Recanalization Therapies for Large Vessel Occlusion Due to Cervical Artery Dissection: A Cohort Study of the EVA-TRISP Collaboration

Article information

J Stroke. 2023;25(2):272-281

Publication date (electronic) : 2023 May 30

doi : https://doi.org/10.5853/jos.2022.03370

Christopher Traenka^,1,2, Johannes Lorscheider^1,3, Christian Hametner⁴, Philipp Baumgartner⁵, Jan Gralla⁶, Mauro Magoni⁷, Nicolas Martinez-Majander⁸, Barbara Casolla^9,10, Katharina Feil^11,12, Rosario Pascarella¹³, Panagiotis Papanagiotou¹⁴, Annika Nordanstig¹⁵, Visnja Padjen¹⁶, Carlo W. Cereda¹⁷, Marios Psychogios^1,18, Christian H. Nolte¹⁹, Andrea Zini²⁰, Patrik Michel²¹, Yannick Béjot²², Andreas Kastrup¹⁴, Marialuisa Zedde²³, Georg Kägi^24,25, Lars Kellert¹¹, Hilde Henon⁹, Sami Curtze⁸, Alessandro Pezzini²⁶, Marcel Arnold²⁵, Susanne Wegener⁵, Peter Ringleb⁴, Turgut Tatlisumak¹⁵, Paul J. Nederkoorn²⁷, Stefan T. Engelter^1,2,*, Henrik Gensicke^1,2,*, for the EVA-TRISP Collaborators

¹Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland

²Neurology and Neurorehabilitation, University Department of Geriatric Medicine FELIX PLATTER, University of Basel, Basel, Switzerland

³Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland

⁴Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany

⁵Division of Vascular Neurology and Neurorehabilitation, Department of Neurology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland

⁶Institute of Diagnostic and Interventional Neuroradiology University Hospital Bern, University of Bern, Bern, Switzerland

⁷ASST Spedali Civili, Neurologia Vascolare, Brescia, Italy

⁸Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

⁹Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France

¹⁰Stroke Unit, UR2CA-URRIS Neurology, CHU Pasteur 2, Nice Cote d’Azur University, Nice, France

¹¹Department of Neurology, Ludwig Maximilian University (LMU), Munich, Germany

¹²Department of Neurology, University Hospital Tübingen, Tübingen, Germany

¹³Neuroradiology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy

¹⁴Department of Neurology, Klinikum Bremen-Ost, Bremen, Germany

¹⁵Department of Neurology, Sahlgrenska University Hospital and Department of Clinical Neuroscience Institute for Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

¹⁶University of Belgrade, Faculty of Medicine, Neurology Clinic, University Clinical Centre of Serbia, Belgrade, Serbia

¹⁷Stroke Center, Department of Neurology, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale (EOC), Lugano, Switzerland

¹⁸Department of Neuroradiology, Clinic of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland

¹⁹Klinik für Neurologie mit experimenteller Neurologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany and Center for Stroke Research Berlin (CSB), Charité-Universitätsmedizin Berlin, Germany

²⁰IRCCS Istituto delle Scienze Neurologiche di Bologna, Department of Neurology and Stroke Center, Maggiore Hospital, Bologna, Italy

²¹Stroke Service, Neurology Service, Lausanne University Hospital, Lausanne, Switzerland

²²Department of Neurology, University Hospital Dijon, Dijon, France

²³Neurology Unit, Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy

²⁴Department of Neurology, Kantonsspital St. Gallen, St. Gallen, Switzerland

²⁵Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

²⁶Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy

²⁷Department of Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands

Correspondence: Christopher Traenka Department of Neurology and Stroke Center, University Hospital and University of Basel, Petersgraben 4, CH – 4031 Basel, Switzerland Tel: +41-61-55-65707 E-mail: christopher.traenka@usb.ch

*These authors contributed equally as last author.

Received 2022 October 26; Revised 2023 February 13; Accepted 2023 February 27.

Abstract

Introduction

Cervical artery dissection (CeAD) is a leading cause of ischemic stroke in the young (<50 years) [1]. Arterial embolism originating from the site of dissection, potentially leading to intracranial large vessel occlusion (LVO) is thought to be the primary mechanism for acute ischemic stroke (AIS) in CeAD-patients [2].

For AIS patients with LVO in the anterior circulation, multiple randomized-controlled trials (RCTs) have demonstrated superiority of endovascular treatment (EVT, with or without intravenous thrombolysis [IVT]) over IVT alone [3-7]. More recently, encouraging evidence has emerged also for EVT for basilary artery occlusion [8,9]. For CeAD-patients, however, observational studies failed to show superiority of EVT over IVT regarding clinical outcomes [2,10]. This might have technical and procedural grounds as most existing data on EVT in CeAD-patients were collected before 2015 [10] and thus before the major advances in EVT therapy. Even so, in a meta-analysis of the pivotal EVT-RCTs using current EVT standards, no treatment effect of EVT (compared to IVT) on clinical outcome at 3 months was shown for the subgroup of patients aged <50 years [11] in whom CeAD is a major cause of stroke. Although no specific data on CeAD-patients were provided, this finding might indicate that—even if current EVT standards are used—EVT may not be superior to IVT in AIS-LVO with underlying CeAD.

With these considerations in mind, we aimed to investigate the effect of EVT (with or without IVT) versus IVT alone on outcomes in CeAD-patients with LVO (due to thrombus embolization from the dissection) treated since 2015 in participating centers of the EVA-TRISP (EndoVAscular treatment and ThRombolysis in Ischemic Stroke Patients) collaboration.

Methods

Results

Primary analyses

Of 369 CeAD-patients included in EVA-TRISP between 2015– 2019, 290 (78.6%) met the eligibility criteria and were included in the analyses. Main reasons for exclusion were the absence of LVO (n=36, 9.8%) and missing baseline or follow-up information (n=43, 11.7%). Details are given in the study flowchart (Figure 1). Of 290 patients included in the final analyses, 222 patients (76.6%) received EVT and 68 (23.4%) received IVT (Table 1).

Figure 1.

Flowchart of included and excluded patients. CeAD, cervical artery dissection; EVA-TRISP, EndoVAscular treatment and ThRombolysis in Ischemic Stroke Patients; LVO, large vessel occlusion; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale score; IVT, intravenous thrombolysis; EVT, endovascular treatment.

Table 1.

Baseline characteristics of all patients included in the primary analyses

Baseline characteristics

Patients in the EVT-group differed from those in the IVT-group in a higher median NIHSS at admission (14 [interquartile range, IQR 10–19] vs. 4 [IQR 2–7]) and in a higher rate of patients with wake-up stroke (17.4% vs. 2.9%) (Table 2). LVO in the anterior circulation was more frequent in the EVT-group (89.2% vs. 51.5%). Age, sex, medical history, baseline vital signs as well as laboratory results did not differ significantly between both treatment groups (Table 1).

Table 2.

Baseline clinical and stroke characteristics of all patients included in the primary analyses

In the EVT-group, 153 of 222 (68.9%) patients received IVT bridging therapy. Patients who had bridging therapy had significantly lower onset-to-needle times compared to patients who received IVT alone (108 vs. 139 minutes) (Table 2).

Primary clinical outcome measure

Favorable 3-month functional outcome was less frequent in the EVT-group (64.0%) compared to the IVT-group (86.6%), yielding an unadjusted OR of 0.27 (95% CI 0.13–0.58, P=0.001) (Table 3). This difference was no longer significant after adjustment for age, sex, and NIHSS at admission (OR_adjusted 0.56 [95% CI 0.24–1.32], P=0.183).

Table 3.

Primary and secondary study outcomes in all patients

Primary radiological outcome measure

Complete recanalization was more frequent in the EVT-group (80.5% vs. 40.7%) and the probability of complete recanalization was independently higher in the EVT-group (OR_adjusted 8.85 [95% CI 4.28–18.29], P<0.001) (Table 3).

Secondary outcomes

Early neurological improvement occurred less frequently in the EVT-group (42.8%) as compared to the IVT-group (60.3%), yielding an unadjusted OR of 0.49 (95% CI 0.28–0.86, P=0.012). After adjustment for age, sex, and NIHSS at admission, this difference was no longer significant (OR_adjusted 0.59 [95% CI 0.31–1.14], P=0.118).

Overall, 12 (of 290, 4.1%) sICH and 19 (of 290, 6.6%) deaths occurred. Thereby, both sICH and death were numerically more frequent in the EVT-group. This difference was not statistically significant in unadjusted analyses (Table 3). In the EVT-group, 7 of the 11 (63.6%) patients who had sICH, had received additional IVT.

Secondary analyses

Analyses in patients with LVO in the anterior circulation LVO_ant was present in 233 of 290 (80.3%) patients of whom 198 had received EVT and 35 had received IVT (Table 2 and Supplementary Table 1). Baseline characteristics in EVT- and IVT-treated patients with LVO_ant were comparable except for a higher median NIHSS (14.5 vs. 5, P<0.001) and higher median glucoseand CRP-levels in the EVT-group and a lower rate of patients with prior stroke in the EVT-group (Supplementary Table 1). In turn, median onset-to-needle time was higher in the IVT-group. In patients with LVO_ant, favorable 3-month outcome was significantly less frequent in EVT-treated than in IVT-treated patients (91.4% vs. 64.1%). After adjustment for age, sex, and baseline NIHSS, the probability of favorable 3-month outcome was lower for patients treated with EVT (OR_adjusted 0.93 [95% CI 0.89–0.98]). The frequency and adjusted odds for complete recanalization were higher in the EVT-group (78.5% vs. 52.0%; OR_adjusted 4.17 [95% CI 1.66–10.45]).

PSM analyses

PSM analyses in patients with LVO_ant were based on 32 patients each from the EVT- and the IVT-group. Patient baseline characteristics of the matched variables (including NIHSS at admission) were comparable (Table 4). Unadjusted logistic regression analyses performed on the matched sample of patients with LVO_ant yielded lower odds for a favorable 3-month functional outcome in the EVT-group (OR 0.20 [95% CI 0.04–0.72]). The odds for complete recanalization were higher in the EVT-group (OR 2.2 [95% CI 0.86–9.36]); however—contrary to the primary and unmatched secondary analyses—this was no longer statistically significant.

Table 4.

Patient baseline characteristics after propensity score matching in patients with LVO in the anterior circulation

Discussion

In this multinational analysis comparing EVT to IVT in CeAD-patients with LVO, there was no signal of superiority of EVT over IVT even if the higher stroke severity is considered and despite higher rates of complete recanalization in the EVT-group.

Considering the clear results from multiple RCTs demonstrating superiority of EVT compared to IVT alone in AIS with LVO in the general stroke population, we had assumed that CeAD-patients treated in this new EVT-era would benefit similarly. Unexpectedly, this hypothesis is not supported by our findings.

In contrast to our findings on clinical outcome, recanalization rates in the EVT-group in our study were significantly higher than in the IVT-group. This finding was consistent across all analyses we performed, indicating its robustness. Such discrepancy between favorable recanalization rates, yet lack of superiority in clinical outcomes was also seen to a similar extent in a prior study comparing EVT to IVT in CeAD patients [21]. Moreover, the rate of complete recanalization (TICI 2b/3) in the EVT-group in our study was comparable [5] to even higher [4,6] when compared to EVT-treated patients in the pivotal EVT-RCTs, thus proving technical success is achievable in EVT treatment of CeAD-patients as well. Nevertheless, this high recanalization rate did not translate into a better functional outcome of the EVT-group compared to the IVT-group, even if outcome predictive variables and in particular stroke severity were considered by different statistical means. Thus, further reasons for lack of (clinical) superiority of EVT over IVT in CeAD-patients must be explored.

The knowledge about the impact of EVT versus IVT on outcomes in CeAD-patients is currently based on few observational studies [10,21] while RCT-based comparative data is lacking. A recent meta-analysis across 14 observational studies and case series—most of which were published before 2015—showed no statistically significant difference between the EVT- and the IVT-group regarding favorable functional outcome in CeAD-patients [10].

Interestingly, in an age-dependent subgroup analysis of HERMES [Highly Effective Reperfusion Using Multiple Endovascular Devices], the group of stroke patients aged <50 years—in which CeAD is a leading stroke cause—was the only age-group that did not benefit from EVT [11]. Although information about stroke etiology was not available in this analysis, this observation might suggest that treatment effects of EVT in CeAD may be inferior compared to EVT in the general stroke population.

It is possible that the lack of superiority of EVT in our study is a spurious finding or—at least partly—due to yet undetected differences in baseline characteristics. We accounted for stroke severity, age, and sex and used PSM to minimize the effect of confounders; however, there might be other factors that we could not account for.

EVT might be technically more challenging in CeAD with presence of intimal tearing and a double lumen. However, this assumption is not supported by data from the interventional arm of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) (n=15 CeAD-patients) trial as well as the MR CLEAN registry (n=59) comparing outcomes in AIS-LVO patients with CeAD to those with atherosclerotic lesions, which indicated a more favorable short-term neurological course in CeAD-patients [22]. In another study, clinical or procedural outcomes after thrombectomy in stroke patients with tandem lesions (i.e., intracranial artery occlusion and proximal stenosis or occlusion of the carotid artery) did not differ significantly between patients with CeAD (n=65) and those with atherosclerotic lesions (n=230) [23].

Alternatively, other aspects, which are independent from CeAD, but which are age-dependent might matter. This includes the role of collateral status and brain plasticity [24,25]. In younger stroke patients, an excellent collateral status and good brain plasticity could lower the relevance of recanalization of LVO on outcomes. In line with this assumption, studies comparing EVT versus IVT in AIS patients with LVO and mild symptoms (NIHSS ≤5)—which are likely to have excellent collaterals—EVT did not perform better than IVT despite higher rates of complete recanalization with EVT [26,27]. Interestingly, and probably supportive of this hypothesis, in an observational study performed by Yeo et al. [28] presenting outcomes of EVT in stroke patients aged <50 years and with various non-atherosclerotic stroke causes particularly prevalent in young patients, rates of favorable functional outcome varied between 57.1% and 71.4%—numbers comparing well with the outcomes seen in the EVT-group in our study.

The imbalance of LVO involving the anterior versus the posterior circulation was another potential confounder, as superiority of EVT over IVT in stroke in general is more established for LVO in the anterior than in the posterior circulation [8,9,29]. Betweengroup differences in favorable outcome became more pronounced (and in part statistically significant) in the subgroup of patients with LVO_ant. Though, conclusions from subgroup analysis may be misleading, they may support the idea that EVT might indeed be less effective in CeAD-patients in the general stroke patient population. These findings need further investigation.

In our study, sICH occurred numerically more often in the EVT-group, without reaching statistical significance. The overall rate of sICH in our EVT-group (5.0%) as well as the rate of sICH in patients who had had EVT with prior IVT (4.6%), however, is comparable to or even lower (when comparing patients without bridging) than in prior observational analyses investigating EVT in CeAD-patients [21,30]. More importantly, the sICH rate in our study is comparable to sICH rates in the pivotal randomized RCTs [3-7] indicating that EVT using current technologies seems relatively safe also in CeAD-patients regarding the occurrence of sICH.

We are aware of limitations of our study. First, treatment allocation was not randomized leading to an imbalance with higher stroke severity and predominant involvement of the anterior circulation in particular the carotid-T-occlusions in the EVT-group. Our means to counter such imbalances—including analyses focusing on patients with LVO_ant and the use of PSM—did not suggest a signal of clinical superiority of EVT over IVT in CeAD but came up to their limits and did not fully eliminate between-group differences. Thus, we urge a cautious interpretation of our key findings. This is particularly important for the analyses based on PSM, which led to comparable stroke severity in both groups but skewed the comparisons towards patients with less severe strokes. Further, other unknown or unmeasured confounders might be present and were not adjusted for. Second, given the design of our study, confounding by indication is likely. Particularly in patients with vertebral artery occlusion necessity to perform EVT depends on factors that we have not been able to account for (e.g., occlusion of the dominant vs. hypoplastic artery) but are likely to have influenced the decision to perform EVT or IVT or both. Third, despite being the largest cohort investigating EVT compared to IVT in CeAD to date, our sample size is still limited increasing the risk for spurious findings. Fourth, comparability of the primary radiological outcome (complete recanalization on first arterial imaging post-intervention in each group) can be debated, as an important factor—namely the very exact timepoint of recanalization—can rarely be assessed in patients receiving IVT. Fifth, except for the presence of early ischemic changes on baseline imaging, other important imaging variables which are likely associated with outcomes (i.e., Alberta Stroke Program Early Computed Tomography Score [ASPECTS], infarct volume on perfusion imaging, and collateral status) were not routinely assessed in the present dataset and therefore not included in the statistical models.

We are aware that our key observations are in dissent to both clinical expectations and guidelines about the use of EVT in LVO in general. Therefore, our findings should not be interpreted as argument to refrain from EVT in CeAD patients in clinical routine. Still, our unexpected results are nevertheless worth being made publicly known and should stimulate future research about why some LVO-patients might benefit less than expected from EVT and why this might be particularly the case in CeAD patients.

Our study has several strengths. The multicentric and multinational approach of the EVA-TRISP collaboration and the presented data ensure comparability of the data across centers and countries. Data in EVA-TRISP are collected prospectively including consecutive patients treated at the respective centers, thus reducing the risks of selection or inclusion bias.

Conclusions

Despite higher rates of complete recanalization, EVT in CeAD patients with AIS and LVO did not result in improved clinical outcomes when compared to IVT alone. This applied particularly for patients with LVO in the anterior circulation, even when matched for important clinical and outcome predictive variables. Whether pathophysiological characteristics of CeAD with potential technical implications for EVT in CeAD or particularities of stroke in younger patients might explain our observations deserve further research. The persisting conundrum of the use of EVT in CeAD patients would ideally be clarified in a randomized clinical trial, of which feasibility is questionable. Reassuringly, however, our study did not produce evidence, that EVT in these patients is clinically harmful. Thus, EVT should not be withheld in CeAD-patients in clinical practice.

Supplementary materials

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