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Abstract
Background Tandem occlusions of the extracranial carotid and intracranial carotid or middle cerebral artery have a particularly poor prognosis without treatment. Several management strategies have been used with no clear consensus recommendations. We examined subjects with tandem occlusions enrolled in the ESCAPE trial and their outcomes.
Methods Data are from the ESCAPE trial. Additional data were sought on interventions for each subject.
Results There were 54 (17%) subjects with tandem extracranial and intracranial occlusions. Patients in the endovascular treatment arm (n=30) were more likely to be younger (median age 66 years, p<0.01), male (66.7%, p=0.03), diabetic, and without atrial fibrillation. Subjects with tandem occlusions were more likely to have intracranial internal carotid artery occlusions than M1 occlusions (p<0.01). Of the 30 intervention-arm subjects, 17 (57%) underwent emergency endovascular treatment of the extracranial disease, 10 subjects before and seven subjects after intracranial thrombectomy. Of the remaining 13 subjects, only four required staged carotid revascularization due to persistent severe carotid stenosis; four had cervical pseudo-occlusions with no residual stenosis after large distal carotid thrombus burden aspiration/retrieval. Outcomes were similar between subjects with and without tandem lesions. The use of antithrombotic agents after acute carotid artery stenting was variable but no symptomatic intracerebral hemorrhage was seen in subjects who underwent emergency endovascular treatment of extracranial carotid artery.
Conclusions Tandem occlusions occurred in one-sixth of patients and were treated highly variably within the ESCAPE trial. While outcomes were similar, the best method to treat the carotid artery in patients with tandem occlusion awaits further randomized data.
Trial registration number NCT01778335.
- stroke
- endovascular treatment
- randomized controlled trial
- carotid occlusion
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Introduction
Acute tandem occlusions are operationally defined as simultaneous extracranial cervical internal carotid artery (ICA) severe stenosis (or near-occlusion) or complete occlusion plus large vessel intracranial occlusion on CT angiography (CTA). Untreated acute ischemic stroke due to tandem occlusions generally has a poor prognosis.1 It is now clear, based on recent randomized controlled trials, that endovascular treatment of these patients results in better outcomes,2 3 but the best interventional strategy to manage the extracranial carotid lesion is debated. Strategies include immediate carotid artery angioplasty with or without stenting before addressing the intracranial lesion; carotid angioplasty with or without stenting after the intracranial lesion has been retrieved; or staged carotid revascularization days after mechanical thrombectomy of the intracranial occlusion. These three treatment strategies vary by institution and neurointerventionalist with no current consensus.
In recent large trials of endovascular stroke treatment,3–8 management of extracranial carotid artery disease was either not specified or was disallowed. The ESCAPE trial,3 a multicenter randomized controlled academic trial, screened subjects fulfilling clinical eligibility criteria if they presented within 12 hours of stroke symptom onset and included them only if they met prespecified neurovascular imaging criteria. The trial enrolled 315 subjects from 22 sites across three continents between February 2013 and October 2014.2 7 The detailed methodology and the main results have been reported elsewhere.3 9 During the trial the coordinating center issued a guidance document to the investigators recommending treatment of the intracranial target occlusion first. However, extracranial carotid artery intervention was left to the discretion of the treating team. We report the technical interventional management of subjects with tandem occlusions and their outcomes. While this report will not change practice in itself, the purpose of this report is provide data to support development of future studies.
Methods
Data are from the ESCAPE trial. All subjects or their surrogates provided informed consent for study enrolment and the study was approved by the local ethics board at each site. The imaging database was reviewed to identify subjects with carotid occlusion or near-occlusion on baseline CTA. In addition to the subjects reported with carotid occlusions in the original study report, we identified additional subjects with carotid near-occlusion. Additional data on carotid interventions were retrospectively sought from the interventionists at sites where these subjects with tandem occlusions were enrolled. These data included: (a) treatment in the acute setting; (b) sequence of treatment; (c) method of treatment; (d) use of antithrombotic medication with acute carotid stenting; (e) immediate endovascular technical outcome.
We assessed clinical, radiological, and vascular outcomes on both tandem and non-tandem occlusion subjects by treatment. The angiographic results were interpreted by the core laboratory; modfied Rankin Scale (mRS) scores and other clinical outcomes were determined by a blinded reviewer at the respective site. Data are described using standard descriptive statistics. Comparisons between the two groups were made using the Fisher exact test, t test, or Mann–Whitney U test according to data distribution. The small number of cases precluded multivariable analysis. All tests were two-sided and conventional levels of statistical significance were used (α=0.05).
Results
Patient demographics
A total of 54 (17.1%) subjects had tandem occlusions defined by baseline CTA as complete or near-occlusion of the proximal carotid artery at the bifurcation, 24 in the control group and 30 subjects in the intervention group (table 1). Subjects in the tandem occlusion group tended to be diabetic and were less likely to have atrial fibrillation than those without tandem occlusion. Six of 30 patients were taking antiplatelet agents at the time of presentation (acetylsalicylic acid 80 mg in four patients, clopidogrel 75 mg in two patients).
Baseline subject characteristics stratified by tandem lesion/no tandem lesion
Collateral contribution from circle of Willis
Most patients in the intervention group (n=27/30) showed normal or insignificant stenosis (<50%) of the contralateral cervical carotid artery on CTA; the remainder (3/30) showed variably significant steno-occlusive disease (50–70%, >70% and >90% each). All of the patients in the intervention group showed presence of either the anterior communicating artery, ipsilateral posterior communicating artery, or both.
Management strategies of tandem occlusions in the intervention group
The flow of subjects (n=30) in the intervention group is shown in figure 1. Of the 30 subjects in the intervention group, 17 (57%) underwent emergency endovascular treatment of the extracranial occlusion; 10 subjects underwent recanalization of the extracranial occlusion first followed by intracranial thrombectomy, and seven underwent intracranial thrombus retrieval first followed by cervical ICA treatment on the way out. Of the 10 subjects who underwent extracranial ICA recanalization first, two were managed by thromboaspiration, four were managed by angioplasty alone and four subjects underwent angioplasty followed by stenting. Among the remaining subjects (n=7) who underwent intracranial recanalization first followed by extracranial recanalization, four subjects were treated by a combination of angioplasty and stenting, two were managed by thromboaspiration, and only one was managed by angioplasty alone.
Workflow of subjects (n=30) in the intervention group.
Eight of the 17 subjects acutely treated for extracranial occlusion were treated with carotid stenting in the acute setting. The mode of emergency anticoagulation and antiplatelet therapy varied among the eight subjects (variable combinations of oral aspirin (81–325 mg) and clopidogrel (75–300 mg), with one patient receiving intravenous aspirin 250 mg). Two of the eight subjects were also systemically heparinized during the endovascular procedure. None of the subjects were given GP2b3a inhibitors acutely. All eight patients demonstrated stent patency on short-term (within 1 week) follow-up vascular imaging.
Among the remaining 13 of 30 subjects (43%) who did not undergo emergency treatment of the extracranial cervical disease, variable degrees of residual stenosis were documented after the endovascular procedure (4 cases showed no residual carotid disease, likely suggesting cervical carotid pseudo-occlusion due to large intracranial thrombus burden, 4 subjects showed >70% residual stenosis, and the remaining 5 showed <70% residual stenosis). Only four of these 13 subjects underwent invasive treatment of the cervical occlusions in the subacute phase (within 3 months); two underwent carotid artery stenting and two had carotid endarterectomy. The remaining nine subjects were managed medically.
Safety and clinical outcomes of tandem occlusions in the intervention group
Process, safety, and clinical outcomes are shown in table 2. Remarkably, patients with tandem occlusions showed recanalization of the target intracranial lesion at the same rate as those with intracranial occlusion only. Interval times and safety were similar between groups. The ESCAPE intervention arm showed greater overall reperfusion rates and better clinical outcomes in the intervention group compared with the control in the tandem occlusion group with an unadjusted effect size of 45%.
Efficacy and safety outcomes in in the intervention arm: tandem group versus no-tandem groups and subanalysis of the tandem occlusion group only
Among the subjects in the ESCAPE intervention group, outcomes were not different between those with and without tandem occlusion. Among those in the intervention group with tandem occlusion, outcomes did not differ according to whether the patients underwent acute carotid intervention or not, even though the absolute numbers favored acute carotid intervention and in turn favored treating the acute intracranial lesion first followed by the carotid. However, reperfusion rates were relatively higher in subjects whose intracranial occlusion was treated first, followed by treatment of extracranial occlusion (6/7, 85.7%) compared with the subgroup where the reverse sequence of treatment was employed (6/10, 60%).
Discussion
The main findings of this post hoc analysis of the ESCAPE trial are that acute treatment of the extracranial carotid artery was highly varied, from conservative (no carotid intervention) to aggressive approach (carotid artery angioplasty and stenting), and the unadjusted clinical and neurovascular outcomes were similar among the two groups. Both carotid stenting and angioplasty only were used, either before or after the intracranial lesion was addressed. Importantly, when used, the treatment appeared to be safe, even in the absence of a clear protocol for managing antithrombotic therapy. Procedural times were similar among the tandem and no-tandem groups in the intervention arm, despite the potential increase in technical difficulty incurred by the extracranial carotid lesion.
Tandem occlusions are seen in a large minority of patients (20%) presenting with major acute ischemic stroke.10 In the ESCAPE trial, 17% of the total patient population presented with acute tandem occlusions. MR CLEAN and REVASCAT investigators reported an incidence of 32.3% and 18.6% tandem occlusions, respectively.4 6 SWIFT PRIME and EXTEND IA trials excluded subjects with cervical carotid dissection or complete occlusion.5 7 Importantly, there is diagnostic error using CTA only. The carotid bifurcation was found to be normal when explored by microcatheter at least a quarter of the time, meaning that CTA is technically not accurate to identify carotid artery occlusions or stenoses when the carotid artery is occluded distally. This occurs because the CT gantry gets ahead of slow flowing contrast resulting in an imaging pseudo-occlusion.
We also note that almost all of the patients who presented with tandem occlusions in our study showed normal or near normal contralateral cervical carotid arteries, with some form of intracranial communication (through anterior or posterior communicating arteries) with the diseased side. This type of collateral vascular support might have been beneficial in slowing the rate of infarct growth.
The recanalization rate for carotid occlusion with intravenous alteplase alone is low.11 Kim et al reported an incidence of 9% complete recanalization with intravenous alteplase in cases with tandem cervical ICA/MCA occlusions, compared with 39% in cases with isolated MCA occlusion.12 The diseased segment of the cervical ICA is known to be composed of a predominantly atherosclerotic plaque and a superimposed thrombus with accelerated platelet activation, making it a difficult substrate for thrombolytic agents alone.10
Workflow in tandem lesion cases is often not a matter of preference, but sometimes dictated by necessity. For example, if it is impossible to cross the cervical carotid stenosis/blockage with an aspiration catheter, then angioplasty first is often considered. Immediate carotid artery angioplasty and stenting before addressing the intracranial lesion is argued to increase the distal perfusion through collaterals, improve the technical access to intracranial occlusion as well as decrease the stroke recurrence rate.10 However, treating the cervical carotid artery first can prolong the procedure incurring more brain injury, require anesthetic support, or increase risks of technical complications. The chances of distal thromboembolism may be higher when proximal occlusions are treated first, especially in the absence of distal protection devices.
A major concern with acute carotid stenting (either before or after treating the intracranial lesion) is the need for emergency antiplatelet therapy to prevent stent thrombosis. In a setting where patients may have already received intravenous alteplase, additional antithrombotic agents will increase the risk of hemorrhagic complications.13 Previous studies have shown mixed results and relatively poor clinical outcomes in part due to the increased hemorrhagic risk.14 15
Our study is limited by the relatively small sample size. Further studies on a larger patient population are needed to substantiate our results. Based on the ESCAPE trial data, tandem occlusions are common in subjects eligible for endovascular treatment with a predominance in younger men with diabetes mellitus. Endovascular treatment improves the overall clinical outcomes in subjects with tandem occlusions and was comparable to the treatment effect size in subjects without tandem occlusions. Several technical options for management of the extracranial carotid artery lesion were used and the outcomes were not obviously different among these choices. Establishment of a large data registry on intervention of these acute tandem occlusions may be helpful in arriving at a consensus or guidelines and laying the groundwork for future randomized trials.16 17
References
Footnotes
Contributors All the authors of this manuscript have given substantial contributions to the conception or design of the work; the acquisition, analysis, and interpretation of data for the work; drafting the work and revising it critically for important intellectual content; final approval of the version to be published; and have given agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The ESCAPE trial was an academic trial funded by a consortium including Medtronic, the University of Calgary (Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, Calgary Stroke Program), Alberta Innovates, the Heart & Stroke Foundation of Canada, the Canadian Institutes for Health Research and Alberta Health Services.
Competing interests Conflicts of interest: BKM: membership of the Steering and Executive Committee, ESCAPE trial that received support from Covidien; Site Principal Investigator, SOCRATES Trial, sponsored by Astra Zeneca; honoraria from Penumbra; a provisional patent 62/086,077 for triaging systems in ischemic stroke; research funding from Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada, Alberta Innovates Health Solutions, Hotchkiss Brain Institute and the Faculty of Medicine, University of Calgary and salary support from CIHR; holds the current Heart and Stroke Foundation/University of Calgary Professorship in Stroke Imaging and receives salary support through the CIHR New Investigator Award. MG: partial support for ESCAPE trial provided to University of Calgary; helped in design and conduct of SWIFT PRIME trial (compensation significant (>$10,000 or 5%)); compensation for speaking engagements from Covidien (significant) and Stryker (modest); patent for Systems of stroke diagnosis licensed to GE Healthcare (compensation significant). AMD: research support from Covidien/Medtronic; unrestricted grant for ESCAPE trial (no compensation); Speaker’s Bureau: Medtronic (significant >$10,000 compensation). DR: grants and personal fees from University of Calgary during the conduct of the study. JT: personal fees from Neuravi, Galway and Ireland outside the submitted work. DFF: personal fees from Covidien, Stryker, Penumbra, Microvention and Siemens during the conduct of the study. BWB: personal fees from Penumbra, Stryker Neurovascular, Covidien (Medtronic), Rapid Medical and Silk Road Medical outside the submitted work. MDH: grants from Covidien (Medtronic), Alberta Innovates Health Solutions, Heart & Stroke Foundation, Hotchkiss Brain Institute, Canadian Stroke Prevention Intervention Networks (CSPIN) (Institute of Circulatory and Respiratory Health, CIHR), Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, non-financial support from Alberta Health Services during the conduct of the study; personal fees from Merck; non-financial support from Hoffmann-La Roche Canada outside the submitted work; patent Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients pending to US Patent Office Number: 62/086,077 and owns stock in Calgary Scientific, a company that focuses on medical imaging software. The other authors report no conflicts of interest.
Ethics approval Ethics board of each 22 sites enrolled in ESCAPE trial.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement None declared.