A multicentre, randomized, double-blinded,

placebo-controlled Phase III study to investigate

EXtending the time for Thrombolysis in Emergency
Neurological Decits (EXTEND)
Henry Ma
1,2
, Mark W. Parsons
3
, Soren Christensen
4
, Bruce C. V. Campbell
4
,
Leonid Churilov
1
, Alan Connelly
5
, Bernard Yan
4
, Chris Bladin
6
, Than Phan
7
,
Alan P. Barber
8
, Stephen Read
9
, Graeme J. Hankey
10
, Romesh Markus
11
,
Tissa Wijeratne
12
, R. Grimley
13
, N. Mahant
14
, Tim Kleinig
15
, John Sturm
16
, A. Lee
17
,
D. Blacker
18
, Richard Gerraty
2,19
, M. Krause
20
, P. M. Desmond
21
, S. J. McBride
23
,
Leanne Carey
1
, David W. Howells
1
, C. Y. Hsu
22
, Stephen M. Davis
4
**, and
Geoffrey A. Donnan
1
*
,
** on behalf of the EXTEND investigators
Background and hypothesis Thrombolytic therapy with
tissue plasminogen activator is effective for acute ischaemic
stroke within 45 h of onset. Patients who wake up with
stroke are generally ineligible for stroke thrombolysis. We
hypothesized that ischaemic stroke patients with signicant
penumbral mismatch on either magnetic resonance imaging
or computer tomography at three- (or 45 depending on local
guidelines) to nine-hours from stroke onset, or patients with
wake-up stroke within nine-hours from midpoint of sleep
duration, would have improved clinical outcomes when
given tissue plasminogen activator compared to placebo.
Study design EXtending the time for Thrombolysis in
Emergency Neurological Decits is an investigator-driven,
Phase III, randomized, multicentre, double-blind, placebo-
Correspondence: Geoffrey A. Donnan*, National Stroke Research
Institute, Austin Health, University of Melbourne, 245 Burgundy Street,
Heidelberg, Vic 3084, Australia.
E-mail: gdonnan@unimelb.edu.au
1
National Stroke Research Institute, Florey Neuroscience Institutes,
Austin Health, University of Melbourne, Heidelberg Heights, Victoria,
Australia
2
Department of Medicine, Monash Medical Centre, Monash University,
Clayton, Victoria, Australia
3
Department of Neurology, John Hunter Hospital, University of
Newcastle, Newcastle, New South Wales, Australia
4
Department of Medicine, Melbourne Brain Centre, Royal Melbourne
Hospital, University of Melbourne, Heidelberg, Victoria, Australia
5
Brain Research Institute, Florey Neuroscience Institutes, Heidelberg
Heights, Victoria, Australia
6
Department of Neurology, Box Hill Hospital, Eastern Health,
Melbourne, Victoria, Australia
7
Department of Neurology, Monash Medical Centre, Monash
University, Clayton, Victoria, Australia
8
Department of Neurology, Auckland Hospital, Auckland, New Zealand
9
Department of Neurology, Royal Brisbane & Womens Hospital,
Brisbane, Queensland, Australia
10
Department of Neurology, Royal Perth Hospital, Perth, Western
Australia, Australia
11
Department of Neurology, St Vincents Hospital, Sydney, New South
Wales, Australia
12
Department of Neurology, Western Hospital, Western Health,
Melbourne, Victoria, Australia
13
Department of Neurology, Nambour General Hospital, Nambour,
Queensland, Australia
14
Department of Neurology, Westmead Hospital, Sydney, New South
Wales, Australia
15
Department of Neurology, Royal Adelaide Hospital, Adelaide, South
Australia, Australia
16
Department of Neurology, Gosford Hospital, University of Newcastle,
Newcastle, New South Wales, Australia
17
Department of Neurology, Flinders Medical Centre, Bedford Park,
South Australia, Australia
18
Department of Neurology, Sir Charles Gardiner Hospital, Perth,
Western Australia, Australia
19
Department of Neurology, Epworth Healthcare, Melbourne, Victoria,
Australia
20
Department of Neurology, Royal North Shore Hospital, Sydney, New
South Wales, Australia
21
Department of Radiology, Royal Melbourne Hospital, Melbourne,
Victoria, Australia
22
Department of Neurology, China Medical University Hospital and
Graduate Institute of Clinical Medical Science, China Medical
University, Taichung, Taiwan
23
CSIRO Preventative Health Flagship, Parkville, Victoria and Australian
e-Health Research Centre, CSIRO ICT Centre, Brisbane, Queensland,
Australia
Conict of interest: None declared.
**Co-chair of START/EXTEND collaborative study group.
DOI: 10.1111/j.1747-4949.2011.00730.x
Protocols
2011 The Authors.
International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012, 7480 74
controlled study. Ischaemic stroke patients presenting after
the three- or 45-h treatment window for tissue plasminogen
activator and within nine-hours of stroke onset or with
wake-up stroke within nine-hours from the midpoint of
sleep duration, who full clinical (National Institutes of
Health Stroke Score 426 and prestroke modied Rankin
Scale <2) will undergo magnetic resonance imaging or com-
puter tomography. Patients who also meet imaging criteria
(infarct core volume <70 ml, perfusion lesion : infarct core
mismatch ratio >12, and absolute mismatch >10 ml) will be
randomized to either tissue plasminogen activator or
placebo.
Study outcome The primary outcome measure will be modi-
ed Rankin Scale 01 at day 90. Clinical secondary outcomes
include categorical shift in modied Rankin Scale at 90 days,
reduction in the National Institutes of Health Stroke Score by
8 or more points or reaching 01 at day 90, recurrent stroke,
or death. Imaging secondary outcomes will include sympto-
matic intracranial haemorrhage, reperfusion and or recanali-
zation at 24 h and infarct growth at day 90.
Key words: clinical trials, EXTEND, protocols, stroke,
thrombolysis, time window
Introduction
In acute ischaemic stroke, intravenous thrombolysis (tissue
plasminogen activator (tPA)) has been shown to result in
improved outcome when given up to 45 h from symptom
onset (1). In spite of the clear benet of tPA, approximately
5% of patients receive therapy, and this small proportion is
mainly related to the short therapeutic time window (2).
Potentially increasing the number of patients eligible to
receive tPA is to extend the time window for therapy. This
approach is biologically plausible as there is evidence that
potentially viable brain tissue in the ischaemic penumbra may
exist for up to 48 h after symptom onset of ischaemic stroke,
and in some cases (3,4), magnetic resonance imaging (MRI)
may give an indication of penumbral tissue as the mismatch
between the hypoperfused perfusion-weighted image (PWI)
and the infarct core seen on the diffusion-weighted image
(DWI). Such PWI/DWI mismatch tissue may be present in up
to half of all ischaemic stroke patients at 24 h (3).
Recent evidence conrms that the time window for throm-
bolysis may be extended beyond the 45-h limit (5). When
designing studies to conrm such an extension, there are two
potential enrolment strategies that may be used. First, using an
indiscriminant approach where all potential patients are
included; however, this entails disadvantage of a large sample
size requirement to compensate for the inclusion of patients
whodonot respondtotherapy. The secondapproachis toenrol
an enriched population of patients with greater likelihood of
therapeutic responsiveness (6), using MRI, and in particular
PWI and DWI to identify potentially penumbral tissue.
The relationship between PWI/DWI mismatch, thrombo-
lytic therapy, and surrogate MR-based outcomes has been
explored in a series of Phase II clinical trials. In the openlabel,
nonrandomized Diffusion and Perfusion Imaging Evaluation
for Understanding Stroke Evolution (DEFUSE) study, patients
presenting within a threesix-hour treatment window
received tPA and had PWI, DWI, and MR angiography (MRA)
performed at study entry and again within 24 h (7). A strong
relationship between recanalization, reperfusion, and attenu-
ation of infarct growth was found. A sub-set of patients with
malignant mismatch where the DWI volume was greater than
100 ml and who were at high risk of symptomatic intracer-
ebral haemorrhage was identied (8).
The Echoplanar Imaging Thrombolytic Evaluation Trial
(EPITHET) was a double-blinded, randomized, placebo-
controlled Phase II trial in ischaemic stroke patients present-
ing threesix-hours after symptom onset and were
randomized to tPA or placebo after MRI scans had been
obtained and which were then repeated at days 35 (9).
EPITHET found a relationship between tPA and reperfusion
and attenuation of infarct growth on the serial PWI and
DWI studies (10). Furthermore, there was a 15% absolute
improvement in clinical outcome measures (modied
Rankin Scale (mRS) 01) in patients with penumbral tissue
as demonstrated by the presence of PWI/DWI mismatch.
When a further analysis was undertaken using co-
registration techniques to more accurately determine mis-
match volumes at study entry, the primary outcome measure
of infarct growth was signicantly attenuated (10). The
DEFUSE and EPITHET studies therefore provide strong bio-
logical support for the extension of the therapeutic window
for tPA beyond the current 345 h in patients with PWI/
DWI mismatch and also a means to limit study populations
to those with the potential to benet from putative reper-
fusion therapies.
Since the completion of DEFUSE and EPITHET, rapid and
precise automated systems for the assessment of PWI/DWI
mismatch has become available for research purpose
(RAPID). Optimal perfusion measures and a clear denition
of what constitutes PWI/DWI mismatch have been dened. A
Tmax delay of plus six-seconds has been shown to be the PWI
parameter that most accurately predicts nal infarct volume,
and a perfusion volume to infarct core ratio of 12 has been
shown to predict response to tPA (1113). DWI volumes of
more than 70 ml confer poor clinical outcome regardless of
whether a patient receives tPA or not (14,15).
Computer Tomography (CT) perfusion has recently been
validated as an alternative modality to determine penumbral
mismatch. The infarct core indicated by diffusion MRI is best
represented by thresholded CT cerebral blood ow (CBF)
(1618). The extent of salvageable tissue dened by MR-Tmax
>6 s directly translates to CT-Tmax >6 s and has good agree-
ment with perfusiondiffusion mismatch using the mismatch
ratio >12, absolute mismatch volume >10 ml, and infarct core
volume <70 ml criteria (Campbell et al., unpublished data).
CT has practical advantages in 24-h accessibility and fewer
practical restrictions compared with MRI.
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H. Ma et al.
2011 The Authors.
International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012, 7480 75
Current guidelines limit tPA therapy to patients who can
receive therapy 345 h after a known symptom onset. This
time-linked treatment window excludes the majority of
patients who wake up with stroke symptoms, the so-called
wake-up strokes (WUS). Recent clinical and imaging studies
have suggested that a substantial number of patients with
WUS have a stroke onset that is close to the time of waking so
that many of these patients may still have potentially salvage-
able penumbral tissue (19,20). Penumbral mismatch is a
logical method to identify WUS patients who may benet
from thrombolytic therapy with an acceptable level of risk.
On the basis of this information, we have designed the
EXTEND, an international, Phase III, randomized, multi-
centre, double-blinded, placebo-controlled study. EXTEND
will be an international collaborative study involving centres
in Australia and countries around the world (EXTEND
International).
Study objectives
The aim of this study was to test the hypothesis that ischaemic
stroke patients of similar age and stroke severity with penum-
bral mismatch between 3 and 45 h (depending on local guide-
lines) and nine-hours after stroke onset will have better
outcomes with intravenous tPA than patients receiving
placebo.
Methods
Study design (Fig. 1)
The EXTEND study will be a randomized, multicentre,
double-blinded, placebo-controlled phase III trial (two arms
with 1 : 1 randomization) in ischaemic stroke patients.
Patients randomized to treatment will be stratied for geo-
graphical region and for time of randomization after stroke
into one of the following strata:

Greater than three-hours (or 45 h depending on local prac-

tice) and up to six-hours

Greater than six-hours and up to nine-hours, and

WUS, where the time of stroke onset will be dened as the

midpoint between the onset of sleep or when the patient was
last known to be normal and the time of waking.
Patient population
Inclusion criteria

Patients presenting with acute hemispheric ischaemic stroke

Patient, family member, or legally responsible person,

depending on local ethics requirements, has given informed
consent

Age 18 years
Fig. 1 EXtending the time for Thrombolysis in Emergency Neurological Decits study assessment ow chart. BI, Barthel Index; ICH, Intracranial
haemorrhage; MRI, magnetic resonance imaging.
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H. Ma et al.
2011 The Authors.
International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012, 7480 76

Treatment onset can commence after three-hours and up to

and including nine-hours after stroke onset according to reg-
istered product information, or greater than 45 h up to and
including nine-hours according to locally accepted guidelines

WUS patients are dened as having no symptoms at sleep

onset, but stroke symptoms on waking; time of stroke onset is
to be taken as the midpoint between sleep onset (or last known
to be normal) and time of waking. The maximum time
window for randomization is then nine-hours from the mid-
point as described, and

National Institutes of Health Stroke Score (NIHSS) of

426 with clinical signs of hemispheric infarction.
Imaging inclusion criteria

Penumbral mismatch a penumbra to core lesion volume

ratio of greater than 12 and an absolute difference greater
than 10 ml (Using a MR or CT Tmax >6-s delay perfusion
lesion and MR-DWI or CT-CBF core lesion), and

An infarct core lesion volume of less than or equal to 70 ml

using MR-DWI or CT-CBF
Exclusion criteria

Intracranial haemorrhage (ICH) identied by CT or MRI

Rapidly improving symptoms, particularly if in the judg-

ment of the managing clinician the improvement is likely to
result in the patient having an NIHSS of <4 at randomization

Prestroke mRS score of 2 (indicating previous disability)

Contraindication to the use of imaging contrast agents

Infarct core >1/3 middle cerebral artery (MCA) territory

qualitatively on CT

Participation in any investigational study in the previous 30

days

Any terminal illness such that the patient would not be

expected to survive more than one-year

Any condition that could impose hazards to the patient or

effect the participation of the patient in the study (this applies
to patients with severe microangiopathy such as haemolytic
uremic syndrome or thrombotic thrombocytopenic purpura)
(at the discretion of the investigator)

Pregnancy

Stroke within the last three-months; recent past history or

clinical presentation of ICH, sub-arachnoid haemorrhage,
arteriovenous malformation, aneurysm, or cerebral neoplasm
(at the discretion of each investigator)

Current use of oral anticoagulants and a prolonged pro-

thrombin time (International Normalised Ratio (INR) >16)

Use of heparin, except for low-dose sub-cutaneous heparin,

in the previous 48 h and a prolonged activated partial throm-
boplastin time exceeding the upper limit of the local labora-
tory normal range

Use of glycoprotein IIbIIIa inhibitors within the past 72 h;

use of single or dual agent oral platelet inhibitors (clopidogrel
and/or or low-dose aspirin) prior to study entry is permitted

Clinically signicant hypoglycaemia

Uncontrolled hypertension dened by a blood pressure

>185 mmHg systolic or >110 mmHg diastolic on at least two
separate occasions at least 10 mins apart, or requiring aggres-
sive treatment to reduce the blood pressure to within these
limits, the denition of aggressive treatment (at the discretion
of the investigator)

Hereditary or acquired haemorrhagic diathesis

Gastrointestinal or urinary bleeding within the preceding

21 days

Major surgery within the preceding 14 days which poses risk

in the opinion of the investigator, and

Exposure to a thrombolytic agent within the previous 72 h.

Clinical assessment
A health care professional trained in administration and
blinded to the treatment designation will measure neurologi-
cal impairment and functional scores. The NIHSS will be
performed before randomization, and repeated at 1224 h,
threedays, and 90 days after treatment. At day 90, clinical
assessments will also include the mRS and the Barthel Index.
Imaging assessment and parameters
Patients will have standardized MRI or CT sequences per-
formed prior to randomization, and, where possible, a second
MRI scan will be performed using the same parameters
1224 h later. MRI sequences include, DWI, PWI, MRA, T2*
Gradient Echo, and Fluid Attenuated Inversion Recovery
(FLAIR) at both time points. Baseline CT includes noncon-
trast CT, CT perfusion, and CT angiography. A mismatch
between the volume of the perfusion lesion and the irrevers-
ibly damaged infarct core is used for penumbral estimation.
The perfusion lesion is dened as Tmax >6 s for MRI and CT.
Infarct core is dened using MRI diffusion imaging or
CT-CBF imaging. Mismatch is dened as a perfusion : core
lesion volume ratio of greater than 12. Absolute mismatch
volume will be greater than 10 ml. Maximum infarct core
volume will be 70 ml.
The MRI protocol will follow current international consen-
sus guidelines (21), although the follow-up imaging will be
performed at 1224 h as recently validated to accurately reect
nal infarct volume (22). An initial scout view will be followed
by isotropic DWI (created from DWI images obtained with
diffusion-sensitizing gradients applied in three orthogonal
planes) using b-values between 0 s/mm
2
, equivalent to a
T2-weighted image, and 1000 s/mm
2
. Whole brain imaging
will use 25 contiguous axial slices each 5 mm in thickness.
Perfusion images will be derived from the concentrationtime
curve obtained after the administration of intravenous gado-
linium (01 mmol/kg) given over threeve-seconds with gra-
dient echo images acquired every 18 s for at least 100 s (15
axial slices at each time point). The imaging times for PWI and
DWI are each approximately three-minutes. Time-of-ight
MRA will be obtained to determine the presence or absence of
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H. Ma et al.
2011 The Authors.
International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012, 7480 77
MCA stem or major branch occlusion. A gradient echo (T2*)
sequence will be performed to assess for the presence of ICH.
A FLAIR sequence is also acquired to identify lesion expansion
to the sub-acute imaging time point.
The imaging data will be processed by an automated
program RAPID (supplied by Stanford University, United
States), and the results will be displayed on the predetermined
workstation or display unit of the recruiting centres. The proc-
essed images and results will be reviewed by the responsible
clinician of the recruiting centre before randomization. All
imaging data will be electronically transferred and read at
the coordinating centre on a weekly basis, to quality assure the
MRI-based decision making at the recruiting centres. The
coordinating centre will be blinded to the clinical information
and treatment designation until after the radiological
outcome measures have been determined.
The presence and degree of reperfusion will be determined
as the difference between the 24-h and acute PWI lesion
volumes (percentage and cm
3
change). Recanalization will be
determined based on initial and 24 h MRA, and classied
according to the Thrombolysis in Myocardial Infarction
(TIMI) system. The presence of symptomatic hemorrhagic
transformation will be assessed on follow-up MR or CT
according to Safe Implementation of Thrombolysis in Stroke-
Monitoring Study (SIT-MOST) criteria (i.e. parenchymal hae-
matoma type 2 (PH2) occurring within threesix-hours of
treatment, combined with neurological deterioration leading
to an increase of four points on the NIHSS from baseline, or
the lowest NIHSS value after baseline to 24 h) (23).
Investigational product
The investigational product (tPA or placebo, blinded) is sup-
plied as 50 mg lyophilized powder in glass vials. The dose of
tPA to be administered is 06 mg/kg or 09 mg/kg (maximum
60 mg or 90 mg according to local legally approved practice
and guidelines) given as 10% of total bolus dose over one-
minute, then the remaining 90% as an infusion over 60 mins.
The lower dose of 06 mg/kg is the legally approved dose based
on its efcacy and safety prole in the Japanese population.
Blinding
All those involved in the conduct of the study will be blinded
to treatment allocation. The Data Safety Monitoring Commit-
tee (DSMC) will have access to data that are grouped, but not
unblinded in terms of treatment allocation.
Sample size
Approximately 400 participants randomized to receive either
intravenous tPA or placebo in a 1 : 1 ratio will be enrolled in
the EXTEND trial. This sample size is to be achieved through
recruitment both in Australia and internationally (EXTEND
(International)). Based on 08 power to detect a signicant
difference of 15% in the proportion of patients with mRS 01
outcome (3% in tPA arm, 21% in placebo arm (9)), P = 005,
two sided, and to compensate for nonevaluable patients, a
total sample size of up to 400 patients would be required with
about 200 in each of treatment and placebo arms.
Randomization and statistical analysis
Patients will be randomized to receive the blinded investiga-
tional product according to a centralized procedure coordi-
nated via the online EXTEND electronic case report form. The
randomization system for investigational product will be
based on computer-generated randomization code lists, with
stratication for geographical region and, further, for time
from onset of stroke to randomization.
All randomized subjects will be included in randomised
controlled trial (RCT) analyses on an intention-to-treat basis.
Missing outcome data will be handled through multiple
imputation procedures subject to the validity of missing-at-
randomness assumptions. For the primary outcome analysis,
the proportions of mRS 01 outcomes will be compared
between treatment and placebo arms of the RCT adjusted for
geographical region and time between stroke onset and treat-
ment (greater than three-hours (or 45 h depending on local
practice) up to six-hours; greater than six-hours and up to
nine-hours; WUS as dened earlier, age, and baseline NIHSS,
using binary logistic regression model). Although both
adjusted and unadjusted results will be reported, adjusted
analysis is prespecied as the primary outcome analysis for
this RCT.
A secondary analysis of the categorical shift in mRS will be
undertaken on the full range (06) of the mRS using
CochranMantelHaenszel shift test and proportional odds
logistic regression subject to the validity of shift analysis
model assumptions. Other secondary outcome analyses will
be carried out according to standard statistical principles for
comparison of parametric or nonparametric distributions as
appropriate (24).
Primary outcome

modied Rankin Scale (mRS) 01 at day 90.

Secondary outcomes

categorical shift in mRS at day 90

reduction in the NIHSS by eight or more points or an

NIHSS of 0 or 1.

death due to any cause

symptomatic ICH

reperfusion at 24 h after onset

recanalization at 24 h after onset

infarct growth on DWI within 24 h

recurrent stroke by day 90

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H. Ma et al.
2011 The Authors.
International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012, 7480 78
Symptomatic intracerebral haemorrhage (SICH) is dened
as Intracerebral haemorrhage (PH2) occurring within six-
hours of treatment, combined with neurological deterioration
leading to an increase of 4 points on the NIHSS from baseline,
or the lowest NIHSS value after baseline to 24 hours (23) and
adjudicated by a centralized committee blinded to treatment
allocation.
Data safety monitoring
Safety interim analyses will be undertaken when 100, 200, and
300 patients have completed the three-month assessments. It
will be conducted by an independent DSMC. The Haybittle
Peto procedure for generating early stopping boundaries will
be used. To compare the safety of the tPA therapy and placebo,
noninferiority hypotheses tests for the two primary safety
parameters mortality at three-months and the incidence of
symptomatic ICH within 72 h of intervention are conducted
independently. The margin of noninferiority (d) chosen is
tentatively set at absolute 5% for both safety parameters. A
recommendation of early termination due to experimental
treatment inferiority on deaths or symptomatic haemorrhages
within 72 h from intervention onset will be considered by the
DSMC if the corresponding HaybittlePeto boundary
(P = 0003, Z = 3) at a given interim analysis is crossed. If there
are concerns about the safety of participants, the DSMC will
make a recommendation to the trial Steering Committee
about continuing, stopping, or modifying the trial. No formal
interim analyses for efcacy or futility are planned.
Study organization and funding
Both the steering committee and executive sub-committees
manage this study. The study is nancially supported by Com-
monwealth Scientic and Industrial Research Organisation,
Florey Neuroscience Institutes (FNI), and National Health and
Medical Research Council of Australia. The National Stroke
Research Institute, a member of the FNI, is the study sponsor.
Conclusion
EXTEND is the rst, randomized, multicentre, double-
blinded, placebo-controlled Phase III trial assessing the ef-
cacy of thrombolytic therapy in an enriched population of
acute stroke patients based on the presence of clinically sig-
nicant ischaemic penumbra (MRI or CT mismatch) between
three- to nine-hours after stroke onset. A novel feature of
EXTEND is the inclusion of patients who wake up with stroke.
The allowance of different tPA dosages (06 or 09 mg/kg)
reects the practical nature and worldwide generalizability of
this study. If the study outcome is positive, it will signicantly
widen the therapeutic time window of acute stroke treatment
and increase the number of patients who can benet. It is
an important step towards reducing the burden of stroke
worldwide.
Acknowledgements
EXTEND is supported in part by Commonwealth Scientic
and Industrial Research Organisation (CSIRO) of Australia
through the CSIRO Preventative Health Flagship Cluster as
part of the START-EXTEND Collaborative Study with
funding from the CSIRO National Research Flagship Collabo-
ration Fund.
The FNI acknowledges the strong support from the Victo-
rian Government and, in particular, the funding from the
Operational Infrastructure Support Grant. In addition, we like
to acknowledge the help in the preparation of this manuscript
from the EXTEND study manager Ms Sue Bates and study
coordinator Ms Elise Cowley.
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