Infarct in a New Territory After Treatment Administration in the ESCAPE Randomized Controlled Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times)
Background and Purpose—Infarct in a new previously unaffected territory (INT) is a potential complication of endovascular treatment. We applied a recently proposed methodology to identify and classify INTs in the ESCAPE randomized controlled trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times).
Methods—The core laboratory identified INTs on 24-hour follow-up imaging, blinded to treatment allocation, after assessing all baseline imaging. INTs were classified into 3 types (I–III) and 2 subtypes (A/B) based on size and if catheter manipulation was likely performed across the vessel territory ostium. Logistic regression was used to understand the effect of multiple a priori identified variables on INT occurrence. Ordinal logistic regression was used to analyze the effect of INTs on modified Rankin Scale shift at 90 days.
Results—From 308 patients included, 14 INTs (4.5% overall; 2.8% on follow-up noncontrast computed tomography, 11.7% on follow-up magnetic resonance imaging) were identified (5.0% in endovascular treatment arm versus 4.0% in control arm [P=0.7]). The use of intravenous alteplase was associated with a 68% reduction in the odds of INT occurrence (3.0% with versus 9.1% without; odds ratio, 0.32; 95% confidence interval, 0.11–0.96; adjusted for age, sex, and treatment type). No other variables were associated with INTs. INT occurrence was associated with reduced probability of good clinical outcome (common odds ratio, 0.25; 95% confidence interval, 0.09–0.74; adjusted for age, type of treatment, and follow-up scan).
Conclusions—INTs are uncommon, detected more frequently on follow-up magnetic resonance imaging, and affect clinical outcome. In experienced centers, endovascular treatment is likely not causal, whereas intravenous alteplase may be therapeutic.
- cerebral infarction
- clinical protocols
- follow-up studies
- magnetic resonance imaging
- plasminogen activator
Endovascular treatment is now the standard of care for acute large vessel ischemic stroke in the anterior circulation.1–5 Infarct in a new territory (INT) is a potential complication of endovascular treatment and implies that the intervention results in a new infarct in a territory that was unaffected by the original occlusion.6 An example of this would be an ipsilateral anterior cerebral artery infarct in a patient who received endovascular treatment for a mid-M1 occlusion in the middle cerebral artery. INT can be identified on a follow-up noncontrast computed tomographic (NCCT) scan or diffusion-weighted magnetic resonance imaging (MRI).
There is a need for consistent reporting of such adverse events in clinical trials to facilitate better understanding of the complications of endovascular therapy.7,8 We recently proposed a methodology for the documentation of INT after the endovascular procedure.6 This classification takes into account variations in vascular anatomy and the location of the thrombus, using information on the preprocedure noninvasive vascular imaging, end-of-procedure angiography images, and the location of infarcts on follow-up imaging. INTs are classified on the basis of size, as well as catheter manipulation across the ostium of the arterial territory (Table I in the online-only Data Supplement).
We applied this methodology to identify and classify INTs in the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) of endovascular stroke treatment.
ESCAPE was a prospective, multicenter, randomized clinical trial (NCT01778335), the methodology of which has been detailed in previous publications.2,9 The trial involved 22 centers in Canada (11), the United States (6), Korea (3), the United Kingdom (1), and Ireland (1). All patients received an NCCT head and a CT angiography (preferably multiphase). Inclusion criteria for the trial, in brief, were acute ischemic stroke with a National Institutes of Health Stroke Scale score >5; symptom onset within 12 hours of presentation; no premorbid disability; a small infarct core defined as an Alberta Stroke Program Early CT Score >5 on NCCT head; internal carotid artery, M1, or functional M1 occlusion, and moderate to good collaterals on CT angiography. Patients randomized into the treatment arm received standard care plus endovascular treatment with available thrombectomy devices. The use of retrievable stents and suction through a balloon guide catheter in the relevant internal carotid artery during thrombus retrieval was recommended. Aggressive target times were chosen, 60 minutes or less from study NCCT to groin puncture and 90 minutes or less from study NCCT to first reperfusion. Patients randomized into the control arm received intravenous alteplase (0.9 mg/kg body weight) or standard stroke care as per established guidelines. For this per-protocol analysis, treatment was defined as the use of a guide catheter across the arch at least once; patients randomized to the endovascular arm not receiving that treatment were therefore excluded from analysis.
The central core laboratory identified INTs on 24-hour follow-up imaging (magnetic resonance diffusion-weighted imaging if available; noncontrast CT if MRI was not available). The follow-up imaging was compared with baseline parenchymal and vascular imaging and procedural angiography. The core laboratory flagged all infarcts located outside the immediate territory of the vessel implicated in the presenting stroke using the new classification of INT (Table I in the online-only Data Supplement). The diameter of these infarcts was measured, and the infarcts were classified into 1 of 3 types (I–III) and 2 subtypes (A or B; for the endovascular arm only) as in Table 1. The number and proportion of INTs in each category were reported in the endovascular and control arms of the trial. We analyzed the effect of a priori identified variables, such as age, sex, history of congestive heart failure, atrial fibrillation on anticoagulation, baseline international normalized ratio, baseline partial thromboplastin time, presence of extracranial carotid disease, baseline site of occlusion (middle versus internal carotid artery segment), baseline clot burden score (trichotomized as 0–4, 5–7, and 8–10; higher scores indicate lower clot burden),10 use of intravenous alteplase at baseline, and time from stroke symptom onset to randomization on development of INT using logistic regression. We also analyzed the use of balloon guide catheters or stent retrievers in the endovascular arm and development of INT. Finally, we analyzed the effect of INTs on the primary clinical outcome in the ESCAPE trial, that is, modified Rankin Scale shift at 90 days, using ordinal logistic regression after adjusting for age, sex, and treatment type. The proportional odds assumption was tested using the Brant Wald test. Sensitivity analyses were performed to analyze if follow-up imaging modality, that is, noncontrast CT versus MRI, affected results. Statistical analysis was performed in Stata/MP version 14.0 (StataCorp LP). Statistical significance was assessed 2-sided at α≤0.05 in all analyses.
One hundred sixty (51.8%) patients received endovascular treatment when compared with 149 (48.2%) patients in the control arm. One patient in the endovascular treatment arm did not have follow-up imaging and was therefore excluded from further analysis. Of the 308 patients included in the analysis, INTs were assessed using magnetic resonance diffusion-weighted imaging in 59 (19.2%) patients. A total of 14 INTs (4.5% overall), 5.0% (n=8) in the endovascular treatment arm and 4.0% (n=6) in the control arm (P=0.7), were identified. Distribution of INTs stratified by follow-up imaging modality and treatment type is shown in Figure 1. Distribution of INTs as per the new classification (Table I in the online-only Data Supplement) in the endovascular treatment arm versus the control arm of the trial is shown in Table 1.
The use of intravenous alteplase at baseline was associated with a 68% reduction in the odds of occurrence of INTs on follow-up (3.0%. versus 9.1% without intravenous alteplase; odds ratio, 0.32; 95% confidence interval, 0.11–0.96; adjusted for age, sex, and treatment type). No other predictor variables were associated with the occurrence of INTs on follow-up in univariate (Table 2) or multivariable analysis (Table II in the online-only Data Supplement). In the endovascular treatment arm, the use of a balloon guide catheter (P=0.325) or stent retriever (P=0.983) was not associated with reduced occurrence of INTs. Occurrence of INTs on follow-up imaging was associated with a significant reduction in odds of good clinical outcome (improvement of 1 point on the modified Rankin Scale) after adjusting for age, treatment type, and type of follow-up scan (MRI versus CT): common odds ratio, 0.25; 95% confidence interval, 0.09 to 0.74; Brant test P=1.0 (Table 3).
In sensitivity analyses looking at the effect of variability in follow-up imaging modality on estimates, the use of MRI was more common in the endovascular treatment arm than in the control arm (25.2% versus 12.7%; P<0.01). The rate of detection of INTs ranged from 2.8% on follow-up NCCT to 11.7% on follow-up MRI. There was no statistically significant difference in detection of INTs between endovascular treatment and control arm when using follow-up noncontrast CT (3.1% versus 2.5%, respectively; P=1.0) or MRI (12.5% versus 10.5%, respectively; P=1.0). The use of intravenous alteplase at baseline was associated with a 66% reduction in the odds of occurrence of INTs on follow-up (odds ratio, 0.34; 95% confidence interval, 0.11–1.00; P=0.05, adjusted for age, sex, treatment type, and type of follow-up imaging). None of the other predictor variables were associated with the occurrence of INTs on follow-up noncontrast CT or MRI (P>0.05).
We found that the occurrence of INTs in the ESCAPE trial was low (4.5% overall), whereas large INTs were rare (1.3%). We noted no difference in the occurrence of INTs between endovascular treatment and control arms of the trial. Even within the endovascular treatment arm, 6 of 8 INTs were type B, that is, the guide catheter was less likely to have been manipulated past the ostium of the affected arterial territory in these INTs (Table 1). Our results suggest that the occurrence of INTs may not be related to the endovascular procedure, especially in experienced centers. Interestingly, we found that the administration of intravenous alteplase was associated with significantly fewer INTs on follow-up imaging.
With the success of the recent endovascular treatment trials, an issue of interest in the stroke community is the safety of the procedure itself. Endovascular treatment is an invasive procedure; as such, it has been assumed that the procedure is likely to dislodge thrombi into as yet unaffected arterial territories, causing INTs. The MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) reported 13 cases (5.6%) of new ischemic stroke in a different vascular territory in the interventional arm compared with 1 case (0.4%) in the control arm, although this was based on clinical signs only (systematic INT analysis is in preparation).1 EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial) reported 2 cases (6%) of embolization into a different vascular territory identified on neuroimaging in the interventional arm,5 and REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) reported 5 (4.9%) cases of distal embolization in a different territory.4 This outcome was not among the adverse events reported by SWIFT-PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment).3 Although the ESCAPE trial initially reported 32 infarcts as INTs, a rereview of imaging using the new classification in Table 1 resulted in our trial reporting only 14 INTs; the remaining infarcts were explainable as preprocedural or likely to be in the primary vascular territory involved. This analysis of INTs within the ESCAPE trial using a standardized classification has not only shown that INTs are uncommon but also that they are less likely to be a complication of the endovascular procedure itself. This is further substantiated by the occurrence of INTs, regardless of the use of balloon guide catheters or stent retrievers in our analysis.
Concerns have also been raised about intravenous alteplase causing INTs by disintegrating potentially preexisting thrombi within the cardiac or large arterial system and causing early recurrent ischemic stroke.11 Our analysis refutes this hypothesis by showing that administration of intravenous alteplase was associated with a reduction in the odds of occurrence of INTs by 68% on average. Our analysis also shows that no other variable of interest was associated with the occurrence of INTs. It could therefore be hypothesized that thrombi causing INTs may occur before, with, or after the index ischemic stroke event potentially as a result of the same pathology. Intravenous alteplase is possibly therapeutic, perhaps by dissolving not just the target thrombus but also any new thrombi that may have formed or embolized during this time. This could potentially be further examined in a randomized controlled trial of intravenous alteplase plus endovascular therapy versus endovascular therapy alone.
INTs are likely to reduce the chance of good clinical outcome in patients with acute ischemic stroke, with larger INTs likely to do so more than smaller INTs (data not shown; Figure 2). The 2 established treatment modalities for acute ischemic stroke, that is, endovascular treatment and administration of intravenous alteplase, are likely not causal. Moreover, intravenous alteplase may reduce the occurrence of INTs, thus improving the chance of good clinical outcome in these patients. A limitation of our study is that a majority (80%) of INTs were identified on CT imaging. Because MRI is more sensitive than CT in picking up acute infarcts, we may have underestimated the true prevalence of INTs. Nonetheless, in sensitivity analyses adjusting for the type of follow-up imaging modality, our results with regard to treatment-type differences (endovascular treatment versus control) and use of intravenous alteplase remain valid. Finally, given the post hoc nature of our analysis, our results will need to be replicated in other studies.
In conclusion, INTs are uncommon but affect clinical outcome and are likely an epiphenomena of the acute ischemic stroke process rather than a complication of ischemic stroke treatment, especially in experienced centers.
Dr Menon had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors fulfill International Committee of Medical Journal Editors (ICMJE) criteria for authorship.
Sources of Funding
The study sponsor was the Governors of the University of Calgary. The sponsor had no role in the design, data gathering, analysis, or reporting of the trial. Covidien Inc provided major funding through an unrestricted grant to the University of Calgary. Additional active and in-kind support for the trial was from a consortium of funding public and charitable sources: Heart and Stroke Foundation Canada, Alberta Innovates Health Solutions, Alberta Health Services, Canadian Stroke Prevention Intervention Network (CSPIN) through the Canadian Institutes of Health Research (CIHR). The University of Calgary provided internal funding from the Hotchkiss Brain Institute, the Department of Clinical Neurosciences, the Department of Radiology, and the Calgary Stroke Program.
Dr Ganesh reports funding from the Rhodes Trust, stock options from SnapDx, TheRounds.ca, and The Self-Care People. Dr Roy reports grants and personal fees from University of Calgary, during the conduct of the study. Dr Demchuk reports research support from Covidien/Medtronic: unrestricted grant for ESCAPE trial, no compensation; Speaker’s Bureau: Medtronic: significant >$10 000 compensation. Dr Frei reports personal fees from Covidien, personal fees from Stryker, personal fees from Penumbra, personal fees from MicroVention, and personal fees from Siemens, during the conduct of the study. Dr Thornton reports personal fees from Neuravi, Galway, and Ireland outside the submitted work. Dr Baxter reports personal fees from Penumbra, Stryker Neurovascular, Covidien (Medtronic), Rapid Medical, and Silk Road Medical outside the submitted work. Dr Jovin reports personal fees from Covidien and personal fees from Stryker, during the conduct of the study. Dr Hill reports grants from Covidien (Medtronic), Alberta Innovates Health Solutions, Heart and Stroke Foundation, Hotchkiss Brain Institute, Canadian Stroke Prevention Intervention Networks (CSPIN) (Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research [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; and nonfinancial support from Hoffmann-La Roche Canada Ltd, outside the submitted work. In addition, Dr Hill has a 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 Incorporated, a company that focuses on medical imaging software. Dr Menon reports membership of the Steering and Executive Committee, ESCAPE trial that received support from Covidien; Site Principal Investigator, SOCRATES trial (Acute Stroke or Transient Ischaemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), sponsored by AstraZeneca, honoraria from Penumbra Incorporated, a provisional patent 62/086 077 for triaging systems in ischemic stroke, research funding from 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. In addition, he holds the current Heart and Stroke Foundation/University of Calgary Professorship in Stroke Imaging and receives salary support through the CIHR New Investigator Award. Dr Goyal reports partial support for ESCAPE trial provided to University of Calgary. Dr Goyal also helped in design and conduct of SWIFT-PRIME trial; compensation: significant (>$10 000 or 5%). In addition, Dr Goyal has received compensation for speaking engagements from Covidien Incorporated (significant) and Stryker Incorporated (modest). He also has a patent for Systems of stroke diagnosis licensed to GE Healthcare (compensation significant). The other authors report no conflicts.
Guest Editor for this article was Louis Caplan, MD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.014852/-/DC1.
- Received July 30, 2016.
- Revision received September 6, 2016.
- Accepted September 30, 2016.
- © 2016 American Heart Association, Inc.
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