ASTRAL R score predicts non recanalisati
1
New Technologies, Diagnostic Tools and Drugs
ASTRAL-R score predicts non-recanalisation after intravenous
thrombolysis in acute ischaemic stroke
Peter Vanacker1,2,3; Mirjam R. Heldner4; David Seiffge5; Hubertus Mueller6; Ashraf Eskandari1; Christopher Traenka5; George Ntaios7;
Pascal J. Mosimann8; Roman Sztajzel6; Vitor Mendes Pereira9*; Patrick Cras3; Stefan Engelter5,10; Philippe Lyrer5; Urs Fischer4;
Dimitris Lambrou1; Marcel Arnold4; Patrik Michel1
1Department
of Neurology, Centre Hospital Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; 2Department of Neurology, General Hospital Sint-Lucas,
Bruges, Belgium; 3Department of Neurology, Born Bunge Institute, University and University Hospital, Antwerp, Belgium; 4Department of Neurology, University Hospital, Bern,
Switzerland; 5Department of Neurology and Stroke Center, University Hospital, Basel, Switzerland; 6Department of Neurology, University Hospital, Geneva, Switzerland;
7Department of Medicine, University of Thessaly, Larissa, Greece; 8Institute for Diagnostic and Interventional Neuroradiology, Centre Hospital Universitaire Vaudois, Lausanne,
Switzerland; 9Institute for Diagnostic and Interventional Neuroradiology, University Hospital, Geneva, Switzerland; 10Neurorehabilitation Unit, University Center for Medicine of
Aging and Rehabilitation, Felix Plattee Hospital, Basel, Switzerland; *Current address: Department of Medical Imaging and Surgery, University of Toronto, Toronto, Ontario, Canada
Summary
Intravenous thrombolysis (IVT) as treatment in acute ischaemic
strokes may be insufficient to achieve recanalisation in certain patients. Predicting probability of non-recanalisation after IVT may have
the potential to influence patient selection to more aggressive management strategies. We aimed at deriving and internally validating a
predictive score for post-thrombolytic non-recanalisation, using clinical and radiological variables. In thrombolysis registries from four
Swiss academic stroke centres (Lausanne, Bern, Basel and Geneva),
patients were selected with large arterial occlusion on acute imaging
and with repeated arterial assessment at 24 hours. Based on a logistic
regression analysis, an integer-based score for each covariate of the
fitted multivariate model was generated. Performance of integerbased predictive model was assessed by bootstrapping available data
and cross validation (delete-d method). In 599 thrombolysed strokes,
five variables were identified as independent predictors of absence of
recanalisation: Acute glucose > 7 mmol/l (A), significant extracranial
Correspondence to:
Peter Vanacker
Centre Hospitalier Universitaire Vaudois
46, Rue de Bugnon
1011 Lausanne, Switzerland
E-mail: peter.vanacker@chuv.ch
vessel STenosis (ST), decreased Range of visual fields (R), large Arterial
occlusion (A) and decreased Level of consciousness (L). All variables
were weighted 1, except for (L) which obtained 2 points based on
β-coefficients on the logistic scale. ASTRAL-R scores 0, 3 and 6 corresponded to non-recanalisation probabilities of 18, 44 and 74 % respectively. Predictive ability showed AUC of 0.66 (95 %CI, 0.61–0.70)
when using bootstrap and 0.66 (0.63–0.68) when using delete-d cross
validation. In conclusion, the 5-item ASTRAL-R score moderately predicts non-recanalisation at 24 hours in thrombolysed ischaemic
strokes. If its performance can be confirmed by external validation and
its clinical usefulness can be proven, the score may influence patient
selection for more aggressive revascularisation strategies in routine
clinical practice.
Keywords
Cerebral infarction, thrombolytic therapy, decision support techniques,
cerebral revascularisation, cerebrovascular occlusion
Received: June 1, 2014
Accepted after major revision: November 21, 2014
Epub ahead of print: January 15, 2015
http://dx.doi.org/10.1160/TH14-06-0482
Thromb Haemost 2015; 113: ■■■
Introduction
Recanalisation of the occluded large vessels in acute ischaemic
strokes (AIS) may occur spontaneously in a subset of acute ischaemic stroke patients, but is more effectively achieved by intravenous thrombolysis (IVT) (1–6). However, patients with strokes
due to large vessel occlusions have low recanalisation rates with
IVT alone, associated with poor functional outcome despite treatment (1, 5). More aggressive, endovascular treatment strategies are
increasingly used to treat large vessel occlusive strokes, as they recanalise these occlusions more effectively and rapidly. However,
recent endovascular trials as IMS III, SYNTHESIS and MR-RESCUE (7) did not show superiority of endovascular therapy, although a trend of effectiveness was present in severe strokes
(NIHSS ≥ 20). Further, recanalisation by an acute endovascular in-
tervention is not always associated with reperfusion and better
clinical outcome (8), given that multiple other factors (time, collaterals, core and penumbra volumes, peripheral occlusions, site of ischaemia, metabolic states etc.) interfere. A better selection of patients who are most likely to benefit from aggressive (endovascular) therapy is therefore necessary (9).
We intended to develop and internally validate a simple score
for prediction of non-recanalisation after IV thrombolysis in AIS
patients by using items easily assessable before IV thrombolysis.
So far, clinical variables as admission glucose levels (10, 11) and
cardiovascular risk factors as atrial fibrillation (12, 13), smoking
(14) and metabolic syndrome (15) were identified as predictors.
Further, the following radiological items were known to be independently associated with recanalisation after intravenous
thrombolysis: location of the vessel occlusion (11, 13, 17), AS-
© Schattauer 2015
Thrombosis and Haemostasis 113.4/2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
2
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
PECTS scores (17), thrombus length (18) and thrombus density
(19).
Patients and methods
Study design and patient selection
The study includes data from a prospective cohort of consecutive, ischaemic stroke patients in four Swiss academic stroke centres (University Hospitals of Lausanne: 2003–2012, Basel: 2007–2013, Berne:
2007–2012 and Geneva: 2007–2012). The coordinating centre
(Lausanne) compiled the data of the different prospective registers
and performed the analysis of the pooled data. The inclusion criteria
for the analysis were A) acute noninvasive vascular imaging (CTA,
MRA or duplex) before IVT showing B) arterial occlusion in cervical and/or cerebral arteries in relation to the ischaemic territory, C)
availability of a second arterial imaging (CTA, MRA, angiography or
duplex) at 24 hours (h) (allowed range 12–48 h) permitting assessment of recanalisation and D) treatment with IVT alone within
proven time windows (3 h after last proof of well-being up to
10/2008, 4.5 h thereafter). Arterial occlusions were defined according to standardised methodologies that were published elsewhere
(20). Vascular imaging (CTA, MRA or duplex) was performed in all
centres before or within minutes after administration of the IV
thrombolysis bolus which should not influence arterial pathology. In
the vast majority of patients (n=563, 94 %) CTangiography was the
initial imaging technique. Indications for IVT with recombinant tissue plasminogen activator (rtPA) followed European Stroke Organisation guidelines (21). Patients with additional acute endovascular
procedures after IVT were excluded.
Medical variables collected and analysed included demographics, cardiovascular risk factors, co-morbidities, pre-stroke
medication, type of clinical deficit, NIHSS at admission (with all
items individually collected), onset-to-admission time, vital signs
and radiological imaging at admission. Pretreatment NIHSS
scores were assessed by certified stroke physicians. The clinical
signs “decreased range of visual fields” and “loss of consciousness”
were defined as in the NIHSS scale. On the acute vascular imaging,
large vessels pathology was analysed in each centre by both a neuroradiologist and stroke neurologist aware of clinical findings. As
both raters collaborated as a team, inter-rater variability has not
been assessed. The information on the presence and site of large
vessel occlusions and significant intra- and extracranial stenoses
were collected, based on pre-specified definitions. Intracranial occlusions in the ischaemic territory were categorised according to
their site in large vs intermediate occlusions. Large intracranial occlusions were defined as an occlusion of the basilar artery (with
our without intracranial vertebral artery occlusion), the intracranial carotid siphon (large and/or including carotid T) and large
middle cerebral artery (M1) both with and without ipsilateral
extracranial carotid occlusion. Intermediate intracranial occlusions were defined as occlusions in anterior cerebral artery (A1 or
A2 segments), peripheral middle cerebral artery (M2), posterior
cerebral artery (P1 or P2 segments), intracranial part of the vertebral artery (V4) and siphon of the internal carotid artery without
distal T-occlusion; the latter two were considered “intermediate”
because thrombus load and clinical symptoms are usually minor in
the absence of extension into the basilar artery and the carotid T,
respectively. Recanalisation of initially occluded arteries was defined for intra- and extracranial vessel occlusions and for the different imaging techniques separately, and was classified as “absent”
vs “partial or complete”. These criteria were published elsewehere
(20) If several good quality studies are available at 12–48 h, prioritiy was given to DSA > CTA > MRA > Doppler.
The collection, analysis and publication of data in the four
stroke registries were performed according to the guidelines of the
respective ethical boards of each centre.
Statistical analyses
Continuous variables are summarised using median and interquartile range, while categorical ones with count and percentage.
Univariate comparisons for all the variables considered, between
the patients who recanalise after intravenous thrombolysis and
those who did not, were performed using logistic regression analysis, where the significance of each variable was assessed separately.
Before starting the multiple analysis, imputation of the missing
values of the covariates considered was performed using the
method of chained equations (i. e. filling in the missing values on a
variable-by-variable basis, by first specifying the imputation model
for each incomplete variable and then using this model to fill in
the gaps). Five imputed datasets were generated using this method.
Multiple logistic regression analysis was performed on each imputed dataset separately. Stepwise methods were implemented on
each one of the five analysis, to identify significant main effects
and interactions. Final results were derived as combinations of the
outcome of the five imputed analysis. The log-odds of the final
model were used to define the coefficients in the proposed score.
Predictive ability of the score is measured via the area under the
receiver-operating characteristic curve (AUC-ROC), calculated for
the imputed datasets using bootstrapping and cross validation.
Bootstrapping assesses the predictive ability of our model by creating copies of the imputed datasets and recalculating AUC on these
copies. Cross-validation splits the imputed dataset in two parts
(not necessarily in half), fits a model to one part, and assesses its
predictive ability using the other part. As the two methods might
be considered as complementary to the other, both techniques
were used to evaluate the predictive ability of models. The ROC
analysis was carried out on the imputed datasets separately, and
final results were derived as combination of the outcome of these
analyses. All tests were carried out at 5 % significance level. All
analyses performed using the statistical package R (version 3.0.2).
Results
Prevalence of partial or complete recanalisation within 24 h
(12–48 h) after IV thrombolysis was 66 % or 396 patients in our
multi-centre cohort (n=599). The demographics and baseline
characteristics of patients with and without recanalisation are
Thrombosis and Haemostasis 113.4/2015
© Schattauer 2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
Table 1: Selection of baseline characteristics and radiological findings, dichotomised according to presence or absence of
post-thrombolytic recanalisation. Values are
expressed as medians and interquartile range
(IQR) for continuous variables unless stated
otherwise, and as absolute counts and percentage for categorical variables.
Non-recanali- Recanalisation OR
sation (n=203) (n=396)
95 % CI
Pvalue
Atrial fibrillation
75 (39 %)
156 (42 %)
1,13
0.79–1.61 0.49
Arterial hypertension
138 (68 %)
258 (65 %)
0,89
0.62–1.27 0.51
Hypercholesterolaemia
108 (53 %)
185 (47 %)
0,77
0.55–1.09 0.14
Previous stroke or TIA
28 (14 %)
53 (14 %)
0,99
0.60–1.62 0.96
Baseline NIHSS
14 ( 13)
12 ( 10)
0,97
0.95–0.99 0.01
Decreased level of consciousness
55 (28 %)
48 (13 %)
0,37
0.24–0.56 < 0.01
Visual field defects
106 (55 %)
165 (43 %)
0,62
0.44–0.88 < 0.01
Acute glucose levels (mmol/l)
6.8 ( 2.2)
6.4 ( 1.6)
0,89
0.82–0.96 < 0.01
Acute glucose levels > 7mmol/l
71 (35 %)
99 (25 %)
0,60
0.42–0.86 < 0.01
Acute systolic blood pressure
(mmHg)
156.0 (37.0)
152.0 (30.3)
1,00
0.99–1.01 0.89
Acute diastolic blood pressure
(mmHg)
85.0 (25.0)
84.0 (22.0)
0,99
0.98–1.00 0.15
Onset-to-needle time (h)
2.5 ( 1.2)
2.6 ( 1.1)
1,23
1.01–1.48 0.03
187 (47 %)
0,57
0.40–0.80 < 0.01
70 (19 %)
0,54
0.36–0.81 < 0.01
Medical history
Presentation on arrival
Vessel occlusion characterisation
Large intracranial occlusion
124 (61 %)
Significant extracranial vessel pa- 56 (30 %)
thology (stenosis or occlusion)
shown partially in ▶ Table 1. Numbers of included patients per
centre were as follows: Lausanne (n=210), Basel (n=217), Bern
(n=136) and Geneva (n=35). Recanalisation was assessed by CTA
in 82 % (n=491), by MRA in 12 % (n=72) and by duplex only in
6 % (n=36). Five clinical and radiological variables were identified
as independent predictors of non-recanalisation: Acute glucose > 7
mmol/l (A), STenosis or occlusion of extracranial vessels (ST),
Range of visual fields decreased (R), Arterial occlusion in a large
site (A) and an decreased level of consciousness (L) (▶ Table 2).
The cut-off value for acute glucose levels was chosen on a treebased method, suggesting that a cut-off of 7 mmol/l would be the
most adequate. As the initial multivariate analysis failed to acknowledge the role of time in relation to recanalisation, additional
statistical analyses were performed to check the effect of different
cut-off values for the onset-to-needle times (< 1.5 h, < 3 h, < 4.5 h)
on the prediction of recanalisation. No significant correlation was
detected between dichotomisation at 3 h (OR 1.2, 95 %CI 0.8–1.8)
Table 2: The ASTRAL-R Score: Independent
predictors of absence of post-thrombolytic
recanalisation at 24 h with the respective
score points.
and at 4.5 h (OR 1.5, 95 %CI 0.5–4.9) with recanalisation after IV
thrombolysis. Only, dichotomisation at 1.5 h was significantly associated with recanalisation (OR 1.97, 95 %CI 1.1–3.5). This parameter, however, did not improve the predictive performance of
the ASTRAL-R score in terms of AUC-ROC.
The ordering of the predictors used in our score, according to
their significance in the final model, judged from the p-value of
the imputation analysis and starting from the most significant to
the least significant, is as follows: decreased consciousness, extracranial pathology, visual field defect, acute glucose level and proximal intracranial occlusion. A predictive model with the item decreased consciousness only has AUC 57.7 %, adding extracranial
pathology the AUC raises to 62.1 %, adding further visual field defect AUC is estimated at 64.6 % and adding acute glucose level
AUC goes to 65.0 % and finally adding proximal occlusion gives an
AUC of 66.2 % (Suppl. Figure 1, available online at www.thrombo
sis-online.com).
Covariates
OR
95 % CI
P-value
Score Point
Acute Glucose level > 7mmol/l
0.91
0.84–0.99
0.02
1
STenosis/Occlusion in extracranial vessel
0.54
0.35–0.83
0.01
1
Range of visual fields decreased
0.69
0.48–1.00
0.04
1
Arterial Occlusion: large size
0.68
0.47–0.98
0.04
1
Level of consciousness altered
0.45
0.28–0.71
0.01
2
© Schattauer 2015
Thrombosis and Haemostasis 113.4/2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
3
4
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
Figure 1: Association between the ASTRAL-R score and the probability of non-recanalisation (12–24 h) after IV thrombolysis.
▶Figure 1 displays the predicted probability of non-recanalisation after IV thrombolysis based on the ASTRAL-R score. The
absolute risk of non-recanalisation for the corresponding ASTRAL-R scores 0, 1, 2, 3, 4, 5 and 6 were 17.7 %, 24.8 %, 33.5 %,
43.6 %, 54.2 %, 64.4 % and 73.5 %, respectively. Patients with an ASTRAL-R score more than 3 have a likelihood of absence of postthrombolytic recanalisation of more than 50 %. Suppl. Figure 2
(available online at www.thrombosis-online.com) shows the distribution of the overall ASTRAL-R score and its components
among the population.
The predictive ability of the model was assessed in two ways: a)
by calculating the AUC of the ROC-curve using the original
sample (599 patients after imputing for missing values) and attaching uncertainty using bootstrap methodology (1,000 repetitions),
and b) by cross-validation (deleted-d method repeated 1,000
times). The estimated AUC in both cases was 0.66 with a 95 %CI of
0.61–0.70 (Suppl. Figure 3, available online at www.thrombosis-on
line.com) using the first method, while the corresponding 95 % CI
for the cross validation was 0.63–0.68 (Suppl. Figure 4, available
online at www.thrombosis-online.com).
Discussion
This study describes the derivation and internal validation of the
ASTRAL-R score in a multi-centre cohort which estimates the
likelihood of non-recanalisation 24 h after IVT. A linear relationship between the total score and non-recanalisation could be
shown, and the performance of the model was assessed in a multicentre cohort.
The score consists of five easily available variables already before IVT: acute glucose (cut-off > 7 mmol/l), extracranial stenosis
> 50 % or occlusion, visual field defects, decreased level of consciousness and a large artery intracranial occlusion. Hyperglycaemia in acute stroke patients is common and may decrease plasma
t-PA activity. Further, acute hyperglycaemia may be related to
atherosclerotic disease, which has been shown to be more resistant
to recanalisation after tPA treatment (10, 22). The concomitant
presence of extracranial arterial stenosis or occlusion may lead to
less recanalisation because of decreased inflow of blood into the
blocked arteries, leading to less arrival of IV rt-PA and less washout of clots (23). Occlusion of larger intracranial arteries is likely to
be related to less recanalisation because of higher thrombus
burden than in smaller arteries, as shown previously (13, 14). It is
unclear why decreased level of vigilance and visual field defects
were independent predictors of recanalisation, although these factors have been associated with worse clinical outcome (24). One
hypothesis may be that these signs of clinical severity may indicate
poorer collaterals which could also contribute to recanalisation
(25).
Some previously described predictors of recanalisation, such as
onset-to-needle time (10), atrial fibrillation (12, 13), smoking (14)
and metabolic syndrome (15) and ASPECTS scores (17) were not
confirmed in our logistic regression analysis. This may be related
to differences in the cohorts or the sample size.
Use of the ASTRAL-R score in clinical practice has the potential
to improve acute stroke management. Given several negative interventional revascularisation trials, a more careful selection of patients is mandatory (9). A more individualised patient selection
based not only on the severity of the stroke but also on the non-recanalisation risk after IV thrombolysis could be promising. In individual cases with a high likelihood of non-recanalisation after
IVT (e. g. large vessel occlusions, extracranial stenosis, hyperglycaemia), endovascular intervention for non-recanalising patients
may be of added benefit, in particular if salvageable tissue can be
demonstrated by multimodal imaging (26, 27). In addition, successful recanalisation is associated with better outcome also in severe stroke patients (28).
Some items in the ASTRAL-R score (level of consciousness, visual field defects and acute glucose level) are the same as in the
prognostic ASTRAL score for clinical outcome (24). Both scores
may be used as selection tools for future clinical trials on endovascular treatment after IVT.
One of the strengths of the ASTRAL-R score is the large
number of patients and variables included and the multi-centre
design including four sites with a longstanding experience in acute
stroke research. Data were available on the specific site of arterial
occlusions sites in all cohorts. Validation of the score was performed by a bootstrap and cross validation (delete-d method).
Several limitations apply: First, implementation in routine
clinical practice may be hampered by the moderate predictive ability of the model with areas under the ROC curve of 0.66. This corresponds to other predictive scores in acute stroke care (e. g.
SEDAN score) which have similar c-statistic values (29). This can
partially be explained by combing four different cohorts of thrombolysed stroke patients. Adding factors such as collateral vessel
status (25), perfusion imaging (30) and thrombus length (13)
could further improve the score. However, such radiological data
and imaging techniques are not routinely used in clinical practice
and are hampered by standardisation issues. Secondly, external
validation in independent cohorts will be necessary to confirm the
performance of the score. The validity of the score in patients who
Thrombosis and Haemostasis 113.4/2015
© Schattauer 2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
underwent endovascular treatment needs to be assessed, as these
patients were excluded in the current analysis. Thirdly, large vessel
occlusions were classified into large and intermediate arterial occlusions, mainly based on anatomical location. The likelihood of
recanalisation between the location sites may be more variable
than expected. This arbitrary classification is debatable, but clinically relevant in the absence of a standardised classification of the
intracranial arteries. Fourthly, our definition of recanalisation was
not based on a single imaging modality but on heterogeneous
methods, the degree of recanalisation was dichotomised at an arbitrary point (between none and partial or complete) and the best
timing for recanalisation assessment is still unknown. Fifthly, a
pre-selection bias may have been introduced in the study by excluding stroke patients with additional acute endovascular procedures after insufficient IV t-PA recanalisation. Potentially, lower
recanalisation rates and different predictive parameters would
have been found in this subgroup of patients. And finally, reading
of the vascular imaging data was not centralised in order to prevent high inter-rater variabilities.
What is known about this topic?
•
A few clinical and radiological factors influencing the recanalisation rate in IV thrombolysis-treated acute ischaemic strokes, are
known from small single-centre studies.
What does this paper add?
•
•
•
•
By performing a logistic regression analysis in a multi-centre cohort, we could detect independent predictors of arterial recanalisation after IV thrombolysis.
For the first time, a diagnostic tool (ASTRAL-R score) has been
shown to have a good predictive accuracy for recanalisation after
IV thrombolysis.
The ASTRAL-R score is an easy-to-use 5 items score (0-> 6).
In the future, some additional radiological can be detected to improve the accuracy of ASTRAL-R score.
Conflicts of interest
Conclusions
In conclusion, the ASTRAL-R score is an easy-to-assess 5-item
score moderately predicting non-recanalisation after IVT in acute
ischaemic strokes.
Acknowledgements
The first and last author (P. Vanacker, P. Michel) had full access to
all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis. This research is
supported by grants from the Swiss Cardiology foundation (P. M.,
P. V.), CardioMet-CHUV (P. M.) and a scholarship of the European
Neurological Society (P. V.).
Author contributions
Vanacker P: Study concept and design, analysis, interpretation,
preparation of the manuscript. Heldner MR: Data acquisition and
analysis, critical revision of the manuscript for important intellectual content. Seiffge D: Data acquisition and analysis, critical revision of the manuscript for important intellectual content. Mueller
H: Data acquisition and analysis. Traenka C: Data acquisition and
analysis. Ntaios G: Study concept and design, data acquisition and
analysis, critical revision of the manuscript for important intellectual content. Stajzel R: Data acquisition and analysis. Lyrer P: Data
analysis, critical revision of the manuscript for important intellectual content. Fischer U: Data acquisition, data analysis, critical
revision of the manuscript for important intellectual content. Lambrou D: Data analysis, statistical analysis. Arnold M: Data analysis,
critical revision of the manuscript for intellectual content. Michel
P: Study concept and design, data acquisition, analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision.
P. V., D. L., A. E., M. R. H. and C. T. report no disclosures. D. S. received a travel grant from Bayer. P. L. has served on scientific advisory boards for Bayer, Schering Pharma, BMS/Pfizer and Boehringer Ingelheim; has received funding for travel or speaker honoraria from Bayer Schering Pharma, Boehringer Ingelheim, and
Shire plc; he serves as Co-Editor for Neurologie und Psychiatrie
and on the editorial board of Swiss Archives of Neurology and
Psychiatry; and has received research support from AstraZeneca,
Boehringer Ingelheim, Sanofi-aventis, Photo-Thera, the Swiss
National Science Foundation, and the Swiss Heart Foundation.
G. N. received consulting fees from Boehringer-Ingelheim; honorarium from Medtronic; speaker fees from Boehringer-Ingelheim
and Sanofi. P. M. received funding for travel or speaker honoraria
from Shire, Bayer, Sanofi-Aventis; consulting fees from Lundbeck
and Pierre-Fabre; honoraria for scientific advisory boards for
Bayer and Boehringer-Ingelheim.
References
1. Rha JH, Saver JL. The impact of recanalisation on ischaemic stroke outcome: a
meta-analysis. Stroke 2007; 38: 967–973.
2. Fiebach JB, Al-Rawi Y, Wintermark M, et al. Vascular Occlusion Enables Selecting Acute Ischaemic Stroke Patients for Treatment With Desmoteplase. Stroke
2012; 43: 1546–1566.
3. Galimanis A, Jung S, Mono ML, et al. Endovascular therapy of 623 patients with
anterior circulation stroke. Stroke 2012; 43: 1052–1057.
4. Mazighi M, Serfaty JM, Labreuche J, et al. RECANALISE investigators. Comparison of intravenous alteplase with a combined intravenous-endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE
study): a prospective cohort study. Lancet Neurol 2009; 8: 802–809.
5. Yeo LLL, Paliwal P, Teoh HL, et al. Timing of Recanalisation after Intravenous
Thrombolysis and Functional Outcomes After Acute Ischaemic Stroke. J Am
Med Assoc Neurol 2013; 70: 353–358.
6. Zaidat OO, Suarez JI, Sunshine JL, et al. Thrombolytic Therapy of Acute Ischaemic Stroke : Correlation of Angiographic Recanalisation with Clinical Outcome. Am J Neuroradiol 2005; 26: 880–884.
7. Broderick JP, Palesch YY, Demchuk AM, et al; for the Interventional Management of Stroke (IMS) III Investigators. N Engl J Med 2013; 368: 893–903.
© Schattauer 2015
Thrombosis and Haemostasis 113.4/2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
5
6
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
8. Soares BP, Tong E, Hom J, et al. Reperfusion is a more accurate predictor of follow-up infarct volume than recanalisation : a proof of concept using CT in acute
ischaemic stroke patients. Stroke 2010; 41: 34–40.
9. Liebeskind DS. The Quest to Prove Endovascular Stroke Therapy: Searching for
the “Sweet Spot” in Patient Selection. Mayo Clin Proc 2013; 88: 1039–1041.
10. Ribo M, Molina C, Montaner J, et al. Acute hyperglycemia state is associated
with lower tPA-induced recanalisation rates in stroke patients. Stroke 2005; 36:
1705–1709.
11. Zangerle A, Kiechl S, Spiegel M, et al. Recanalisation after thrombolysis in
stroke patients: predictors and prognostic implications. Neurology 2007; 68:
39–44.
12. Kimura K, Iguchi Y, Yamashita S, et al. Atrial fibrillation as an independent predictor for no early recanalisation after IV-rtPA in acute ischaemic stroke. J
Neurol Sci 2008; 246: 57–61.
13. Mendonça N, Rodriguez-Luna D, Rubiera M, et al. Predictors of tissue-type
plasminogen activator nonresponders according to location of vessel occlusion.
Stroke 2012; 43: 41714. Kufner A, Nolte CH, Galinovic I, et al. Smoking-Thrombolysis Paradox: Recanalisation and Reperfusion Rates After Intravenous Tissue Plasminogen Activator in Smokers With Ischaemic Stroke. Stroke 2013 ; 44: 407–413.
15. Arenillas JF, Sandoval P, Pérez de la Ossa N, et al. The metabolic syndrome is associated with a higher resistance to intravenous thrombolysis for acute ischaemic stroke in women than in men. Stroke 2009; 40: 344–349.
16. Saqqur M, Uchino K, Demchuk AM, et al; CLOTBUST Investigators. Site of Arterial Occlusion Identified by Transcranial Doppler Predicts the Response to Intravenous Thrombolysis for Stroke. Stroke 2007; 38: 948–954.
17. Tsivgoulis G, Saqqur M, Sharma VK, et al; CLOTBUST Investigators. Association of pretreatment ASPECTS scores with tPA-induced arterial recanalisation
in acute middle cerebral artery occlusion. J Neuroimag 2008; 18: 56–61.
18. Riedel CH, Zimmerann P, Jensen-Kondering U, et al. The importance of size:
succesful recanalisation by intravenous thrombolysis in acute anterior stroke
depends on thrombus length. Stroke 2011; 42: 1775–1777.
19. Moftakhar P, English JD, Cooke DL, et al. Density of Thrombus on Admission
CT Predicts Revascularisation in Large Vessel Occlusion Acute Ischaemic
Stroke. Stroke 2013; 44: 243–245.
20. Vanacker P, Lambrou D, Eskandari A, et al. Improving Prediction of Recanalisation in Acute Large Vessel Occlusive Stroke. J Thromb Haemost 2014; Epub
ahead of print.
21. Wunderlich MT, Goertler M, Postert T, et al; Duplex Sonography in Acute
Stroke (DIAS) Study Group; Competence Network Stroke. Duplex Sonography
in Acute Stroke (DIAS) Study Group; Competence Network Stroke. Recanalisation after intravenous thrombolysis: does a recanalisation time window exist?
Neurology 2007; 68: 1364–1368.
22. Arnold M, Mattle S, Galimanis A, et al. Impact of admission glucose and diabetes on recanalisation and outcome after intra-arterial thrombolysis for ischaemic stroke. Intern J Stroke 2014; 9: 985-991.
23. Ntaios G, Faouzi M, Ferrari J, et al. An integer-based score to predict functional
outcome in acute ischaemic stroke: the ASTRAL score. Neurology 2012; 78:
1916–1922.
24. Bhatia R, Hill MD, Shobha N, et al. Low Rates of Acute Recanalisation With Intravenous Recombinant Tissue Plasminogen Activator in Ischaemic Stroke.
Real-World Experience and a Call for Action. Stroke 2010; 41: 2254–2258.
25. Campbell BC, Christensen S, Parsons MW, et al; EPITHET and DEFUSE Investigators. Advanced imaging improves prediction of hemorrhage after stroke
thrombolysis. Ann Neurol 2013; 73: 510-519.
26. Mayza MV, Bovi U, Castillo J, et al. External validation of the SEDAN score for
prediction of intracerebral hemorrhage in Stroke Thrombolysis. Stroke 2013; 44:
1595–1600.
27. Miteff F, Levi CR, Bateman GA, et al. The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke.
Brain 2009; 132: 2231–2238.
28. Bill O, Zufferey P, Faouzi M, Michel P. Severe stroke: patient profile and predictors of favorable outcome. J Thromb Haemost 2013; 11: 92–99.
29. Liebeskind DS. Trials of endovascular therapies or collaterals? Int J Stroke 2013;
8: 258–259.
30. Zhu G, Michel P, Aghaebrahim A, et al. Prediction of recanalisation trumps prediction of tissue fate: the penumbra: a dual-edged sword. Stroke 2013; 44:
1014–1019.
Thrombosis and Haemostasis 113.4/2015
© Schattauer 2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
New Technologies, Diagnostic Tools and Drugs
ASTRAL-R score predicts non-recanalisation after intravenous
thrombolysis in acute ischaemic stroke
Peter Vanacker1,2,3; Mirjam R. Heldner4; David Seiffge5; Hubertus Mueller6; Ashraf Eskandari1; Christopher Traenka5; George Ntaios7;
Pascal J. Mosimann8; Roman Sztajzel6; Vitor Mendes Pereira9*; Patrick Cras3; Stefan Engelter5,10; Philippe Lyrer5; Urs Fischer4;
Dimitris Lambrou1; Marcel Arnold4; Patrik Michel1
1Department
of Neurology, Centre Hospital Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; 2Department of Neurology, General Hospital Sint-Lucas,
Bruges, Belgium; 3Department of Neurology, Born Bunge Institute, University and University Hospital, Antwerp, Belgium; 4Department of Neurology, University Hospital, Bern,
Switzerland; 5Department of Neurology and Stroke Center, University Hospital, Basel, Switzerland; 6Department of Neurology, University Hospital, Geneva, Switzerland;
7Department of Medicine, University of Thessaly, Larissa, Greece; 8Institute for Diagnostic and Interventional Neuroradiology, Centre Hospital Universitaire Vaudois, Lausanne,
Switzerland; 9Institute for Diagnostic and Interventional Neuroradiology, University Hospital, Geneva, Switzerland; 10Neurorehabilitation Unit, University Center for Medicine of
Aging and Rehabilitation, Felix Plattee Hospital, Basel, Switzerland; *Current address: Department of Medical Imaging and Surgery, University of Toronto, Toronto, Ontario, Canada
Summary
Intravenous thrombolysis (IVT) as treatment in acute ischaemic
strokes may be insufficient to achieve recanalisation in certain patients. Predicting probability of non-recanalisation after IVT may have
the potential to influence patient selection to more aggressive management strategies. We aimed at deriving and internally validating a
predictive score for post-thrombolytic non-recanalisation, using clinical and radiological variables. In thrombolysis registries from four
Swiss academic stroke centres (Lausanne, Bern, Basel and Geneva),
patients were selected with large arterial occlusion on acute imaging
and with repeated arterial assessment at 24 hours. Based on a logistic
regression analysis, an integer-based score for each covariate of the
fitted multivariate model was generated. Performance of integerbased predictive model was assessed by bootstrapping available data
and cross validation (delete-d method). In 599 thrombolysed strokes,
five variables were identified as independent predictors of absence of
recanalisation: Acute glucose > 7 mmol/l (A), significant extracranial
Correspondence to:
Peter Vanacker
Centre Hospitalier Universitaire Vaudois
46, Rue de Bugnon
1011 Lausanne, Switzerland
E-mail: peter.vanacker@chuv.ch
vessel STenosis (ST), decreased Range of visual fields (R), large Arterial
occlusion (A) and decreased Level of consciousness (L). All variables
were weighted 1, except for (L) which obtained 2 points based on
β-coefficients on the logistic scale. ASTRAL-R scores 0, 3 and 6 corresponded to non-recanalisation probabilities of 18, 44 and 74 % respectively. Predictive ability showed AUC of 0.66 (95 %CI, 0.61–0.70)
when using bootstrap and 0.66 (0.63–0.68) when using delete-d cross
validation. In conclusion, the 5-item ASTRAL-R score moderately predicts non-recanalisation at 24 hours in thrombolysed ischaemic
strokes. If its performance can be confirmed by external validation and
its clinical usefulness can be proven, the score may influence patient
selection for more aggressive revascularisation strategies in routine
clinical practice.
Keywords
Cerebral infarction, thrombolytic therapy, decision support techniques,
cerebral revascularisation, cerebrovascular occlusion
Received: June 1, 2014
Accepted after major revision: November 21, 2014
Epub ahead of print: January 15, 2015
http://dx.doi.org/10.1160/TH14-06-0482
Thromb Haemost 2015; 113: ■■■
Introduction
Recanalisation of the occluded large vessels in acute ischaemic
strokes (AIS) may occur spontaneously in a subset of acute ischaemic stroke patients, but is more effectively achieved by intravenous thrombolysis (IVT) (1–6). However, patients with strokes
due to large vessel occlusions have low recanalisation rates with
IVT alone, associated with poor functional outcome despite treatment (1, 5). More aggressive, endovascular treatment strategies are
increasingly used to treat large vessel occlusive strokes, as they recanalise these occlusions more effectively and rapidly. However,
recent endovascular trials as IMS III, SYNTHESIS and MR-RESCUE (7) did not show superiority of endovascular therapy, although a trend of effectiveness was present in severe strokes
(NIHSS ≥ 20). Further, recanalisation by an acute endovascular in-
tervention is not always associated with reperfusion and better
clinical outcome (8), given that multiple other factors (time, collaterals, core and penumbra volumes, peripheral occlusions, site of ischaemia, metabolic states etc.) interfere. A better selection of patients who are most likely to benefit from aggressive (endovascular) therapy is therefore necessary (9).
We intended to develop and internally validate a simple score
for prediction of non-recanalisation after IV thrombolysis in AIS
patients by using items easily assessable before IV thrombolysis.
So far, clinical variables as admission glucose levels (10, 11) and
cardiovascular risk factors as atrial fibrillation (12, 13), smoking
(14) and metabolic syndrome (15) were identified as predictors.
Further, the following radiological items were known to be independently associated with recanalisation after intravenous
thrombolysis: location of the vessel occlusion (11, 13, 17), AS-
© Schattauer 2015
Thrombosis and Haemostasis 113.4/2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
2
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
PECTS scores (17), thrombus length (18) and thrombus density
(19).
Patients and methods
Study design and patient selection
The study includes data from a prospective cohort of consecutive, ischaemic stroke patients in four Swiss academic stroke centres (University Hospitals of Lausanne: 2003–2012, Basel: 2007–2013, Berne:
2007–2012 and Geneva: 2007–2012). The coordinating centre
(Lausanne) compiled the data of the different prospective registers
and performed the analysis of the pooled data. The inclusion criteria
for the analysis were A) acute noninvasive vascular imaging (CTA,
MRA or duplex) before IVT showing B) arterial occlusion in cervical and/or cerebral arteries in relation to the ischaemic territory, C)
availability of a second arterial imaging (CTA, MRA, angiography or
duplex) at 24 hours (h) (allowed range 12–48 h) permitting assessment of recanalisation and D) treatment with IVT alone within
proven time windows (3 h after last proof of well-being up to
10/2008, 4.5 h thereafter). Arterial occlusions were defined according to standardised methodologies that were published elsewhere
(20). Vascular imaging (CTA, MRA or duplex) was performed in all
centres before or within minutes after administration of the IV
thrombolysis bolus which should not influence arterial pathology. In
the vast majority of patients (n=563, 94 %) CTangiography was the
initial imaging technique. Indications for IVT with recombinant tissue plasminogen activator (rtPA) followed European Stroke Organisation guidelines (21). Patients with additional acute endovascular
procedures after IVT were excluded.
Medical variables collected and analysed included demographics, cardiovascular risk factors, co-morbidities, pre-stroke
medication, type of clinical deficit, NIHSS at admission (with all
items individually collected), onset-to-admission time, vital signs
and radiological imaging at admission. Pretreatment NIHSS
scores were assessed by certified stroke physicians. The clinical
signs “decreased range of visual fields” and “loss of consciousness”
were defined as in the NIHSS scale. On the acute vascular imaging,
large vessels pathology was analysed in each centre by both a neuroradiologist and stroke neurologist aware of clinical findings. As
both raters collaborated as a team, inter-rater variability has not
been assessed. The information on the presence and site of large
vessel occlusions and significant intra- and extracranial stenoses
were collected, based on pre-specified definitions. Intracranial occlusions in the ischaemic territory were categorised according to
their site in large vs intermediate occlusions. Large intracranial occlusions were defined as an occlusion of the basilar artery (with
our without intracranial vertebral artery occlusion), the intracranial carotid siphon (large and/or including carotid T) and large
middle cerebral artery (M1) both with and without ipsilateral
extracranial carotid occlusion. Intermediate intracranial occlusions were defined as occlusions in anterior cerebral artery (A1 or
A2 segments), peripheral middle cerebral artery (M2), posterior
cerebral artery (P1 or P2 segments), intracranial part of the vertebral artery (V4) and siphon of the internal carotid artery without
distal T-occlusion; the latter two were considered “intermediate”
because thrombus load and clinical symptoms are usually minor in
the absence of extension into the basilar artery and the carotid T,
respectively. Recanalisation of initially occluded arteries was defined for intra- and extracranial vessel occlusions and for the different imaging techniques separately, and was classified as “absent”
vs “partial or complete”. These criteria were published elsewehere
(20) If several good quality studies are available at 12–48 h, prioritiy was given to DSA > CTA > MRA > Doppler.
The collection, analysis and publication of data in the four
stroke registries were performed according to the guidelines of the
respective ethical boards of each centre.
Statistical analyses
Continuous variables are summarised using median and interquartile range, while categorical ones with count and percentage.
Univariate comparisons for all the variables considered, between
the patients who recanalise after intravenous thrombolysis and
those who did not, were performed using logistic regression analysis, where the significance of each variable was assessed separately.
Before starting the multiple analysis, imputation of the missing
values of the covariates considered was performed using the
method of chained equations (i. e. filling in the missing values on a
variable-by-variable basis, by first specifying the imputation model
for each incomplete variable and then using this model to fill in
the gaps). Five imputed datasets were generated using this method.
Multiple logistic regression analysis was performed on each imputed dataset separately. Stepwise methods were implemented on
each one of the five analysis, to identify significant main effects
and interactions. Final results were derived as combinations of the
outcome of the five imputed analysis. The log-odds of the final
model were used to define the coefficients in the proposed score.
Predictive ability of the score is measured via the area under the
receiver-operating characteristic curve (AUC-ROC), calculated for
the imputed datasets using bootstrapping and cross validation.
Bootstrapping assesses the predictive ability of our model by creating copies of the imputed datasets and recalculating AUC on these
copies. Cross-validation splits the imputed dataset in two parts
(not necessarily in half), fits a model to one part, and assesses its
predictive ability using the other part. As the two methods might
be considered as complementary to the other, both techniques
were used to evaluate the predictive ability of models. The ROC
analysis was carried out on the imputed datasets separately, and
final results were derived as combination of the outcome of these
analyses. All tests were carried out at 5 % significance level. All
analyses performed using the statistical package R (version 3.0.2).
Results
Prevalence of partial or complete recanalisation within 24 h
(12–48 h) after IV thrombolysis was 66 % or 396 patients in our
multi-centre cohort (n=599). The demographics and baseline
characteristics of patients with and without recanalisation are
Thrombosis and Haemostasis 113.4/2015
© Schattauer 2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
Table 1: Selection of baseline characteristics and radiological findings, dichotomised according to presence or absence of
post-thrombolytic recanalisation. Values are
expressed as medians and interquartile range
(IQR) for continuous variables unless stated
otherwise, and as absolute counts and percentage for categorical variables.
Non-recanali- Recanalisation OR
sation (n=203) (n=396)
95 % CI
Pvalue
Atrial fibrillation
75 (39 %)
156 (42 %)
1,13
0.79–1.61 0.49
Arterial hypertension
138 (68 %)
258 (65 %)
0,89
0.62–1.27 0.51
Hypercholesterolaemia
108 (53 %)
185 (47 %)
0,77
0.55–1.09 0.14
Previous stroke or TIA
28 (14 %)
53 (14 %)
0,99
0.60–1.62 0.96
Baseline NIHSS
14 ( 13)
12 ( 10)
0,97
0.95–0.99 0.01
Decreased level of consciousness
55 (28 %)
48 (13 %)
0,37
0.24–0.56 < 0.01
Visual field defects
106 (55 %)
165 (43 %)
0,62
0.44–0.88 < 0.01
Acute glucose levels (mmol/l)
6.8 ( 2.2)
6.4 ( 1.6)
0,89
0.82–0.96 < 0.01
Acute glucose levels > 7mmol/l
71 (35 %)
99 (25 %)
0,60
0.42–0.86 < 0.01
Acute systolic blood pressure
(mmHg)
156.0 (37.0)
152.0 (30.3)
1,00
0.99–1.01 0.89
Acute diastolic blood pressure
(mmHg)
85.0 (25.0)
84.0 (22.0)
0,99
0.98–1.00 0.15
Onset-to-needle time (h)
2.5 ( 1.2)
2.6 ( 1.1)
1,23
1.01–1.48 0.03
187 (47 %)
0,57
0.40–0.80 < 0.01
70 (19 %)
0,54
0.36–0.81 < 0.01
Medical history
Presentation on arrival
Vessel occlusion characterisation
Large intracranial occlusion
124 (61 %)
Significant extracranial vessel pa- 56 (30 %)
thology (stenosis or occlusion)
shown partially in ▶ Table 1. Numbers of included patients per
centre were as follows: Lausanne (n=210), Basel (n=217), Bern
(n=136) and Geneva (n=35). Recanalisation was assessed by CTA
in 82 % (n=491), by MRA in 12 % (n=72) and by duplex only in
6 % (n=36). Five clinical and radiological variables were identified
as independent predictors of non-recanalisation: Acute glucose > 7
mmol/l (A), STenosis or occlusion of extracranial vessels (ST),
Range of visual fields decreased (R), Arterial occlusion in a large
site (A) and an decreased level of consciousness (L) (▶ Table 2).
The cut-off value for acute glucose levels was chosen on a treebased method, suggesting that a cut-off of 7 mmol/l would be the
most adequate. As the initial multivariate analysis failed to acknowledge the role of time in relation to recanalisation, additional
statistical analyses were performed to check the effect of different
cut-off values for the onset-to-needle times (< 1.5 h, < 3 h, < 4.5 h)
on the prediction of recanalisation. No significant correlation was
detected between dichotomisation at 3 h (OR 1.2, 95 %CI 0.8–1.8)
Table 2: The ASTRAL-R Score: Independent
predictors of absence of post-thrombolytic
recanalisation at 24 h with the respective
score points.
and at 4.5 h (OR 1.5, 95 %CI 0.5–4.9) with recanalisation after IV
thrombolysis. Only, dichotomisation at 1.5 h was significantly associated with recanalisation (OR 1.97, 95 %CI 1.1–3.5). This parameter, however, did not improve the predictive performance of
the ASTRAL-R score in terms of AUC-ROC.
The ordering of the predictors used in our score, according to
their significance in the final model, judged from the p-value of
the imputation analysis and starting from the most significant to
the least significant, is as follows: decreased consciousness, extracranial pathology, visual field defect, acute glucose level and proximal intracranial occlusion. A predictive model with the item decreased consciousness only has AUC 57.7 %, adding extracranial
pathology the AUC raises to 62.1 %, adding further visual field defect AUC is estimated at 64.6 % and adding acute glucose level
AUC goes to 65.0 % and finally adding proximal occlusion gives an
AUC of 66.2 % (Suppl. Figure 1, available online at www.thrombo
sis-online.com).
Covariates
OR
95 % CI
P-value
Score Point
Acute Glucose level > 7mmol/l
0.91
0.84–0.99
0.02
1
STenosis/Occlusion in extracranial vessel
0.54
0.35–0.83
0.01
1
Range of visual fields decreased
0.69
0.48–1.00
0.04
1
Arterial Occlusion: large size
0.68
0.47–0.98
0.04
1
Level of consciousness altered
0.45
0.28–0.71
0.01
2
© Schattauer 2015
Thrombosis and Haemostasis 113.4/2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
3
4
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
Figure 1: Association between the ASTRAL-R score and the probability of non-recanalisation (12–24 h) after IV thrombolysis.
▶Figure 1 displays the predicted probability of non-recanalisation after IV thrombolysis based on the ASTRAL-R score. The
absolute risk of non-recanalisation for the corresponding ASTRAL-R scores 0, 1, 2, 3, 4, 5 and 6 were 17.7 %, 24.8 %, 33.5 %,
43.6 %, 54.2 %, 64.4 % and 73.5 %, respectively. Patients with an ASTRAL-R score more than 3 have a likelihood of absence of postthrombolytic recanalisation of more than 50 %. Suppl. Figure 2
(available online at www.thrombosis-online.com) shows the distribution of the overall ASTRAL-R score and its components
among the population.
The predictive ability of the model was assessed in two ways: a)
by calculating the AUC of the ROC-curve using the original
sample (599 patients after imputing for missing values) and attaching uncertainty using bootstrap methodology (1,000 repetitions),
and b) by cross-validation (deleted-d method repeated 1,000
times). The estimated AUC in both cases was 0.66 with a 95 %CI of
0.61–0.70 (Suppl. Figure 3, available online at www.thrombosis-on
line.com) using the first method, while the corresponding 95 % CI
for the cross validation was 0.63–0.68 (Suppl. Figure 4, available
online at www.thrombosis-online.com).
Discussion
This study describes the derivation and internal validation of the
ASTRAL-R score in a multi-centre cohort which estimates the
likelihood of non-recanalisation 24 h after IVT. A linear relationship between the total score and non-recanalisation could be
shown, and the performance of the model was assessed in a multicentre cohort.
The score consists of five easily available variables already before IVT: acute glucose (cut-off > 7 mmol/l), extracranial stenosis
> 50 % or occlusion, visual field defects, decreased level of consciousness and a large artery intracranial occlusion. Hyperglycaemia in acute stroke patients is common and may decrease plasma
t-PA activity. Further, acute hyperglycaemia may be related to
atherosclerotic disease, which has been shown to be more resistant
to recanalisation after tPA treatment (10, 22). The concomitant
presence of extracranial arterial stenosis or occlusion may lead to
less recanalisation because of decreased inflow of blood into the
blocked arteries, leading to less arrival of IV rt-PA and less washout of clots (23). Occlusion of larger intracranial arteries is likely to
be related to less recanalisation because of higher thrombus
burden than in smaller arteries, as shown previously (13, 14). It is
unclear why decreased level of vigilance and visual field defects
were independent predictors of recanalisation, although these factors have been associated with worse clinical outcome (24). One
hypothesis may be that these signs of clinical severity may indicate
poorer collaterals which could also contribute to recanalisation
(25).
Some previously described predictors of recanalisation, such as
onset-to-needle time (10), atrial fibrillation (12, 13), smoking (14)
and metabolic syndrome (15) and ASPECTS scores (17) were not
confirmed in our logistic regression analysis. This may be related
to differences in the cohorts or the sample size.
Use of the ASTRAL-R score in clinical practice has the potential
to improve acute stroke management. Given several negative interventional revascularisation trials, a more careful selection of patients is mandatory (9). A more individualised patient selection
based not only on the severity of the stroke but also on the non-recanalisation risk after IV thrombolysis could be promising. In individual cases with a high likelihood of non-recanalisation after
IVT (e. g. large vessel occlusions, extracranial stenosis, hyperglycaemia), endovascular intervention for non-recanalising patients
may be of added benefit, in particular if salvageable tissue can be
demonstrated by multimodal imaging (26, 27). In addition, successful recanalisation is associated with better outcome also in severe stroke patients (28).
Some items in the ASTRAL-R score (level of consciousness, visual field defects and acute glucose level) are the same as in the
prognostic ASTRAL score for clinical outcome (24). Both scores
may be used as selection tools for future clinical trials on endovascular treatment after IVT.
One of the strengths of the ASTRAL-R score is the large
number of patients and variables included and the multi-centre
design including four sites with a longstanding experience in acute
stroke research. Data were available on the specific site of arterial
occlusions sites in all cohorts. Validation of the score was performed by a bootstrap and cross validation (delete-d method).
Several limitations apply: First, implementation in routine
clinical practice may be hampered by the moderate predictive ability of the model with areas under the ROC curve of 0.66. This corresponds to other predictive scores in acute stroke care (e. g.
SEDAN score) which have similar c-statistic values (29). This can
partially be explained by combing four different cohorts of thrombolysed stroke patients. Adding factors such as collateral vessel
status (25), perfusion imaging (30) and thrombus length (13)
could further improve the score. However, such radiological data
and imaging techniques are not routinely used in clinical practice
and are hampered by standardisation issues. Secondly, external
validation in independent cohorts will be necessary to confirm the
performance of the score. The validity of the score in patients who
Thrombosis and Haemostasis 113.4/2015
© Schattauer 2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
underwent endovascular treatment needs to be assessed, as these
patients were excluded in the current analysis. Thirdly, large vessel
occlusions were classified into large and intermediate arterial occlusions, mainly based on anatomical location. The likelihood of
recanalisation between the location sites may be more variable
than expected. This arbitrary classification is debatable, but clinically relevant in the absence of a standardised classification of the
intracranial arteries. Fourthly, our definition of recanalisation was
not based on a single imaging modality but on heterogeneous
methods, the degree of recanalisation was dichotomised at an arbitrary point (between none and partial or complete) and the best
timing for recanalisation assessment is still unknown. Fifthly, a
pre-selection bias may have been introduced in the study by excluding stroke patients with additional acute endovascular procedures after insufficient IV t-PA recanalisation. Potentially, lower
recanalisation rates and different predictive parameters would
have been found in this subgroup of patients. And finally, reading
of the vascular imaging data was not centralised in order to prevent high inter-rater variabilities.
What is known about this topic?
•
A few clinical and radiological factors influencing the recanalisation rate in IV thrombolysis-treated acute ischaemic strokes, are
known from small single-centre studies.
What does this paper add?
•
•
•
•
By performing a logistic regression analysis in a multi-centre cohort, we could detect independent predictors of arterial recanalisation after IV thrombolysis.
For the first time, a diagnostic tool (ASTRAL-R score) has been
shown to have a good predictive accuracy for recanalisation after
IV thrombolysis.
The ASTRAL-R score is an easy-to-use 5 items score (0-> 6).
In the future, some additional radiological can be detected to improve the accuracy of ASTRAL-R score.
Conflicts of interest
Conclusions
In conclusion, the ASTRAL-R score is an easy-to-assess 5-item
score moderately predicting non-recanalisation after IVT in acute
ischaemic strokes.
Acknowledgements
The first and last author (P. Vanacker, P. Michel) had full access to
all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis. This research is
supported by grants from the Swiss Cardiology foundation (P. M.,
P. V.), CardioMet-CHUV (P. M.) and a scholarship of the European
Neurological Society (P. V.).
Author contributions
Vanacker P: Study concept and design, analysis, interpretation,
preparation of the manuscript. Heldner MR: Data acquisition and
analysis, critical revision of the manuscript for important intellectual content. Seiffge D: Data acquisition and analysis, critical revision of the manuscript for important intellectual content. Mueller
H: Data acquisition and analysis. Traenka C: Data acquisition and
analysis. Ntaios G: Study concept and design, data acquisition and
analysis, critical revision of the manuscript for important intellectual content. Stajzel R: Data acquisition and analysis. Lyrer P: Data
analysis, critical revision of the manuscript for important intellectual content. Fischer U: Data acquisition, data analysis, critical
revision of the manuscript for important intellectual content. Lambrou D: Data analysis, statistical analysis. Arnold M: Data analysis,
critical revision of the manuscript for intellectual content. Michel
P: Study concept and design, data acquisition, analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision.
P. V., D. L., A. E., M. R. H. and C. T. report no disclosures. D. S. received a travel grant from Bayer. P. L. has served on scientific advisory boards for Bayer, Schering Pharma, BMS/Pfizer and Boehringer Ingelheim; has received funding for travel or speaker honoraria from Bayer Schering Pharma, Boehringer Ingelheim, and
Shire plc; he serves as Co-Editor for Neurologie und Psychiatrie
and on the editorial board of Swiss Archives of Neurology and
Psychiatry; and has received research support from AstraZeneca,
Boehringer Ingelheim, Sanofi-aventis, Photo-Thera, the Swiss
National Science Foundation, and the Swiss Heart Foundation.
G. N. received consulting fees from Boehringer-Ingelheim; honorarium from Medtronic; speaker fees from Boehringer-Ingelheim
and Sanofi. P. M. received funding for travel or speaker honoraria
from Shire, Bayer, Sanofi-Aventis; consulting fees from Lundbeck
and Pierre-Fabre; honoraria for scientific advisory boards for
Bayer and Boehringer-Ingelheim.
References
1. Rha JH, Saver JL. The impact of recanalisation on ischaemic stroke outcome: a
meta-analysis. Stroke 2007; 38: 967–973.
2. Fiebach JB, Al-Rawi Y, Wintermark M, et al. Vascular Occlusion Enables Selecting Acute Ischaemic Stroke Patients for Treatment With Desmoteplase. Stroke
2012; 43: 1546–1566.
3. Galimanis A, Jung S, Mono ML, et al. Endovascular therapy of 623 patients with
anterior circulation stroke. Stroke 2012; 43: 1052–1057.
4. Mazighi M, Serfaty JM, Labreuche J, et al. RECANALISE investigators. Comparison of intravenous alteplase with a combined intravenous-endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE
study): a prospective cohort study. Lancet Neurol 2009; 8: 802–809.
5. Yeo LLL, Paliwal P, Teoh HL, et al. Timing of Recanalisation after Intravenous
Thrombolysis and Functional Outcomes After Acute Ischaemic Stroke. J Am
Med Assoc Neurol 2013; 70: 353–358.
6. Zaidat OO, Suarez JI, Sunshine JL, et al. Thrombolytic Therapy of Acute Ischaemic Stroke : Correlation of Angiographic Recanalisation with Clinical Outcome. Am J Neuroradiol 2005; 26: 880–884.
7. Broderick JP, Palesch YY, Demchuk AM, et al; for the Interventional Management of Stroke (IMS) III Investigators. N Engl J Med 2013; 368: 893–903.
© Schattauer 2015
Thrombosis and Haemostasis 113.4/2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
5
6
Vanacker et al. ASTRAL-R: non-recanalisation in thrombolysed strokes
8. Soares BP, Tong E, Hom J, et al. Reperfusion is a more accurate predictor of follow-up infarct volume than recanalisation : a proof of concept using CT in acute
ischaemic stroke patients. Stroke 2010; 41: 34–40.
9. Liebeskind DS. The Quest to Prove Endovascular Stroke Therapy: Searching for
the “Sweet Spot” in Patient Selection. Mayo Clin Proc 2013; 88: 1039–1041.
10. Ribo M, Molina C, Montaner J, et al. Acute hyperglycemia state is associated
with lower tPA-induced recanalisation rates in stroke patients. Stroke 2005; 36:
1705–1709.
11. Zangerle A, Kiechl S, Spiegel M, et al. Recanalisation after thrombolysis in
stroke patients: predictors and prognostic implications. Neurology 2007; 68:
39–44.
12. Kimura K, Iguchi Y, Yamashita S, et al. Atrial fibrillation as an independent predictor for no early recanalisation after IV-rtPA in acute ischaemic stroke. J
Neurol Sci 2008; 246: 57–61.
13. Mendonça N, Rodriguez-Luna D, Rubiera M, et al. Predictors of tissue-type
plasminogen activator nonresponders according to location of vessel occlusion.
Stroke 2012; 43: 41714. Kufner A, Nolte CH, Galinovic I, et al. Smoking-Thrombolysis Paradox: Recanalisation and Reperfusion Rates After Intravenous Tissue Plasminogen Activator in Smokers With Ischaemic Stroke. Stroke 2013 ; 44: 407–413.
15. Arenillas JF, Sandoval P, Pérez de la Ossa N, et al. The metabolic syndrome is associated with a higher resistance to intravenous thrombolysis for acute ischaemic stroke in women than in men. Stroke 2009; 40: 344–349.
16. Saqqur M, Uchino K, Demchuk AM, et al; CLOTBUST Investigators. Site of Arterial Occlusion Identified by Transcranial Doppler Predicts the Response to Intravenous Thrombolysis for Stroke. Stroke 2007; 38: 948–954.
17. Tsivgoulis G, Saqqur M, Sharma VK, et al; CLOTBUST Investigators. Association of pretreatment ASPECTS scores with tPA-induced arterial recanalisation
in acute middle cerebral artery occlusion. J Neuroimag 2008; 18: 56–61.
18. Riedel CH, Zimmerann P, Jensen-Kondering U, et al. The importance of size:
succesful recanalisation by intravenous thrombolysis in acute anterior stroke
depends on thrombus length. Stroke 2011; 42: 1775–1777.
19. Moftakhar P, English JD, Cooke DL, et al. Density of Thrombus on Admission
CT Predicts Revascularisation in Large Vessel Occlusion Acute Ischaemic
Stroke. Stroke 2013; 44: 243–245.
20. Vanacker P, Lambrou D, Eskandari A, et al. Improving Prediction of Recanalisation in Acute Large Vessel Occlusive Stroke. J Thromb Haemost 2014; Epub
ahead of print.
21. Wunderlich MT, Goertler M, Postert T, et al; Duplex Sonography in Acute
Stroke (DIAS) Study Group; Competence Network Stroke. Duplex Sonography
in Acute Stroke (DIAS) Study Group; Competence Network Stroke. Recanalisation after intravenous thrombolysis: does a recanalisation time window exist?
Neurology 2007; 68: 1364–1368.
22. Arnold M, Mattle S, Galimanis A, et al. Impact of admission glucose and diabetes on recanalisation and outcome after intra-arterial thrombolysis for ischaemic stroke. Intern J Stroke 2014; 9: 985-991.
23. Ntaios G, Faouzi M, Ferrari J, et al. An integer-based score to predict functional
outcome in acute ischaemic stroke: the ASTRAL score. Neurology 2012; 78:
1916–1922.
24. Bhatia R, Hill MD, Shobha N, et al. Low Rates of Acute Recanalisation With Intravenous Recombinant Tissue Plasminogen Activator in Ischaemic Stroke.
Real-World Experience and a Call for Action. Stroke 2010; 41: 2254–2258.
25. Campbell BC, Christensen S, Parsons MW, et al; EPITHET and DEFUSE Investigators. Advanced imaging improves prediction of hemorrhage after stroke
thrombolysis. Ann Neurol 2013; 73: 510-519.
26. Mayza MV, Bovi U, Castillo J, et al. External validation of the SEDAN score for
prediction of intracerebral hemorrhage in Stroke Thrombolysis. Stroke 2013; 44:
1595–1600.
27. Miteff F, Levi CR, Bateman GA, et al. The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke.
Brain 2009; 132: 2231–2238.
28. Bill O, Zufferey P, Faouzi M, Michel P. Severe stroke: patient profile and predictors of favorable outcome. J Thromb Haemost 2013; 11: 92–99.
29. Liebeskind DS. Trials of endovascular therapies or collaterals? Int J Stroke 2013;
8: 258–259.
30. Zhu G, Michel P, Aghaebrahim A, et al. Prediction of recanalisation trumps prediction of tissue fate: the penumbra: a dual-edged sword. Stroke 2013; 44:
1014–1019.
Thrombosis and Haemostasis 113.4/2015
© Schattauer 2015
Downloaded from www.thrombosis-online.com on 2015-01-15 | ID: 1000468122 | IP: 155.105.7.44
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.