Alberta Stroke Program Early Computed Tomography Score

to Select Patients for Endovascular Treatment

Interventional Management of Stroke (IMS)-III Trial
Michael D. Hill, MD, FRCPC; Andrew M. Demchuk, MD, FRCPC;
Mayank Goyal, MD, FRCPC; Tudor G. Jovin, MD, Lydia D. Foster, MSc;
Thomas A. Tomsick, MD; Rüdiger von Kummer, MD; Sharon D. Yeatts, PhD; Yuko Y. Palesch, PhD;
Joseph P. Broderick, MD; for the IMS3 Investigators

Background and Purpose—The Interventional Management of Stroke (IMS)-III trial randomized patients with acute
ischemic stroke to intravenous tissue-type plasminogen activator (tPA) plus endovascular therapy versus intravenous tPA
therapy alone within 3 hours from symptom onset. A predefined secondary hypothesis was that subjects with significant
early ischemic change on the baseline scan would not respond to endovascular therapy.
Downloaded from http://stroke.ahajournals.org/ by guest on September 2, 2016

Methods—The primary outcome was 90-day modified Rankin Scale score 0 to 2. The baseline and follow-up computed
tomographic (CT) scan images were reviewed centrally and blinded to any clinical information. We assessed whether the
baseline Alberta Stroke Program Early CT Score (ASPECTS) predicted outcome and interacted with study treatment.
We analyzed subgroups defined by time from onset to intravenous tPA initiation and baseline occlusion status at a
prespecified α=0.01.
Results—Baseline demographic and clinical characteristics of 656 randomized patients were similar between subjects with
a baseline ASPECTS 8 to 10 (58% of the study sample) versus 0 to 7. Subjects with ASPECTS 8 to 10 were almost twice
as likely (relative risk, 1.8; 99% confidence interval, 1.4–2.4) to achieve a favorable outcome. There was insufficient
evidence of a treatment-by-ASPECTS interaction. In those treated with onset to intravenous tPA <120 minutes, in CT
angiography–proven internal carotid artery or middle cerebral artery occlusion, and in both, results were similar. The
probability of achieving recanalization (arterial occlusion lesion, 2–3) of the primary arterial occlusive lesion (relative
risk, 1.3; 99% confidence interval, 1.0–1.8) or achieving thrombolysis in cerebral ischemia score 2b/3 reperfusion (relative
risk 2.0; 99% confidence interval, 1.2–3.2) was higher among subjects with higher ASPECTS.
Conclusions—ASPECTS is a strong predictor of outcome and a predictor of reperfusion. ASPECTS did not identify a
subpopulation of subjects that particularly benefitted from endovascular therapy immediately after routine intravenous
tPA.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.   
(Stroke. 2014;45:444-449.)
Key Words: computed tomography scanner, x-ray ◼ stroke ◼ thrombolysis, therapeutic

Received September 24, 2013; final revision received October 21, 2013; accepted October 31, 2013.
From the Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Current address for M.D.H.: Departments of Clinical Neurosciences, Medicine, Radiology and Community Health Sciences, Hotchkiss Brain Institute,
Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Current address for A.M.D.: Departments of Clinical Neurosciences, Radiology, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary,
Calgary, Alberta, Canada.
Current address for M.G.: Departments of Radiology, Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Current address for T.G.J.: Stroke Institute, Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA.
Current address for S.D.Y.: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.
Current address for T.A.T.: University of Cincinnati, Neuroscience Institute, Cincinnati, OH.
Current address for R.v.K.: Department of Neuroradiology, Dresden University Stroke Center, Faculty of Medicine, University Hospital Dresden,
Dresden, Germany.
Current address for L.D.F.: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.
Current address for Y.Y.P.: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.
Current address for J.P.B.: Department of Neurology, University of Cincinnati Neuroscience Institute, Cincinnati, OH.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
113.003580/-/DC1.
Correspondence to Michael D. Hill, MD, FRCPC, Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University
of Calgary, Foothills Hospital, Rm 1242A, 1403 29th St NW, Calgary, Alberta T2N 2T9, Canada. E-mail michael.hill@ucalgary.ca
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.113.003580

444
 Hill et al   ASPECTS and Endovascular Treatment in IMS-III    445

W ith technically high-quality noncontrast brain com-

puted tomography (CT), changes of acute ischemia
may be observed in a high proportion of patients with major
stroke.1,2 Radiological hypoattenuation varies linearly with
brain tissue water content and increases linearly with time
after middle cerebral artery occlusion and is thus a measure
of net water uptake of ischemic brain tissue (ionic edema).3,4
Early ischemic change, scored semiquantitatively using the
Alberta Stroke Program Early CT Score (ASPECTS), has
been shown to be a strong prognostic factor, equivalent
in magnitude of effect to the assessment of clinical stroke
severity using the National Institutes of Health Stroke Scale
(NIHSS) score.5–8 In 2 studies, a dichotomized ASPECTS
(8–10 versus 0–7) has been shown to modify the effect of
endovascular thrombolytic therapy.9,10 Only patients with
favorable baseline scans (ASPECTS, 8–10) benefitted from
endovascular revascularization therapy. The prospective
evaluation of baseline CT scans in European Cooperative
Downloaded from http://stroke.ahajournals.org/ by guest on September 2, 2016
Methods
The IMS-III trial was an international, phase III, randomized, open-
label with blinded outcome assessment, clinical trial designed to test
the approach of intravenous tissue-type plasminogen activator (tPA),
started within 3 hours of symptoms onset, followed by protocol-ap-
proved endovascular treatment when compared with standard intra-
venous tPA.11,12 The trial was halted because a futility boundary was
crossed at an interim analysis.
At the beginning of the trial, CT angiography (CTA) was infre-
quently used at participating hospitals to assess the presence of arteri-
al occlusions in patients with acute stroke. Thus, the baseline NIHSS
score, a clinical measure of neurological deficit with a range of 0
(no deficit) to 42 (maximum possible deficit), was used to identify
those patients (with a score ≥10) and a >80% likelihood of a major
arterial occlusion on subsequent angiography after intravenous tPA.
In Amendment 3 (April 2009), after 284 participants were random-
ized, identification of occlusion using CTA was allowed to determine
trial eligibility for those participants with NIHSS of 8 or 9 because
its routine use increased rapidly during the early course of the study.
CT scans were performed at baseline, at 24±6 hours, and in the
setting of neurological decline. A CTA was performed at baseline at

Acute Stroke Study (ECASS) showed the best treatment
response in patients with <1/3 middle cerebral artery terri-
tory hypoattenuation (n=215) when compared with patients
with normal CT (n=336) and patients with brain tissue
hypoattenuation exceeding 1/3 of the middle cerebral artery
territory (n=52).2
We assessed the prognostic value of the CT ASPECTS in
the Interventional Management of Stroke (IMS)-III study
and, in particular, whether response to treatment was different
according to the baseline ASPECTS.
those study sites that routinely included CTA in their baseline im-
aging protocol. CTA was planned for all participants at 24 hours to
assess vascular patency. CT scans were acquired using contiguous
noncontrast axial 5-mm slices. A minority of CT images were ac-
quired using 10-mm axial slices. The power (kV and mAs) and scan
obliquity were not prespecified. All CT scans were acquired within 3
hours of stroke onset. ASPECTS was scored (Methods in the online-
only Data Supplement) on all baseline and follow-up CT scans us-
ing a 3-people panel consensus method, including a neuroradiologist
for all interpretations. The reviewers were blind to all clinical data.
Hemorrhage was scored using the Pessin criteria and formalized in
the ECASS trials (hemorrhagic infarction, types 1 and 2; parenchy-
mal hematoma, types 1 and 2).13–15

Table 1.  Baseline Characteristics: Intention-to-Treat Population

ASPECTS 8–10 (n=378) ASPECTS 0–7 (n=278) ASPECTS 0–4 (n=92)
Demographics
 Age (median, IQR) 70 (17) 67 (19) 69 (15.5)
 Sex (women) % (n) 49% (187) 46% (129) 49% (45)
 White % (n) 86% (326) 82% (228) 82% (75)
Historical variables
 Hypertension % (n) 76% (288) 73% (202) 87% (80)
 Diabetes mellitus % (n) 24% (92) 20% (56) 21% (19)
 Atrial fibrillation % (n)* 32% (122) 36% (101) 34% (31)
 Hyperlipidemia % (n) 51% (193) 48% (134) 50% (46)
 Current smoker % (n) 21% (78) 31% (85) 34% (31)
 Congestive heart failure % (n) 14% (52) 10% (29) 11% (10)
 Peripheral vascular disease % (n) 7% (28) 9% (24) 15% (14)
Clinical variables
NIHSS (median, IQR) 16 (7) 18 (7) 19 (5)
 Onset-to-IV tPA time, min (median, IQR) 120 (50) 120 (47) 122 (55.5)
 Onset-to-groin puncture time, min 206.5 (60) 211 (70) 214 (80)
(median, IQR; n=424)
 Glucose, mmol/L (median, IQR) 6.7 (2.7) 6.6 (2.3) 6.7 (1.9)
Treatment assignment
 IV+endovascular arm % (n) 65% (247) 67% (187) 62% (57)
ASPECTS indicates Alberta Stroke Program Early CT Score; IQR, interquartile range; IV, intravenous; NIHSS, National
Institutes of Health Stroke Scale; and tPA, tissue-type plasminogen activator.
*Atrial fibrillation from medical history and baseline ECG.
 446  Stroke  February 2014

Statistical Methods Results

The primary clinical outcome was a modified Rankin Scale score of
0 to 2 at 90 days from randomization. Secondary clinical outcomes
included the modified Rankin Scale score of 0 to 1 and NIHSS
score of 0 to 1 at 90 days from randomization. Recanalization,
defined as the arterial occlusion lesion, and reperfusion by the
thrombolysis in cerebral ischemia score were secondary surrogate
outcome measures. A priori, we divided ASPECTS into 2 groups:
favorable (ASPECTS, 8–10) and unfavorable (ASPECTS, 0–7).
In addition, we evaluated a third group (ASPECTS, 0–4) that cor-
relates well with the previously defined one third middle cerebral
artery rule6 and which defines an ASPECTS trichotomy: ASPECT
8 to 10 as favorable, ASPECTS 5 to 7 as moderately favorable,
and ASPECTS 0 to 4 as unfavorable. Data are reported using con-
ventional descriptive statistics, by group. We used an intention-to-
treat approach in reporting the outcome data by ASPECTS group.
Subjects with missing baseline CT images (n=7) were imputed
to have a poor ASPECTS (0–7) score. The CTA subset consist-
ed of those patients who had a routine CTA before enrollment,
which defined their location of arterial occlusion pretreatment. For
exploratory analyses, we considered the cohort of patients with
Downloaded from http://stroke.ahajournals.org/ by guest on September 2, 2016
Baseline characteristics are shown in Table 1. Baseline demo-
graphic and clinical characteristics were similar between
subjects with a baseline ASPECTS 8 to 10 (58% of the study
sample) versus 0 to 7. There was a gradient of more severe
NIHSS scores with more unfavorable ASPECTS and an asso-
ciation between more proximal occlusion location and poorer
ASPECTS scores. Thus, clinical stroke severity, vessel occlu-
sion location, and ASPECTS are correlated variables. There
was an increased chance of reperfusion at 24 hours with higher
ASPECTS. Patients with favorable ASPECTS were more
likely to show reperfusion overall (Table 2), but this effect was
overcome by endovascular therapy with high rates of recanali-
zation at 24 hours even in the ASPECTS 0 to 4 group.
The treatment effect was not modified by the dichotomized
ASPECTS (P=0.871). Because the study did not show benefit
of 1 treatment arm compared with the other and both groups
had active treatment, effect modification, as a secondary analy-

proven baseline occlusions and with treatment within 2 hours of

stroke onset. sis, would a priori be difficult to demonstrate unless there was

Table 2.  ASPECTS and Vascular Occlusion Status CTA Population but as Randomized (as Intention-
to-Treat, and Specifically Not as Treated/Per Protocol)
ASPECTS 8–10 ASPECTS 0–7 ASPECTS 0–4
Baseline CTA* (N=154) (N=128) (N=40)
 ICA T or L or other ICA occlusion, % (n)† 16% (24) 33% (42) 43% (17)
 M1 occlusion, % (n) 53% (82) 52% (67) 43% (17)
 M2 occlusion, % (n) 21% (33) 14% (18) 13% (5)
 M3 occlusion, % (n/N) 2% (3) 1% (1) 3% (1)
 M4 or distal occlusion, % (n) 1% (2) 0% (0) 0% (0)
 PCA occlusion, % (n) 2% (3) ... ...
 BA/VA occlusion, % (n) 3% (5) ... ...
Treatment N=177 N=129 N=40
 IV+endovascular arm % (n) 67% (119) 71% (92) 63% (25)
 Onset-to-IV tPA time (median, IQR) 120 (54) 116 (44) 119 (52)
 Onset-to-groin puncture time (median, IQR; 208.5 (69) 202.5 (62) 210 (71)
N=210‡
Angiographic outcome (endovascular group only)
 AOL recanalization, 3 (% n/N) 71% (60/84) 54% (46/85) 59% (13/22)
 TICI 2b-3 flow (% n/N) 60% (47/78) 31% (26/85) 45% (10/22)
CTA 24-h vascular outcome
 Recanalization (% n/N) 83% (104/126) 71% (64/90) 50% (13/26)
IV-IA IV IV-IA IV IV-IA IV
87% (73/84) 74% (31/42) 88% (42/48) 56% (9/16) 73% (11/15) 18% (2/11)
ICH
 Symptomatic 6% (10/177) 9% (11/129) 5% (2/40)
 Asymptomatic 20% (36/177) 27% (37/129) 30% (12/40)
AOL indicates arterial occlusive lesion; ASPECTS, Alberta Stroke Program Early CT Score; BA, basilar artery; CTA, computed
tomographic angiography; ICA, internal carotid artery; ICH, intracranial hemorrhage; IQR, interquartile range; IV, intravenous; M1,
M1 middle cerebral artery occlusion; M2, M2 branch middle cerebral artery; M3, M3 branch middle cerebral artery; PCA, posterior
cerebral artery; TICI, thrombolysis in cerebral ischemia score; tPA, tissue-type plasminogen activator; and VA, vertebral artery.
*Twenty-three cases in ASPECTS 8–10 were missing CTA adjudication of the baseline occlusion site and 1 case in the
ASPECTS 0–7 group.
†Does not include proximal ICA occlusions.
‡One subject randomized to IV who underwent acute endovascular treatment.
 Hill et al   ASPECTS and Endovascular Treatment in IMS-III    447

a clear qualitative interaction with counterbalanced effects in Discussion

each group. However, the direction of effect for endovascu-
lar therapy, although imprecise because of the small sample
size, was toward fewer good outcomes among patients with
unfavorable baseline CT scans (ASPECTS, 0–4), similar to the
analysis undertaken for IMS-1.10 Among patients with favor-
able scans, a directional trend to a greater treatment effect was
observed among patients treated earlier and with proven arte-
rial occlusions (Table I and Figure I in the online-only Data).
Irrespective of treatment modality, ASPECTS was a
strong prognostic variable. A favorable scan conferred a
2-fold or greater chance of an independent functional out-
come (Table 3). This result was unchanged after multivari-
able adjustment. Similar to the above, the direction of effect
showed a larger effect size among patients treated earlier and
with proven arterial occlusions (Table 3). Remarkably, some
20% of patients with highly unfavorable scans (ASPECTS,
0–4) achieved an independent functional outcome (Table 4).
Downloaded from http://stroke.ahajournals.org/ by guest on September 2, 2016
ASPECTS is a measure of imaging-defined ischemic injury
to the brain that is a strong and consistent predictor of clini-
cal outcome. Although previous smaller studies of endovas-
cular therapy, a retrospective analysis of the Prolyse in Acute
Cerebral Thromboembolism (PROACT)-2 study and a histori-
cally controlled analysis of IMS-1,9,10 and prior intravenous
thrombolysis studies,13 showed evidence of effect modification
(a multiplicative interaction) between favorable ASPECTS
(score, 8–10) and good clinical outcome, this was not dem-
onstrated in our study. Subjects with low ASPECTS scores
benefitted far less in IMS-III and this observation, consistent
with prior trials of thrombolysis,9,10 supports the concept of
non-nutritive, futile, or even harmful reperfusion. Reperfusing
dead brain is simply unhelpful to acute neurological recov-
ery. Although reliable and pragmatic imaging biomarkers
for patient selection continue to be sought, these data do not
convincingly support the use of noncontrast CT ASPECTS in

Table 3.  Outcomes: ASPECTS as a Predictor Irrespective of Treatment Assignment

ASPECTS 8–10 ASPECTS 0–7 RR (CI99) ASPECTS 0–4
ITT population n=378 n=278 n=92
 mRS 0–2 at 90 d, % (n) 49% (187) 27% (76) 1.8 (1.4–2.4) 21% (19)
 mRS 0–1 at 90 d, % (n) 34% (130) 18% (50) 1.9 (1.3–2.8) 12% (11)
 NIHSS 0–1 at 90 d, % (n) 33% (123) 17% (47) 1.9 (1.3–2.8) 7% (6)
Onset-to-IV tPA time ≤120 min n=202 n=143 n=45
 mRS 0–2 at 90 d, % (n) 50% (101) 29% (42) 1.7 (1.2–2.5) 29% (13)
 mRS 0–1 at 90 d, % (n) 34% (69) 22% (31) 1.6 (1.0–2.5) 20% (9)
 NIHSS 0–1 at 90 d, % (n) 35% (71) 21% (30) 1.7 (1.0–2.7) 11% (5)
Baseline ICA and M1-MCA n=106 n=109 n=34
occlusion on CTA
 mRS 0–2 at 90 d, % (n) 57% (60) 25% (27) 2.3 (1.4–3.7) 15% (5)
 mRS 0–1 at 90 d, % (n) 40% (42) 14% (15) 2.9 (1.4–5.7) 6% (2)
 NIHSS 0–1 at 90 d, % (n) 39% (41) 16% (17) 2.5 (1.3–4.8) 3% (1)
Onset-IV tPA time ≤120 min n=57 n=65 n=17
and baseline ICA and M1-MCA
occlusion on CTA
 mRS 0–2 at 90 d, % (n) 61% (35) 25% (16) 2.5 (1.3–4.6) 12% (2)
 mRS 0–1 at 90 d, % (n) 44% (25) 17% (11) 2.6 (1.2–5.8) 12% (2)
 NIHSS 0–1 at 90 d, % (n) 44% (25) 20% (13) 2.2 (1.0–4.6) 6% (1)
Baseline ICA and MCA (M1–M4) n=144 n=128 n=40
occlusion on CTA
 mRS 0–2 at 90d, % n 54% (78) 29% (37) 1.9 (1.2–2.8) 20% (8)
 mRS 0–1 at 90d, % n 39% (56) 16% (20) 2.5 (1.4–4.5) 5% (2)
 NIHSS 0–1 at 90d, % n 36% (52) 16% (21) 2.2 (1.2–4.0) 3% (1)
Onset-IV tPA time ≤120 min and n=76 n=74 n=21
baseline ICA and MCA (M1–M4)
occlusion on CTA
 mRS 0–2 at 90 d, % (n) 61% (46) 31% (23) 1.9 (1.2–3.2) 24% (5)
 mRS 0–1 at 90 d, % (n) 46% (35) 19% (14) 2.4 (1.2–4.9) 10% (2)
 NIHSS 0–1 at 90 d, % (n) 43% (33) 20% (15) 2.1 (1.1–4.2) 5% (1)
AOL indicates arterial occlusive lesion; ASPECTS, Alberta Stroke Program Early CT Score; BA, basilar artery; CI99, 99%
confidence interval; CTA, computed tomographic angiography; ICA, internal carotid artery; ICH, intracranial hemorrhage; ITT,
intention-to-treat; IV, intravenous; M1, M1 middle cerebral artery occlusion; M2, M2 branch middle cerebral artery; M3, M3
branch middle cerebral artery; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; PCA, posterior
cerebral artery; RR, relative risk; and tPA, tissue-type plasminogen activator.
 448  Stroke  February 2014

Table 4.  ASPECTS 0 to 4 Patients Only (1–4 hours) were not defined for the intravenous tPA-only
group. The quality and proportional recanalization in the
mRS 0–2 mRS 3–6
endovascular arm (measured using the thrombolysis in cere-
Demographics n=19 n=73
bral ischemia scoring system) were poor. Thus, the relation-
 Age (median, IQR) 63 (22) 70 (15) ship between outcome and pretreatment ASPECTS continues
 Sex (women), % (n) 42% (8) 51% (37) to be confounded by variability in treatment response.
 White, % (n) 84% (16) 81% (59) Third, the baseline scan is a snapshot in time that reflects
Historical variables a physiological state only for a short period of time; the scan
 Hypertension, % (n) 89% (17) 86% (63) has a shelf-life and consequently the shorter the time interval
 Diabetes mellitus, % (n) 11% (2) 23% (17) from CT scan to reperfusion, the stronger the potential predic-
tive value of ASPECTS.17 In future studies, it will be critical
 Atrial fibrillation, % (n) 47% (9) 30% (22)
to measure the picture-to-puncture and picture-to-reperfusion
 Hyperlipidemia, % (n) 58% (11) 48% (35)
times.18 In IMS-III, the average time to treatment was long,
 Current smoker, % (n) 37% (7) 33% (24)
during which time infarction progressed. Therefore, time to
 Congestive heart failure, % (n) 11% (2) 11% (8) reperfusion is a related confounding variable.
 Peripheral vascular disease, % (n) 16% (3) 15% (11) Finally, most studies, including this one, are underpowered
Clinical variables to assess for interaction effects. All of these issues applied
less to the PROACT-2 analysis,9 which did show evidence of
Downloaded from http://stroke.ahajournals.org/ by guest on September 2, 2016

 NIHSS (median, IQR) 16 (8) 19 (4)

 Onset-to-IV tPA time (median, IQR) 115 (32) 125 (56) interaction. Key differences between PROACT-2 and IMS-III
 Onset-to-groin puncture time (median, IQR) 196 (80) 215 (70) were the much later onset-to-treatment time and the large dif-
ference in reperfusion rates between the 2 treatment groups in
 Glucose, mmol/L (median, IQR) 6.3 (1.1) 6.9 (1.9)
PROACT-2 when compared with IMS-III.12,19
Affected hemisphere on baseline imaging
There is strong biological evidence that a low ASPECTS
 Left hemisphere 26% (5) 27% (20)
score implies a poor outcome irrespective of treatment.
 Right hemisphere 58% (11) 70% (51) Consistent with past reports, a favorable ASPECTS predicted
 Unknown/multiple 5% (1) 0% (0) good outcome. Interestingly, patients with favorable ASPECTS
 No acute occlusion 11% (2) 3% (2) were also more likely to recanalize and reperfuse. The stroke
Treatment assignment itself may be impacting defensive vascular mechanisms that
 IV+endovascular arm, % (n) 58% (11) 63% (46) are designed to restore blood flow in the brain. Favorable
Safety events ASPECTS is associated with good collateral blood flow allow-
ing ischemic brain tissue to survive for longer time periods
 Symptomatic ICH 0% (0) 7% (5)
and enabling intravenous thrombolytics to attack the thrombus
ASPECTS indicates Alberta Stroke Program Early CT Score; ICH, intracranial
from both sides.20–22 Moreover, higher ASPECTS may be asso-
hemorrhage; IQR, interquartile range; IV, intravenous; mRS, modified
Rankin Scale score; NIHSS, National Institutes of Health Stroke Scale; TICI, ciated with more distal arterial occlusions with smaller sized
thrombolysis in cerebral ischemia score; and tPA, tissue-type plasminogen thrombi when compared with the proximal occlusion of major
activator. cerebral arteries. Intriguingly, we did observe that about one
fifth of patients with highly unfavorable scans (ASPECTS,
isolation to select patients for an intravenous plus endovascu- 0–4) achieved a good functional clinical outcome. We attribute
lar approach to therapy. this finding to a linear combination of lower age, faster treat-
There are multiple limitations in the assessment of poten- ment, lower baseline stroke severity, lower baseline serum glu-
tial ASPECTS-by-treatment interactions, in the search for an cose, higher number of no baseline occlusion cases, and fewer
imaging-defined biomarker that helps select patients for treat- symptomatic intracranial hemorrhage occurrences as principal
ment. These are generalizable in varying degree to other imag- reasons for good outcome in this group (Table 4).
ing modalities (including CTP and multimodal MR) and other One limitation of our data was the imaging itself.
potential biomarkers. Qualitatively, we found significant variability in image qual-
First, measurement error is underappreciated. The reliability of ity related to age of the CT scanner, helical versus sequential
ASPECTS interpretation is moderate within 90 minutes of stroke scan acquisition, scanning energy used (keV and mAs set-
onset, good between 90 and 180 minutes, and excellent beyond tings), scanner-type image reconstruction algorithms, includ-
that.1,16 There are subtleties of interpretation, which may result in ing iterative reconstruction. Older scanners, helical image
situations where a patient with an apparently unfavorable scan acquisition, lower scanning energy, and nonoptimized image
does well. Patients with unfavorable ASPECTS at baseline may reconstruction algorithms were associated with much poorer
do well if the infarcts are located in tolerant regions of brain, such image contrast between gray and white matter. Optimizing CT
as the right temporal lobe; there is a real-estate effect. In addition, scanner parameters may substantially improve measurement
patients may do well despite a large infarction if the capacity for issues at an individual site.
regeneration, adaptation, and recovery is exceptional. Overall, ASPECTS is a strong prognostic variable. Until we
Second, reperfusion therapy has only worked part of the can treat all patients quickly with 80% to 90% thrombolysis
time. Although reperfusion rates were relatively high at 24 in cerebral ischemia-3 flow, we will not be able to understand
hours in IMS-III, the reperfusion rates early after treatment the degree to which baseline imaging—using ASPECTS—is
 Hill et al   ASPECTS and Endovascular Treatment in IMS-III    449
a useful method to select patients for combined intravenous
thrombolysis immediately followed by endovascular therapy.
Acknowledgments
Dr Hill wrote the first draft of the article. Dr Palesch, Dr Yeatts, and
L.D. Foster performed statistical analysis. Drs Broderick and Tomsick
are the principal investigators for the Interventional Management of
Stroke (IMS)-III study. Drs Demchuk and Goyal are the principals
for the core imaging laboratory. Dr Jovin is a member of the IMS-III
Executive Committee and has reviewed the article. Dr von Kummer is
principal investigator for IMS-III in Europe and reviewed the article.
All authors provided key roles in study design, execution data collec-
tion, analysis, and interpretation of the study results.
Sources of Funding
This study was supported by National Institutes of Health/National
Institute of Neurological Disorders and Stroke grant numbers:
Univeristy of Cincinnati U01NS052220; Medical University of South
Carolina U01NS054630. Genentech Inc supplied study drug used for
intra-arterial tissue-type plasminogen activator in the Endovascular
Downloaded from http://stroke.ahajournals.org/ by guest on September 2, 2016
group. EKOS Corp, Concentric Inc, Cordis Neurovascular, Inc
supplied study catheters during Amendments 1 to 3. In Europe,
Interventional Management of Stroke-III Investigator meeting sup-
port was provided in part by Boehringer Ingelheim.
Disclosures
Dr von Kummer is a consultant to Lundbeck AC and Penumbra
Inc. Dr Goyal has received honouraria for speaking from Covidien
EV3. Dr Jovin is a consultant to Silk Road Medical. Dr Demchuk
is a consultant to Covidien EV3. Dr Broderick has is a consultant
to Genentech Ltd, Schering Plough, EKOS Corp. Dr Hill has been
a consultant to Covidien EV3. The other authors report no conflicts.
References
1. Barber PA, Hill MD, Eliasziw M, Demchuk AM, Pexman JH, Hudon
ME, et al; ASPECTS Study Group. Imaging of the brain in acute isch-
aemic stroke: comparison of computed tomography and magnetic reso-
nance diffusion-weighted imaging. J Neurol Neurosurg Psychiatry.
2005;76:1528–1533.
2. von Kummer R, Allen KL, Holle R, Bozzao L, Bastianello S, Manelfe C,
et al. Acute stroke: usefulness of early CT findings before thrombolytic
therapy. Radiology. 1997;205:327–333.
3. Dzialowski I, Weber J, Doerfler A, Forsting M, von Kummer R. Brain
tissue water uptake after middle cerebral artery occlusion assessed with
CT. J Neuroimaging. 2004;14:42–48.
4. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V. Brain oedema
in focal ischaemia: molecular pathophysiology and theoretical implica-
tions. Lancet Neurol. 2007;6:258–268.
5. Demchuk AM, Hill MD, Barber PA, Silver B, Patel SC, Levine SR;
NINDS rtPA Stroke Study Group, NIH. Importance of early ischemic
computed tomography changes using ASPECTS in NINDS rtPA Stroke
Study. Stroke. 2005;36:2110–2115.
6. Dzialowski I, Hill MD, Coutts SB, Demchuk AM, Kent DM, Wunderlich
O, et al. Extent of early ischemic changes on computed tomography (CT)
before thrombolysis: prognostic value of the Alberta Stroke Program
Early CT Score in ECASS II. Stroke. 2006;37:973–978.
7. Puetz V, Dzialowski I, Hill MD, Demchuk AM. The Alberta Stroke
Program Early CT Score in clinical practice: what have we learned? Int
J Stroke. 2009;4:354–364.
8. Hill MD, Buchan AM; Canadian Alteplase for Stroke Effectiveness
Study (CASES) Investigators. Thrombolysis for acute ischemic stroke:
results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ.
2005;172:1307–1312.
9. Hill MD, Rowley HA, Adler F, Eliasziw M, Furlan A, Higashida RT, et
al; PROACT-II Investigators. Selection of acute ischemic stroke patients
for intra-arterial thrombolysis with pro-urokinase by using ASPECTS.
Stroke. 2003;34:1925–1931.
10. Hill MD, Demchuk AM, Tomsick TA, Palesch YY, Broderick JP. Using
the baseline CT scan to select acute stroke patients for IV-IA therapy.
AJNR Am J Neuroradiol. 2006;27:1612–1616.
11. Khatri P, Hill MD, Palesch YY, Spilker J, Jauch EC, Carrozzella JA, et al;
Interventional Management of Stroke III Investigators. Methodology of the
Interventional Management of Stroke III Trial. Int J Stroke. 2008;3:130–137.
12. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD,
et al; Interventional Management of Stroke (IMS) III Investigators.
Endovascular therapy after intravenous t-PA versus t-PA alone for stroke.
N Engl J Med. 2013;368:893–903.
13. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al.
Intravenous thrombolysis with recombinant tissue plasminogen activator
for acute hemispheric stroke. The European Cooperative Acute Stroke
Study (ECASS). JAMA. 1995;274:1017–1025.
14. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D,
et al. Randomised double-blind placebo-controlled trial of thrombolytic
therapy with intravenous alteplase in acute ischaemic stroke (ECASS
II). Second European-Australasian Acute Stroke Study Investigators.
Lancet. 1998;352:1245–1251.
15. Pessin MS, Teal PA, Caplan LR. Hemorrhagic infarction: guilt by asso-
ciation? AJNR Am J Neuroradiol. 1991;12:1123–1126.
16. Bal S, Bhatia R, Menon BK, Shobha N, Puetz V, Dzialowski I, et al.
Time dependence of reliability of noncontrast computed tomogra-
phy in comparison to computed tomography angiography source
image in acute ischemic stroke. Int J Stroke. September 13, 2012. doi:
10.1111/j.1747-4949.2012.00859.x.
17. Goyal M, Menon BK, Coutts SB, Hill MD, Demchuk AM; Penumbra
Pivotal Stroke Trial Investigators, Calgary Stroke Program, and the
Seaman MR Research Center. Effect of baseline CT scan appearance
and time to recanalization on clinical outcomes in endovascular throm-
bectomy of acute ischemic strokes. Stroke. 2011;42:93–97.
18. Sun CH, Nogueira RG, Glenn BA, Connelly K, Zimmermann S, Anda
K, et al. “Picture to puncture”: a novel time metric to enhance outcomes
in patients transferred for endovascular reperfusion in acute ischemic
stroke. Circulation. 2013;127:1139–1148.
19. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al.
Intra-arterial prourokinase for acute ischemic stroke. The PROACT
II study: a randomized controlled trial. Prolyse in Acute Cerebral
Thromboembolism. JAMA. 1999;282:2003–2011.
20. Tsivgoulis G, Saqqur M, Sharma VK, Lao AY, Hoover SL, Alexandrov
AV; CLOTBUST Investigators. Association of pretreatment ASPECTS
scores with tPA-induced arterial recanalization in acute middle cerebral
artery occlusion. J Neuroimaging. 2008;18:56–61.
21. Bang OY, Saver JL, Kim SJ, Kim GM, Chung CS, Ovbiagele B, et al.
Collateral flow predicts response to endovascular therapy for acute isch-
emic stroke. Stroke. 2011;42:693–699.
22. Jovin TG, Gupta R, Horowitz MB, Grahovac SZ, Jungreis CA, Wechsler
L, et al. Pretreatment ipsilateral regional cortical blood flow influences
vessel recanalization in intra-arterial thrombolysis for MCA occlusion.
AJNR Am J Neuroradiol. 2007;28:164–167.
 Alberta Stroke Program Early Computed Tomography Score to Select Patients for
Endovascular Treatment: Interventional Management of Stroke (IMS)-III Trial
Michael D. Hill, Andrew M. Demchuk, Mayank Goyal, Tudor G. Jovin, Lydia D. Foster,
Thomas A. Tomsick, Rüdiger von Kummer, Sharon D. Yeatts, Yuko Y. Palesch and Joseph P.
Broderick
Downloaded from http://stroke.ahajournals.org/ by guest on September 2, 2016

for the IMS3 Investigators

Stroke. 2014;45:444-449; originally published online December 12, 2013;

doi: 10.1161/STROKEAHA.113.003580
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/45/2/444

Data Supplement (unedited) at:

http://stroke.ahajournals.org/content/suppl/2013/12/12/STROKEAHA.113.003580.DC1.html

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Stroke is online at:

http://stroke.ahajournals.org//subscriptions/
 1

Supplementary Material

Supplementary Methods – ASPECTS and CTA methodology

ASPECTS is assessed by systematically scoring each of ten MCA territory regions on the CT
scan and assigning a score of 1 for a normal, and 0 for a region showing signs of ischemia.1-3
Signs of ischemia are defined as X-ray hypoattenuation, loss of the grey-white boundary (which
is due to X-ray hypoattenuation of the gray matter), but not isolated effacement of cortical sulci;
isolated swelling was not scored as abnormal as it has been shown to be fully reversible.4-6 Only
new areas of acute ischemia are scored. All images from skull-base to vertex are reviewed. The
lower regions include the subcortical structures which are allotted three points (C caudate
nucleus, L lentiform nucleus, and IC internal capule – genu and posterior limb only) and the
MCA cortex which is allotted four points (Insular cortex, M1, 2, 3). The upper regions are
defined above the head of the caudate nucleus and include the MCA cortex which is alloted 3
point (M4, 5, and 6). The score combines localisation in the brain and volume into a semi-
quantitative topographical score. A score of ten implies no evidence of new early signs of
ischemia in the middle cerebral artery territory and a progressively lower score indicates more
extensive ischemic changes. The details of the scoring system can be reviewed at
www.aspectsinstroke.com.

CT angiograms were assessed using a similar consensus method. No specific CTA or MRA
protocol was mandated in the study although guidance for 24-hour CTA imaging parameters
were provided. When imaged and interpretable, each segment of the extracranial and
intracranial arterial vasculature was assessed for the presence of contrast with the lumen and
graded for any stenosis or occlusion.

References
1. Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed
tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Aspects study
group. Alberta stroke programme early ct score. Lancet. 2000;355:1670-1674
2. Pexman JH, Barber PA, Hill MD, Sevick RJ, Demchuk AM, Hudon ME, et al. Use of the alberta stroke
program early ct score (aspects) for assessing ct scans in patients with acute stroke. AJNR
Am.J.Neuroradiol. 2001;22:1534-1542
3. Modi J, Bai HD, Menon BK, Goyal M. Enhancing acute ischemic stroke interpretation with online aspects
training. Can J Neurol Sci. 2012;39:112-114
4. Watanabe O, West CR, Bremer A. Experimental regional cerebral ischemia in the middle cerebral artery
territory in primates. Part 2: Effects on brain water and electrolytes in the early phase of mca stroke. Stroke;
a journal of cerebral circulation. 1977;8:71-76
5. Parsons MW, Pepper EM, Bateman GA, Wang Y, Levi CR. Identification of the penumbra and infarct core
on hyperacute noncontrast and perfusion ct. Neurology. 2007;68:730-736
6. Butcher KS, Lee SB, Parsons MW, Allport L, Fink J, Tress B, et al. Differential prognosis of isolated
cortical swelling and hypoattenuation on ct in acute stroke. Stroke. 2007;38:941-947
 1

Supplementary Table I – Outcomes – Full ITT and CTA populations – Unadjusted Comparison IV vs. IV-IA

ASPECTS 8-10 ASPECTS 0-7 ASPECTS 0-4

ITT IV- IV RR IV- IV RR Pooled P IV- IV RR
population endo only (99% endo only (99% RR (hetero- endo only (99%
N=247 N=131 CI) N=187 N=91 CI) (99% geneity) N=57 N=35 CI)
CI)
mRS 0-2 51% 47% 1.1 28% 26% 1.1 1.1 0.871 19% 23% 0.8
at 90d (125) (62) (0.8- (52) (24) (0.6- (0.8- (11) (8) (0.3-
%,n 1.4) 1.8) 1.4) 2.4)
mRS 0-1 36% 31% 1.2 18% 19% 0.9 1.1 0.484 9% 17% 0.5
at 90d (89) (41) (0.8- (33) (17) (0.5- (0.8- (5) (6) (0.1-
%,n 1.7) 1.9) 1.5) 2.2)
NIHSS 34% 29% 1.2 19% 13% 1.4 1.2 0.700 5% 9% 0.6
0-1 at (85) (38) (0.8- (35) (12) (0.6- (0.9- (3) (3) (0.1-
90d, % n 1.8) 3.1) 1.8) 4.7)
Onset-to-IV tPA time <= 120 min
N=129 N=73 N=97 N=46 N=29 N=16
mRS 0-2 53% 45% 1.2 33% 22% 1.5 1.3 0.595 28% 31% 0.9
at 90d (68) (33) (0.8- (32) (10) (0.6- (0.8- (8) (5) (0.3-
%,n 1.7) 3.4) 1.8) 3.0)
mRS 0-1 37% 29% 1.3 23% 17% 1.4 1.3 0.991 17% 25% 0.7
at 90d (48) (21) (0.7- (23) (8) (0.5- (0.8- (5) (4) (0.1-
%,n 2.3) 3.5) 2.1) 3.2)
NIHSS 38% 30% 1.3 23% 15% 1.6 1.3 0.727 10% 13% 0.8
0-1 at (49) (22) (0.7- (23) (7) (0.6- (0.8- (3) (2) (0.1-
90d, % n 2.2) 4.3) 2.2) 7.5)
Onset-to-IV tPA time > 120 min
N=118 N=58 N=89 N=45 N=28 N=19
mRS 0-2 48% 50% 1.0 22% 31% 0.7 0.9 0.470 11% 16% 0.7
at 90d (57) (29) (0.6- (20) (14) (0.3- (0.6- (3) (3) (0.1-
%,n 1.5) 1.6) 1.3) 4.8)
mRS 0-1 35% 34% 1.0 11% 20% 0.6 0.9 0.250 0% 11% NA
at 90d (41) (20) (0.6- (10) (9) (0.2- (0.5- (0) (2)
%,n 1.8) 1.7) 1.5)
NIHSS 31% 28% 1.1 13% 11% 1.2 1.1 0.906 0% 5% NA
0-1 at (36) (16) (0.6- (12) (5) (0.3- (0.6- (0) (1)
90d, % n 2.1) 4.4) 2.0)
Baseline ICA and/or MCA occlusion (M1-M4) on CTA
N=92 N=52 N= 91 N= N=25 N=15
37
mRS 0-2 57% 50% 1.1 31% 24% 1.3 1.2 0.913 24% 13% 1.8
at 90d (52) (26) (0.7- (28) (9) (0.5- (0.7- (6) (2) (0.3-
%,n 1.7) 3.0) 1.7) 12.4)
mRS 0-1 46% 27% 1.7 18% 11% 1.6 1.7 0.713 8% 0% ∞
at 90d (42) (14) (0.9- (16) (4) (0.4- (0.9- (2) (0)
%,n 3.3) 6.3) 3.0)
NIHSS 42% 25% 1.7 19% 11% 1.7 1.7 0.829 4% 0% ∞
0-1 at (39) (13) (0.8- (17) (4) (0.5- (0.9- (1) (0)
90d, % n 3.4) 6.6) 3.2)
Onset-IV tPA time <= 120 min AND baseline ICA and /or MCA occlusion
(M1-M4) on CTA
N=43 N=33 N=53 N=21 N=14 N=7
mRS 0-2 67% 52% 1.3 36% 19% 1.9 1.4 0.801 29% 14% 2.0
at 90d (29) (17) (0.8- (19) (4) (0.5- (0.9- (4) (1) (0.1-
%,n 2.2) 6.6) 2.2) 27.5)
 2

mRS 0-1 58% 30% 1.9 23% 10% 2.4 2.0 0.883 14% 0% ∞
at 90d (25) (10) (0.9- (12) (2) (0.4- (1.0- (2) (0)
%,n 4.1) 15.1) 4.0)
NIHSS 53% 30% 1.8 23% 14% 1.6 1.7 0.632 7% 0% ∞
0-1 at (23) (10) (0.8- (12) (3) (0.3- (0.9- (1) (0)
90d, % n 3.8) 7.3) 3.4)

ITT  =  intention-­‐to-­‐treat;  CTA  =  computed  tomographic  angiography;  ICA  =  internal  carotid  artery;  M1  =  M1  
middle  cerebral  artery  occlusion;  M2  =  M2  branch  middle  cerebral  artery;  M3  =  M3  branch  middle  cerebral  
artery;  PCA  =  posterior  cerebral  artery;  BA  =  basilar  artery;  VA  =  vertebral  artery;  IV  =  intravenous;  tPA  =  
tissue  plasminogen  activator;  AOL  =  arterial  occlusive  lesion;  TICI  =  thrombolysis  in  cerebral  ischemia  score;  
ICH  =  intracranial  hemorrhage;  ASPECTS = Alberta Stroke Program Early CT Score; NIHSS = National Institutes
of Health Stroke Scale; mRS = modified Rankin scale score
 3

Supplementary Figure I

Forest plots of the RR of good outcome defined as mRS 0-2, mRS 0-1 or NIHSS 0-1, by ASPECTS
category among 5 sub-populations of patients.

ITT = intention to treat; SOTOIV = stroke onset to IV tPA treatment time; CTA = CT angiography; M1-
M4 = MCA territory occlusion; mRS = modified Rankins Scale; NIHSS = National Institutes of Health
Stroke Scale