Medical, Inc, and Viseon Spine, Inc; is a consultant/belongs to the advisory board at Amnis Therapeutics, Boston Scientific, Canon Medical Systems USA, Inc, Cerebrotech Medical Systems, Inc, Cerenovus, Claret Medical, Corindus, Inc, Endostream Medical, Ltd, Guidepoint 15Global Consulting, Imperative Care, Integra, Medtronic, MicroVention, and Northwest University; DSMB Chair for the HEAT trial at Penumbra, Rapid Medical, Rebound Therapeutics Corp, Silk Road Medical, StimMed, Stryker, Three Rivers Medical, Inc, VasSol, and W.L. Gore & Associates; is the national PI/belongs to the Steering Committees: Cerenovus: the LARGE and ARISE II trials, Medtronic: the SWIFTPRIME and SWIFT DIRECT trials, MicroVention: the FRED trial and CONFIDENCE study, MUSC POSITIVE Trial, Penumbra 3D Separator Trial, COMPASS Trial, and INVEST Trial; and is the principal investigator for the Cummings Foundation grant. Dr Cognard reports consulting for Medtronic, Cerenovus, Stryker, MIVI, Sensome, Microvention Christensen Consulting, and Ischema View. The other authors report no conflicts.

Footnotes

*A list of TITAN and ETIS Investigators is given in the Appendix.

The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.033032.

For Sources of Funding and Disclosures, see page 3103.

The podcast and transcript are available at https://www.ahajournals.org/str/podcast.

Correspondence to Benjamin Gory, MD, PhD, Department of Diagnostic and Therapeutic Neuroradiology, CHRU Nancy, Hôpital Central, 29 Ave du Maréchal de Lattre de Tassigny, 54035 Nancy, France. Email

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