Five recent clinical trials have

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1 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Bijoy K. Menon, MD, MSc Mayank Goyal, MD 1 From the Calgary Stroke Program and Department of Clinical Neurosciences (B.K.M., M.G.), Department of Radiology (B.K.M., M.G.), and Department of Community Health Sciences (B.K.M.), University of Calgary, Calgary, Alberta, Canada; and Hotchkiss Brain Institute, Calgary, Alberta, Canada (B.K.M., M.G.). Received May 4, 2015; revision requested June 1; revision received June 15; final version accepted June 26. Address correspondence to M.G., Department of Radiology, Seaman Family MR Research Centre, Foothills Medical Centre, th St NW, Calgary, AB, Canada T2N 2T9 ( mgoyal@ucalgary.ca). q RSNA, 2015 Imaging Paradigms in Acute Ischemic Stroke: A Pragmatic Evidence-based Approach 1 Five recent clinical trials have shown the efficacy of endovascular treatment with mechanical devices in the care of patients with acute ischemic stroke (1 5). Only patients with proximal anterior circulation thrombi were included in these trials. Four of these trials also excluded patients with a large baseline infarct from enrolment (2 5). Although not part of the explicit exclusion criteria, analysis of baseline imaging data suggests that investigators in the remaining trial may also have used imaging to exclude patients with a large baseline infarct (1). A focus on quick, effective, and safe reperfusion in patients with large intracranial thrombi and small to moderate baseline infarcts identified with imaging strategies that were well integrated into the workflow distinguished these trials from earlier trials (6,7). Of note, however, the imaging strategies used in these trials differed to some extent. We seek to examine evidence from these trials to identify common imaging strategies that physicians can use to select patients who are likely to benefit from endovascular therapy. A summary of imaging and workflow parameters from these clinical trials is shown in the Table. Unenhanced CT Time is of quintessential importance in the care of patients with acute stroke (8 10). Thus, imaging strategies within the acute stroke workflow must be quick to perform, be available at all times of the day or night, yield images that are easy to interpret, and be reliable in the discrimination of suitability for endovascular treatment (11 13). Unenhanced CT has many of these properties. Unenhanced CT is quick to perform, widely available, and a useful prognostic tool in patients with acute ischemic stroke (14). Through systematic assessment of early ischemic changes in the middle cerebral artery with the ASPECTS template, physicians can potentially estimate the size of a baseline infarct (15,16). The hyperdense artery sign, preferably seen on thin-section unenhanced CT images, indicates proximal intracranial thrombi in many, but not all, patients (17). All five recent clinical trials used unenhanced CT as a first-line imaging tool in the vast majority of patients. A perusal of the eligibility criteria of the five clinical trials suggests that the overarching philosophy was to identify an optimal target for endovascular treatment in patients without large infarcts at baseline (1 5). Unenhanced CT has some disadvantages that limit its exclusive use in the context of this philosophy. Estimation of the size of a baseline infarct through assessment of early ischemic changes in ASPECTS is less reliable in patients who present within 90 minutes of stroke symptom onset (18). Variability in imaging equipment (eg, type of scanner, spiral vs sequential), image acquisition parameters (tube potential, tube current), and patient factors (eg, atrophy and leukoaraiosis) also may affect reliability (15,18). Unenhanced CT does not enable identification of all patients with target anterior circulation proximal thrombi; variability in section thickness, vessel wall calcification, and patient hematocrit level may affect reliability in the detection of intracranial thrombi (17,19,20). A physician receives information on variables like age, stroke severity, and time from stroke symptom onset while using imaging to make clinical decisions. This prior information influences the physician s interpretation of images when he or she is making a dichotomous decision for or against treatment (21). This nature of clinical decision making, where prior information and imaging data are used to make Reviews and Commentary n Perspectives Radiology: Volume 277: Number 1 October 2015 n radiology.rsna.org 7

2 clinical decisions, is Bayesian. Disadvantages with unenhanced CT, including decreased reliability in measuring the extent of early ischemic changes and the presence of proximal intracranial thrombi, are reduced in a Bayesian framework. For example, a patient with severe stroke at baseline (National Institutes of Health Stroke Scale score.20) who presents early (within 90 minutes) after stroke onset is highly likely to have both proximal intracranial thrombi and a salvageable brain, even if the unenhanced CT image is degraded by motion artifacts. Another patient who presents 6 hours after stroke onset with unenhanced CT ASPECTS of 5 and a hyperdense artery sign is highly likely to receive treatment if he or she is 40 years old or younger. Thus, it is reasonable to argue that unenhanced CT is the first common denominator in the work-up of patients who present with symptoms of acute ischemic stroke and who could be candidates for endovascular treatment. Physicians should use unenhanced CT to select patients without obvious and extensive early ischemic changes in the appropriate clinical context for endovascular therapy. MR Imaging Diffusion-weighted (DW) MR imaging can be used to assess a baseline infarct. Short 6-minute MR stroke protocols have been described (22). MR imaging, however, has many practical drawbacks. These include the need to screen patients who have experienced a stroke for metallic implants and the difficulty in monitoring these patients within the MR imaging suite (23). MR imaging is not available 24 hours a day 7 days a week in many stroke centers. MR imaging is also susceptible to patient motion. MR imaging, in spite of its accuracy, can potentially take more time than unenhanced CT within the acute stroke workflow (24). When the additional time taken and the logistical challenges of implementing MR imaging are balanced by the fact that acute stroke decision making happens within a Bayesian framework, the relative advantage of MR imaging versus unenhanced CT is not apparent. In a hypothetical example, a younger patient with no previous comorbidities who presents very early (within 90 minutes of stroke onset) with severe symptoms, minimal early ischemic changes at unenhanced CT, and a large lesion on DW MR images is more likely to be offered endovascular therapy by the treating physician than is an older patient with multiple medical comorbidities who presents 5 hours after stroke onset with similar imaging findings. Because clinicians let prior patient information influence how imaging helps clinical decision making, the relative disadvantages of unenhanced CT versus MR imaging in the estimation of early ischemic changes are reduced, even more so with literature showing that early DW imaging changes may be reversible with reperfusion (25). Of note, MR imaging was used in only a minority of patients in a few of the recent clinical trials (1 5). Thus, evidence for the use of MR imaging in the acute endovascular stroke workflow is modest at best. It is our opinion that MR imaging should be used only in the acute stroke workflow if centers are able to achieve speed and triaging efficiency similar to that which is currently available with CT-based imaging. Moreover, physicians may need to reflect on the additional utility of MR imaging versus CT-based imaging in a Bayesian framework when making such a choice. CT Angiography Vascular imaging, primarily performed with CT angiography, was a mainstay in all five clinical trials (1 5). When patients are undergoing endovascular therapy, CT angiography provides physicians with information on the ability to deliver the treatment to the target. CT angiography depicts the presence or absence of the target for endovascular therapy 100% of the time (26). Past studies have shown that endovascular therapy is most likely to benefit patients with proximal intracranial thrombi in whom early recanalization with intravenous tissue plasminogen activator is low (19,27,28). All five recent clinical trials used vascular imaging (primarily CT angiography) to identify patients with proximal intracranial thrombus in the anterior circulation (1 5). CT angiography also provides information on the anatomy of the arch of the aorta, tortuosity of the proximal extracranial neck vessels, and anatomy of the ipsilateral carotid bifurcation, all of which help the physician plan the endovascular procedure (26). This prior planning, in our opinion, helps achieve quicker, safer, and more efficient reperfusion (13). Thus, in our opinion, CT angiography is the second recommended imaging technique when selecting patients for endovascular therapy. Physicians should use CT angiography to identify patients with proximal intracranial thrombi in whom endovascular therapy is appropriate and to plan the endovascular procedure. Collateral Vessel Imaging with CT Angiography The ESCAPE trial used an innovative imaging strategy to address concerns about the reliability of unenhanced CT in estimating the extent of early ischemic changes (2). The trial used collateral vessel imaging with CT angiography to improve the accuracy of assessing early ischemic changes on unenhanced CT images. Collateral Published online /radiol Radiology 2015; 277:7 12 Content code: Abbreviations: ASPECTS = Alberta Stroke Program Early CT score DW = diffusion weighted ESCAPE = Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness EXTEND-IA = Extending the Time for Thrombolysis in Emergency Neurologic Deficits Intra-Arterial MR CLEAN = Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands REVASCAT = Endovascular Revascularization with Solitaire Device versus Best Medical Therapy in Anterior Circulation Stroke within 8 Hours SWIFT PRIME = Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment Online supplemental material is available for this article. 8 radiology.rsna.org n Radiology: Volume 277: Number 1 October 2015

3 Imaging Techniques Used for Patient Selection and Workflow Time Metrics in the Five Recent Endovascular Treatment Trials Modality and Workflow Time Metric MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Imaging modality for trial inclusion Unenhanced computed tomography (CT) Yes Yes* Yes Yes* Yes* CT angiography Yes Yes Yes Yes Yes Collateral assessment on multiphase No Yes No No No CT angiograms CT perfusion No No Yes Yes (in 81% of patients) NR Magnetic resonance (MR) imaging No No No Yes (in very few patients) NR Workflow time metric (min) Time from stroke onset to CT NR 134 (77 247) NR NR NR Time from stroke onset to first reperfusion 332 ( ) 241 ( ) 248 ( ) 252 ( ) 355 ( ) Time from stroke onset to groin puncture, 260 ( ) NR 210 ( ) NR 269 ( ) mins-median (IQR) Time from stroke onset to last angiogram 339 ( ) NR NR NR NR Time from CT to groin puncture NR 51 (39 68) 93 (71 138) NR NR Time from CT to first reperfusion NR 84 (65 115) NR NR NR Time from qualifying image to groin puncture # NR NA NA 58 (41 83) 67 (47 84) Time from qualifying image to first deployment # NR NA NA 87 (63 108) NR Time from groin puncture to reperfusion NR 30 (27.5) 43 (24 53) NR 59 (36 95) Note. Unless otherwise indicated, data are median, and data in parentheses are the interquartile range. ESCAPE = Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness, EXTEND-IA = Extending the Time for Thrombolysis in Emergency Neurologic Deficits Intra-Arterial, MR CLEAN = Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands, NA = not applicable, NR = data not reported, REVASCAT = Endovascular Revascularization with Solitaire Device versus Best Medical Therapy in Anterior Circulation Stroke within 8 Hours, SWIFT PRIME = Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment. * Alberta Stroke Program Early CT Score (ASPECTS) template was used to assess early ischemic changes. Preferably multiphase CT angiography. Although an option, CT perfusion based traditional perfusion maps were not used for patient selection in the ESCAPE study. Time from first CT image. In the EXTEND-IA study, this time was onset to modified Thrombolysis in Infarction Score (or mtici) 2b/3 or completion. # Time from qualifying image for study need not mean the first acquired image. vessels are tiny arterioles that connect the distal branches of the cerebral arteries (29). Collateral vessels supply the ischemic region beyond an intracranial occlusion with blood until recanalization is achieved. Collaterals can be indirectly measured with CT angiography by assessing the degree and extent of backfilling in pial arteries beyond an occlusion. Ischemic brain regions with moderate to good backfilling pial arteries (good collateral vessels) are potentially salvageable, whereas those with minimal or no backfilling (poor collateral vessels) are unlikely to be salvageable (30). Thus, poor pial arterial backfilling in ischemic brain regions is likely associated with early ischemic changes at unenhanced CT (14). This complementarity between unenhanced CT ASPECTS and collateral imaging at CT angiography was used in the ESCAPE trial (2). The ESCAPE trial collateral vessel assessment on CT angiograms was matched with the ASPECTS anatomic template on unenhanced CT images; minimal or no pial collateral vessels in more than 50% of the ischemic anterior circulation corresponded to ASPECTS of 5 or less in patients with internal carotid artery or middle cerebral artery M1 segment occlusion (2). Moreover, the combined unenhanced CT and collateral imaging method was quick to perform, the results were easy to interpret, and the examination was available 24 hours a day 7 days a week; this was reflected in the rapid enrolment in the ESCAPE trial (2). The ESCAPE trial (n = 316) introduced another imaging innovation (the use of multiphase CT angiography to assess collateral vessels) (2,31). A disadvantage of collateral vessel assessment with single-phase CT angiograms is that it relies on assessment of one image in time of blood vessels filled with contrast material. Thus, the risk is that patients with adequate collateral vessels will be misclassified as having poor collateral vessels if images are acquired early in the arterial phase (31). Multiphase CT angiography generates time-resolved cerebral angiograms of the brain vasculature from the skull base to the vertex (31). Standard aortic arch vertex CT angiography performed with a multidetector CT scanner is the first phase. This acquisition is timed to be in the late arterial phase by triggering the scan on the basis of bolus monitoring. The remaining two phases are from the skull base to the vertex in the midvenous and late venous phase. The Radiology: Volume 277: Number 1 October 2015 n radiology.rsna.org 9

4 two additional phases of multiphase CT angiography use no additional contrast material; the total additional radiation dose is minimal (mean, 1.0 msv [standard deviation]) (31). The technique, with its use of reconstructed 24-mm maximum intensity projection images, minimizes artifacts due to patient motion (31). A detailed analysis of the comparative efficacy of the various CT-based imaging techniques (unenhanced CT; unenhanced CT and single-phase CT angiography; unenhanced CT, multiphase CT angiography, and CT perfusion) was used to confirm the utility of this imaging technique in clinical decision making (31). In addition, a post hoc analysis from the MR CLEAN and Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trials shows that patients with poor collateral vessels at baseline CT angiography receive no additional benefit from endovascular therapy (32,33). Thus, in our opinion, collateral imaging at CT angiography (preferably multiphase CT angiography) improves clinical decision making for endovascular therapy within an unenhanced CT and CT angiography paradigm at minimal additional cost (in terms of time, radiation, contrast material, and logistics). Thus, physicians should consider evaluating collateral vessels on CT angiograms (preferably those obtained with multiphase CT angiography) to aid in selecting patients with proximal intracranial thrombi for endovascular therapy. Of note, the REVASCAT trial (n = 206) used unenhanced CT ASPECTS (score,7) or DW MR imaging ASPECTS (score,6) to exclude patients with large baseline infarcts within 4.5 hours of stroke symptom onset in addition to CT angiography to identify patients with proximal anterior circulation occlusions (3). In patients who presented more than 4.5 hours after stroke symptom onset, the trial insisted on an additional imaging modality, such as CT angiography source image AS- PECTS, CT perfusion cerebral blood volume map ASPECTS, or MR DW imaging ASPECTS in patients deemed eligible for study inclusion on the basis of unenhanced CT ASPECTS. CT Perfusion The SWIFT PRIME trial (n = 196) and the EXTEND-IA trial (n = 70) used CT perfusion in 85% of patients in the SWIFT PRIME trial and in 100% of patients in the EXTEND-IA trial (4,5). These trials used unenhanced CT (DW MR imaging in a minority of patients) at baseline along with CT angiography (MR angiography in a minority of patients). The SWIFT PRIME trial also used unenhanced CT ASPECTS to identify eligible patients (4). Thus, these two trials, along with the other three trials, support the use of unenhanced CT and CT angiography images in the selection of patients with acute ischemic stroke for endovascular therapy. CT perfusion was used in these two trials to increase accuracy of imaging in the exclusion of patients with a large baseline infarct or minimal salvageable tissue (4,5). CT perfusion as an imaging modality has some disadvantages. These include limited brain coverage (8 cm with most current scanners), susceptibility to z-axis motion, and the amount of time taken to acquire, process, and interpret images (34). To address concerns regarding variability in output due to variability in choice of arterial input function, motion correction, and processing algorithms, the two trials used software that provided investigators with an automated output on extent of baseline infarct and mismatch between baseline infarct and salvageable brain (35). Nonetheless, even with this type of software, challenges remain in optimizing motion correction and setting the appropriate blood flow threshold and criteria used to define infarct and salvageable tissue (36). Post hoc analysis of patients undergoing CT perfusion in the MR CLEAN trial showed that in 90 of 265 patients, CT perfusion data could not be used because of various technical issues, including patient motion (n = 28), insufficient contrast material supply (n = 16), and truncation of the arterial input function or venous output function (n = 46). Moreover, no statistical interaction was noted between CT perfusion imaging criteria and treatment, suggesting that the criteria used by the investigators in their post hoc analysis did not help them discriminate between patients who benefited from treatment and those who did not (32). Of note however, when unenhanced CT and CT angiography are already available and necessary for endovascular decision making (based on evidence from all five clinical trials) and when collateral imaging is additionally available to increase the accuracy of the unenhanced CT and CT angiography based imaging paradigm, questions regarding the additional utility of CT perfusion in clinical decision making remain (Fig E1 [online]). CT perfusion may have a role in patients who present late (.6 hours) after stroke onset. However, the positive trials that enrolled patients more than 6 hours after stroke onset (ESCAPE used unenhanced CT and CT angiography collateral imaging, REVASCAT used unenhanced CT ASPECTS with or without CT perfusion or MR imaging) used other imaging strategies. The ES- CAPE trial had a total of 49 patients in the window of 6 12 hours after stroke onset where analysis continued to show the same direction of effect (modified Rankin score of 0 2 at 90-day follow-up; risk ratio, 1.7; 95% confidence interval: 0.7, 4.0), although this difference was not statistically significant. Additionally, in the appropriate clinical setting (clinically severe stroke, good premorbid status), unenhanced CT and CT angiography findings of a small core, proximal vessel occlusion, and good collateral vessels are likely to lead to the same clinical decision as a CT perfusion based paradigm (31). Thus, in our opinion, centers that are already using CT perfusion should consider using unenhanced CT ASPECTS and CT angiography collateral vessels (preferably at multiphase CT angiography) for clinical decision making. CT perfusion can then provide additional information on issues, such as the ability to (a) predict early thrombus lysis with intravenous thrombolytics, (b) 10 radiology.rsna.org n Radiology: Volume 277: Number 1 October 2015

5 assess risk of hemorrhage with reperfusion, and (c) recognize stroke mimics in patients without occlusions at CT angiography (37 39). This type of information may not influence current clinical decision making with regard to offering endovascular therapy in tertiary hospitals, especially when the prior probability of the patient having an ischemic stroke and not a stroke mimic is high, but it may be of use in the triage of patients who have had a stroke. Summary of Imaging Strategies Used in Recent Clinical Trials The aforementioned five recent clinical trials focused on quick and efficient reperfusion in patients with large intracranial thrombi and small to moderate baseline infarcts (1 5). An overarching philosophy of these trials was to exclude patients with large baseline infarcts. In the past, multiple analyses have shown that patients with large baseline infarcts are unlikely to benefit from revascularization therapy; in fact, some patients may even be harmed (40 42). Of note however, the recent trials used different strategies to identify such patients. The largest of these trials, the MR CLEAN study included 500 patients with proximal arterial occlusion in the anterior cerebral circulation that was confirmed with vessel imaging and could be treated intraarterially within 6 hours after symptom onset (1). The researchers did not use any imaging modality to exclude patients on the basis of the size of the baseline infarct. In our opinion, their study design rested on the assumption that a significant proportion of patients who present within 6 hours are likely to have a salvageable brain at baseline and are not likely to have large baseline infarcts. This assumption is inherently Bayesian in nature (21). Interestingly, the point estimate for treatment effect in the prespecified subgroup with unenhanced CT ASPECTS of less than 5 was close to unity (adjusted common odds ratio, 1.09; 95% confidence interval: 0.14, 8.46) (1). Moreover, the trial only had 28 (5.6%) of 496 patients with AS- PECTS of less than 5 at baseline, raising the possibility that investigators may have used their discretion to exclude patients with extensive early ischemic changes at unenhanced CT from the trial (1). One of the reasons for a lower effect size in this trial when compared with that in the other trials could be the absence of an imaging strategy to rule out patients with large baseline infarcts (1 5). In summary, unenhanced CT with CT angiography was the primary imaging strategy used in the recent clinical trials to select patients for endovascular therapy (1 5). It is possible that patients who may have benefited from endovascular treatment were excluded from these current trials. These patients could be those with (a) proximal vessel occlusion with a low National Institutes of Health Stroke Scale score; (b) a large baseline infarct core (AS- PECTS 4 5, relative cerebral blood flow,30% of.70 ml, or both); (c) an even larger infarct core manifesting within the first 60 minutes after stroke onset; (d) middle cerebral artery segment 2, anterior cerebral artery segment 2, or posterior cerebral artery segment 2 occlusion with clinically disabling stroke; or (e) posterior circulation strokes. Whether such patients will benefit from endovascular treatment cannot be adequately determined from current trial results. Nonetheless, in our opinion, an imaging paradigm based on unenhanced CT and CT angiography can be used to inform clinical decision making in these patients. The current trials focused on efficient and effective reperfusion. In the ESCAPE trial, the median time from head CT to first reperfusion was 84 minutes (2). However, it should be noted that this time occurred in the setting of a clinical trial. It is likely that with establishment of endovascular therapy as the standard of care and with resources, innovation, technology, and further improvement in the quality of reperfusion, imaging methods with which to identify irreversibly infarcted brain tissue and patients in whom recanalization will be futile will evolve. Criteria for defining brain tissue that is irreversibly infarcted with reperfusion may depend on variables such as time from stroke onset to reperfusion, efficiency of reperfusion, and patient age. It is clear that imaging will play a major role in further advancing the indications for endovascular treatment. Imaging can also help make stroke systems of care more efficient by helping physicians make decisions regarding transfer of patients with an acute ischemic stroke from primary stroke centers to centers capable of performing endovascular procedures (43). Disclosures of Conflicts of Interest: B.K.M. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is a member of the Steering and Executive ESCAPE trial. Other relationships: has a patent pending for systems of triage in acute stroke. M.G. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a grant from Covidien for partial support of the ESCAPE trail, served as a consultant to Covidien for design and conduct of the SWIFT PRIME trial. Other relationships: has a patent pending with GE Healthcare for systems of acute stroke diagnosis. References 1. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372(1): Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. 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