Various imaging paradigms are used for endovascular treatment (EVT) decision-making and outcome estimation in acute ischemic stroke (AIS). We aim to compare how these imaging paradigms perform for EVT patient selection and outcome estimation.
Prospective multi-center cohort study of patients with AIS symptoms with multi-phase computed tomography angiography (mCTA) and computed tomography perfusion (CTP) baseline imaging. mCTA-based EVT-eligibility was defined as presence of large vessel occlusion (LVO) and moderate-to-good collaterals on mCTA. CTP-based eligibility was defined as presence of LVO, ischemic core (defined on relative cerebral blood flow, absolute cerebral blood flow, and cerebral blood volume maps) <70 mL, mismatch-ratio >1.8, absolute mismatch >15 mL. EVT-eligibility and adjusted rates of good outcome (modified Rankin Scale 0–2) based on these imaging paradigms were compared.
Of 289/464 patients with LVO, 263 (91%) were EVT-eligible by mCTA-criteria versus 63 (22%), 19 (7%) and 103 (36%) by rCBF, aCBF, and CBV-CTP-criteria. CTP and mCTA-criteria were discordant in 40% to 53%. Estimated outcomes were best in patients who met both mCTA and CTP eligibility-criteria and were treated with EVT (62% to 87% good outcome). Patients eligible for EVT by mCTA-criteria and not by CTP-criteria receiving EVT achieved good outcome rates of 53% to 57%. Few patients met CTP-criteria and not mCTA-criteria for EVT.
Simpler imaging selection criteria that rely on little else than detection of the occluded blood vessel may be more sensitive and less specific, thus resulting in more patients being offered EVT and arguably benefiting from it.
The vanguard trials that established efficacy of endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) used various imaging criteria for patient selection. These ranged from simple paradigms like non-contrast head computed tomography (NCCT) and single-phase computed tomography angiography (CTA) in the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) [
Of all the imaging paradigms in use in patients with acute stroke, NCCT with single phase CTA is the simplest and arguably the fastest, but reliability of assessment of the extent of ischemia is low, particularly among non-experts. Pial collateral status assessment has high specificity if the collaterals are good on a single phase CTA but poor collateral filling could be a false result due to delay in timing of the contrast bolus and consequent arterial filling [
Using a population of suspected AIS patients presenting within 12 hours of last known well, we compare CTP imaging for EVT decision-making to mCTA-based imaging to examine how much advanced imaging information is needed for patient selection and outcome prediction at a population level.
This study was approved by the local Institutional Review Board. The study protocol was registered on clinicaltrials.org (NCT02184936). The study was conducted according to the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. Patient consent was obtained prior to enrolment.
Anonymized data will be made available by the corresponding author upon reasonable request.
The Precise and Rapid Assessment of Collaterals Multi-phase CTA in the Triage of Patients With Acute Ischemic Stroke for IA Therapy (Prove-IT) study was a prospective multi-center cohort study that enrolled 595 patients who presented with AIS symptoms. Patients were included if they presented to the emergency department with symptoms consistent with AIS, were older than 18 years, and mCTA and CTP were both performed within 12 hours of symptom onset and before recanalization therapy. Exclusion criteria were intracranial hemorrhage at baseline NCCT, previous sizeable stroke in the ipsilateral hemisphere, modified Rankin Scale (mRS) >2 at baseline, estimated creatinine clearance <60 mL/min, contrast material allergy, or other contraindications for iodinated contrast and estimated life expectancy <1 year [
NCCT with 5 mm slice thickness was obtained, followed by a CTA with arch to vertex coverage (CTA Head and Neck; conventional single phase CTA). This first phase was followed by skull base to vertex coverage for the second (peak venous) and third (late venous) phase of a mCTA acquisition. Detailed mCTA acquisition parameters have been published previously [
Forty-five milliliter of iodinated contrast agent were injected at a rate of 4.5 mL/sec followed by a 40 mL saline bolus injected at a rate of 6 mL/sec. Image acquisition started 5 seconds after contrast injection and 24 passes over 66 seconds were performed with 5 mm section thickness and a cranio-caudal coverage of 8 cm. CTP source data were centrally processed in a non-acute setting for each study using a delay-insensitive deconvolution software (CTP 4D; GE Healthcare, Waukesha, WI, USA). Time density curves were obtained and functional maps created, as described previously [
Depending on the individual center’s follow-up protocol, either diffusion-weighted MRI or NCCT images were obtained 24±6 hours after initial presentation.
Images were assessed visually in three reading sessions (session 1, baseline NCCT only; session 2, baseline NCCT and mCTA; session 3, follow-up MRI/CT) with a 2 weeks interval between each of the sessions. Two raters (J.M.O., O.V.) read the images by consensus. Unclear findings were reviewed and interpreted by a senior neuroradiologist (M.G.). The readers had access to baseline clinical information (clinically affected hemisphere, National Institutes of Health Stroke Scale [NIHSS], time since symptom onset) during all reading sessions. They were blinded to other imaging and clinical outcomes. All CTP studies were interpreted with independent computerized methods. For a more detailed description of the image interpretation methodology see
We classified patients by EVT eligibility criteria defined by both: (1) NCCT+mCTA and (2) NCCT, single-phase CTA and CTP. Eligibility was defined by the presence of a large vessel occlusion (LVO) plus adequate collateral scores or appropriate perfusion criteria (
Co-primary outcomes were (1) independent outcome, defined as mRS score of 0–2 at 90 days and (2) major clinical improvement, defined as a 50% relative reduction in the NIHSS score from baseline to 24-hour clinical follow-up. We chose major clinical improvement as a co-primary outcome a priori [
Patient baseline characteristics were reported using descriptive statistics. We constructed and compared a series of logistic regression models to assess the association between each imaging selection paradigm and the two pre-specified outcomes separately. A base model (model 1/“baseline model”) was generated including pre-specified independent variables (age, baseline stroke severity as measured by the NIHSS, time from stroke symptom onset to baseline NCCT, baseline Alberta Stroke Program Early CT Score [ASPECTS; 11 point ordinal scale with lower values indicating greater degree of early ischemic changes] on NCCT, and occlusion location [anterior circulation LVO vs. not] and treatment type [EVT vs. not]). In other words, Model 1 included imaging information from NCCT (ASPECTS) and single-phase CTA only, which is the recommended imaging paradigm for patients with suspected AIS presenting in the early time window as per current guidelines [
To understand the relative predictive value of each imaging criteria further, we constructed an 8-level nominal categorical variable for each of the models above (base model, three CTP approaches, mCTA approach, three CTP plus mCTA approaches). We used logistic regression, adjusted for patient age, baseline NIHSS, time from stroke symptom onset to baseline NCCT, baseline ASPECTS, occlusion location, and a dummy variable representing the eight possible combinations of mCTA eligibility (yes vs. no) versus CTP-eligibility (yes vs. no) conditional on treatment type (EVT performed vs. not) to assess the effect on outcome. This model helps generate probabilities for good outcomes for the following eight conditions namely (1) mCTA eligible, CTP eligible, EVT performed; (2) mCTA not eligible, CTP eligible, EVT performed; (3) mCTA not eligible, CTP eligible, EVT performed; (4) mCTA not eligible, CTP not eligible, EVT performed; (5) mCTA eligible, CTP eligible, EVT not performed; (6) mCTA not eligible, CTP eligible, EVT not performed; (7) mCTA not eligible, CTP eligible, EVT not performed; and (8) mCTA not eligible, CTP not eligible, EVT not performed. We deliberately chose to report adjusted rather than unadjusted outcomes since in a non-randomized setting, the latter are subject to substantial confounding by baseline prognostic variables. The effect size estimate using this approach is then relative to the base model and allows direct comparison of each imaging modality and treatment combination.
Finally, the net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to compare imaging paradigms in predicting outcome to provide an estimate of the relative incremental benefit of each imaging approach. All analyses were performed in Stata version 15.1 (StataCorp., College Station, TX, USA). Two-sided
Of the 595 patients enrolled in the study, complete clinical and imaging information were available in 464 patients, who were included in this analysis (
Venn diagrams illustrating mCTA and CTP eligibility proportions when compared to the sample with LVOs and the entire sample are shown in
Modelling results with the two co-primary clinical outcomes as dependent variables are shown in
Estimated probabilities of pre-defined clinical outcomes (along with interquartile range), adjusted for pre-specified baseline variables and CTP versus mCTA eligibility criteria conditional on receiving EVT treatment, are shown in
When comparing a statistical model that included baseline clinical information, NCCT ASPECTS, LVO presence, and mCTA based EVT eligibility criteria to another model that included the CTP based EVT eligibility criteria in addition, the NRI and IDI for major clinical improvement were small and not statistically significant (
This study finds that nine of every 10 patients with LVO presenting within 12 hours of symptom onset are considered eligible for EVT by mCTA criteria when compared to two of every 10 subjects considered eligible for EVT by rCBF based CTP criteria, four of every 10 subjects by CBV CTP criteria and one of every 20 subjects by aCBF CTP criteria. Clinical outcomes are likely best when patients meet both mCTA and CTP eligibility criteria for EVT and are offered EVT (57% to 63% rate of major clinical improvement, 62% to 87% rate of good outcome, depending on the CTP threshold used). Clinical outcomes in patients who meet mCTA eligibility criteria for EVT but not CTP eligibility criteria (55% to 58% rate of major clinical improvement, 53% to 57% rate of good outcome) and in patients who do not meet either mCTA or CTP eligibility criteria (major clinical improvement rates of 42% to 49% and good outcome rates of 51% to 62%) are also good if they are offered EVT.
Acute stroke imaging serves two major purposes: treatment decision-making and prognostication. As opposed to prognostication, treatment decision making (patient selection for therapy) is a dichotomous process; either a decision is made in favor of, or against treatment. If imaging selection is to be considered valid, patients who are considered ineligible for treatment based on imaging should not benefit from that treatment. With the arguable exception of the MR CLEAN trial, all randomized controlled trials (including the late window DAWN and DEFUSE-3 trials) showing benefit of EVT in patients with LVOs used imaging selection criteria to exclude patients with LVOs from EVT. These imaging selection criteria range from the stringent e.g. CTP core and mismatch based criteria to the less stringent, e.g., mCTA or single phase CTA based criteria with NCCT ASPECTS criteria. Current guidelines suggest that additional imaging beyond NCCT and single-phase CTA is not required in the early time window [
The fact that our results show approximately 50% to 62% good clinical outcome and 42% to 49% major clinical improvement rates in patients who are deemed ineligible for EVT by CTP or mCTA imaging criteria but were treated with EVT (when compared to 19% good clinical outcome in the control arm of the MR CLEAN trial [
Our results also show that very few patients (≤3%) were eligible for EVT by CTP but not by mCTA. A patient level pooled analysis of data from the HERMES consortium of all recent EVT trials showed that patients with large ischemic cores on CTP may also benefit from EVT [
A major strength of this study is that results are derived from a prospective multi-center cohort study with a large sample size and broad inclusion criteria. There are however some limitations to this study. First, patients were not randomly allocated to EVT versus medical management. We therefore do not know the “alternative” outcome had they been treated differently and could not directly compare the impact of CTP versus mCTA based EVT decision making on clinical outcome. Doing so would warrant a large diagnostic randomized controlled trial [
In conclusion, this study suggests that simpler imaging selection criteria that rely on little else than detection of the occluded blood vessel may be more sensitive and less specific at a population level, thus resulting in more patients being offered EVT and arguably benefiting from it in patients with AIS and LVOs presenting within 12 hours of last known well. Advanced imaging however may have some additional value for prognostication in these patients.
Supplementary materials related to this article can be found online at
EVT-eligibility criteria for different imaging modalities
Detailed location of intracranial vessel occlusion sites (n=464)
Clinical and imaging outcomes of the study sample (n=464)
Predicting major clinical improvement with imaging
Flow chart of initially enrolled and excluded patients. mCTA, multi-phase computed tomography angiography; CTP, computed tomography perfusion.
Proportional Venn diagrams illustrating the number of patients with anterior circulation large vessel occlusion (LVO), i.e., target for endovascular treatment (EVT; grey circles), and EVT eligible patients based on computed tomography perfusion (CTP) criteria (blue circles) and multiphase computed tomography angiography (mCTA) criteria (green circles) in patients presenting beyond 6 hours (n=69). (A) illustrates CTP based EVT-eligibility for relative cerebral blood flow (rCBF) <30% as core threshold, (B) illustrates CTP based EVT-eligibility for absolute cerebral blood flow (aCBF) <7 mL/100 g/min as core threshold, and (C) illustrates CTP based EVT-eligibility for absolute cerebral blood volume (aCBV) <2 mL/100 g as core threshold. Note that the slight mismatch between the right margin of the green and grey circles in (C) is related to the diagram type; there were no patients without LVO who are EVT eligible based on mCTA criteria.
Mayank Goyal: consultant (Medtronic, Stryker, Microvention, GE Healthcare, Mentice). Michael Hill: grants from Stryker, Medtronic, NoNO Inc., Boehringer Ingelheim. Bijoy Menon: patent (system/method for decision making/triaging in acute stroke). Johanna Ospel: research scholarships from the University of Basel Research Foundation, Julia Bangerter Rhyner Foundation and “Freiwillige Akademische Gesellschaft Basel.” The remaining authors have nothing to disclose.
This study was supported by a grant from the Canadian Institute of Health Research. The authors are most grateful to all enrolling sites.
Proportional Venn diagrams illustrating the number of patients with anterior circulation large vessel occlusion (LVO), i.e., target for endovascular treatment (EVT; grey circles), and EVT eligible patients based on computed tomography perfusion (CTP) criteria (blue circles) and multi-phase computed tomography angiography (mCTA) criteria (green circles). (A) Illustrates CTP based EVT-eligibility for relative cerebral blood flow (rCBF) <30% as core threshold, (B) illustrates CTP based EVT-eligibility for absolute cerebral blood flow (aCBF) <7 mL/100 g/min as core threshold, and (C) illustrates CTP based EVT-eligibility for absolute cerebral blood volume (aCBV) <2 mL/100 g as core threshold.
Median adjusted probability (model estimated) of major clinical improvement (A) and good outcome (B) conditional on computed tomography perfusion (CTP) vs. multi-phase computed tomography angiography (mCTA) based imaging selection criteria vs. both vs. neither and by treatment offered (endovascular treatment [EVT] vs. no EVT). Bars labelled with indicate probabilities for relative cerebral blood flow <30% as core threshold; bars labelled with indicate probabilities for absolute cerebral blood flow <7 mL/100 g/min as core threshold; and bars labelled with indicate probabilities for cerebral blood volume <2 mL/100 g as core threshold. Note that groups with less than 20 patients are not represented in this figure.
Patient baseline characteristics and treatment details of the study sample (n=464)
Characteristic | Value |
---|---|
Clinical baseline | |
Age (yr) | 73 (62.5–80) |
Female sex | 219 (47.2) |
Body mass index (kg/m2) (n=324) | 27.9±11.9 |
Medical history | |
Prior stroke or TIA | 88 (19.0) |
Hypertension (n=463) | 307 (66.3) |
Diabetes mellitus (n=460) | 70 (15.2) |
Dyslipidemia (n=462) | 182 (39.4) |
Atrial fibrillation (n=460) | 146 (31.7) |
Chronic heart failure (n=463) | 40 (8.6) |
Valvular disease (n=463) | 28 (6.1) |
Coronary artery disease (n=463) | 83 (17.9) |
Peripheral vascular disease (n=461) | 27 (5.9) |
Anticoagulant treatment (n=458) | 64 (14.0) |
Systolic blood pressure at admission (mm Hg) (n=459) | 153.2±27.4 |
Heart rate at admission (beats per minute) (n=445) | 76 (66–89) |
Glucose level at admission (mmol/L) (n=459) | 8.1±23.2 |
NIHSS at admission | 13 (6–20) |
Time from last known well to CT, median (range) (min) | 125 (0–1,428) |
Imaging baseline | |
ASPECTS on NCCT (n=463) | 10 (8–10) |
Hemorrhagic stroke at presentation (n=463) | 1 (0.2) |
Subacute infarct on NCCT at presentation (n=463) | 12 (2.6) |
Location of occlusion on multiphase CTA | |
Proximal anterior circulation (ICA, M1, and proximal M2) | 289 (62.3) |
Distal anterior circulation (distal M2 and further distal) | 103 (22.2) |
Posterior circulation | 23 (5.0) |
No occlusion seen | 49 (10.6) |
Secondary occlusion | 43 (9.3) |
Multiple clots in the affected territory (n=463) | 195 (42.1) |
Type of treatment | |
Mechanical thrombectomy | 80 (17.2) |
Intravenous alteplase | 132 (28.5) |
Intravenous tenecteplase | 11 (2.4) |
Mechanical thrombectomy and intravenous alteplase | 140 (30.2) |
Supportive medical treatment only | 101 (21.8) |
Values are presented as median (interquartile range), number (%), or mean±standard deviation.
TIA, transient ischemic attack; NIHSS, National Institutes of Health Stroke Scale; CT, computed tomography; ASPECTS, Alberta Stroke Program Early CT Score; NCCT, non-contrast head computed tomography; CTA, computed tomography angiography; ICA, internal carotid artery.
Statistical models
Variable | AIC | BIC | C statistic (95% CI) | |
---|---|---|---|---|
Statistical models |
||||
Model 1. Baseline model (simplest) |
611.57 | 640.54 | 0.664 (0.614–0.713) | |
Model 2. Baseline model+CTP based eligibility for EVT (rCBF) | 611.36 | 640.32 | 0.670 (0.621–0.719) | |
Model 3. Baseline model+CTP based eligibility for EVT (aCBF) | 612.57 | 641.54 | 0.665 (0.616–0.714) | |
Model 4. Baseline model+CTP based eligibility for EVT (CBV) | 610.44 | 639.41 | 0.671 (0.622–0.720) | |
Model 5. Baseline model+mCTA based eligibility for EVT | 610.52 | 639.48 | 0.665 (0.616–0.714) | |
Baseline model |
||||
Model 6. Model 5+CTP based EVT eligibility (rCBF) | 609.51 | 642.61 | 0.670 (0.621–0.719) | |
Model 7. Model 5+CTP based EVT eligibility (aCBF) | 612.49 | 645.60 | 0.664 (0.615–0.713) | |
Model 8. Model 5+CTP based EVT eligibility (CBV) | 611.20 | 644.30 | 0.669 (0.621–0.718) |
NIHSS, National Institutes of Health Stroke Scale; AIC, Akaike information criterion; BIC, Bayesian information criterion; CI, confidence interval; CTP, computed tomography perfusion; EVT, endovascular treatment; rCBF, relative cerebral blood flow; aCBF, absolute cerebral blood flow; CBV, cerebral blood volume; mCTA, multi-phase computed tomography angiography.
mCTA: EVT treatment decision (yes is indicated by presence of a large vessel occlusion and good or intermediate collaterals), CTP treatment decision (yes is indicated by an ischemic core volume [defined as rCBF <30% for model 2, a CBF <7 mL/100 g/min for model 3, CBV <2 mL/100 g for model 4]) <70 mL and absolute mismatch >15 mL and penumbra (defined as Tmax >6 seconds)/core mismatch ratio >1.8 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 [DEFUSE-3] criteria6);
Adjustment was performed for the following pre-specified baseline variables: age, baseline stroke severity as measured by the NIHSS, time from stroke symptom onset to baseline non-contrast head computed tomography (NCCT), baseline Alberta Stroke Program Early CT Score (ASPECTS) (11 point ordinal scale) on NCCT, occlusion location (anterior circulation large vessel occlusion vs. not) and treatment type (EVT vs. not). Since large vessel occlusion presence was part of the mCTA and CTP-based treatment decision rules, it was not incorporated as an independent variable in models 2–8.
Statistical models
Variable | AIC | BIC | C statistic (95% CI) | |
---|---|---|---|---|
Statistical models |
||||
Model 1. Baseline model (simplest) |
490.95 | 519.91 | 0.808 (0.769–0.847) | |
Model 2. Baseline model+CTP based EVT eligibility (rCBF) | 491.09 | 520.05 | 0.808 (0.769–0.847) | |
Model 3. Baseline model+CTP based EVT eligibility (aCBF) | 486.60 | 515.56 | 0.812 (0.774–0.851) | |
Model 4. Baseline model+CTP based EVT eligibility (CBV) | 491.02 | 519.98 | 0.808 (0.769–0.847) | |
Model 5. Baseline model+mCTA treatment decision | 490.99 | 519.96 | 0.808 (0.769–0.847) | |
Baseline model |
||||
Model 6. Model 5+CTP based EVT eligibility (rCBF) | 492.95 | 526.05 | 0.808 (0.769–0.847) | |
Model 7. Model 5+CTP based EVT eligibility (aCBF) | 488.55 | 521.66 | 0.813 (0.774–0.851) | |
Model 8. Model 5+CTP based EVT eligibility (CBV) | 492.94 | 526.05 | 0.808 (0.769–0.847) |
AIC, Akaike information criterion; BIC, Bayesian information criterion; CI, confidence interval; CTP, computed tomography perfusion; EVT, endovascular treatment; rCBF, relative cerebral blood flow; aCBF, absolute cerebral blood flow; CBV, cerebral blood volume; mCTA, multi-phase computed tomography angiography.
mCTA: EVT treatment decision (yes is indicated by presence of a large vessel occlusion and good or intermediate collaterals), CTP treatment decision (yes is indicated by an ischemic core volume [defined as rCBF <30% for model 2, a CBF <7 mL/100 g/min for model 3, CBV <2 mL/100 g for model 4]) <70 mL and absolute mismatch >15 mL and penumbra (defined as Tmax >6 seconds)/core mismatch ratio >1.8 (DEFUSE-3 criteria6);
Adjustment was performed for the following pre-specified baseline variables: age, baseline stroke severity as measured by the National Institutes of Health Stroke Scale, time from stroke symptom onset to baseline non-contrast head computed tomography (NCCT), baseline Alberta Stroke Program Early CT Score (ASPECTS) (11 point ordinal scale) on NCCT, occlusion location (anterior circulation large vessel occlusion vs. not) and treatment type (EVT vs. not). Since large vessel occlusion presence was part of the mCTA and CTP-based treatment decision rules, it was not incorporated as an independent variable in models 2–8.
Net reclassification index and integrated discrimination improvement for statistical models
Additional parameter | NRI | IDI | |||
---|---|---|---|---|---|
Dependent variable: major clinical improvement | |||||
CTP core volume (rCBF <30%) | –0.011 | 0.677 | 0.005 | 0.123 | |
CTP core volume (aCBF <7 mL/100 g/min) | 0.009 | 0.158 | <0.001 | 0.709 | |
CTP core volume (CBV <2 mL/100 g) | –0.002 | 0.953 | 0.004 | 0.151 | |
Dependent variable: good outcome | |||||
CTP core volume (rCBF <30%) | 0.002 | 0.840 | <0.001 | 0.891 | |
CTP core volume (aCBF <7 mL/100 g/min) | 0.018 | 0.260 | 0.012 | 0.014 | |
CTP core volume (CBV <2 mL/100 g) | 0.007 | 0.448 | <0.001 | 0.767 |
Net reclassification index and integrated discrimination improvement for a statistical model that included additional CTP eligibility criteria compared to a statistical model that included pre-specified baseline variables
NRI, net reclassification index; IDI, incremental discrimination improvement; CTP, computed tomography perfusion; rCBF, relative cerebral blood flow; aCBF, absolute cerebral blood flow; CBV, cerebral blood volume.
Age, baseline stroke severity as measured by the NIHSS, time from stroke symptom onset to baseline non-contrast head computed tomography (NCCT), baseline Alberta Stroke Program Early CT Score (ASPECTS) (11-point ordinal scale) on NCCT and treatment type (endovascular treatment vs. not).