Expediting MRI-Based Proof-of-Concept Stroke Trials Using
an Earlier Imaging End Point
Martin Ebinger, DrMed, DrPhil; Soren Christensen, MMSc; Deidre A. De Silva, MRCP;
Mark W. Parsons, PhD, FRACP; Christopher R. Levi, FRACP; Kenneth S. Butcher, PhD, FRACPC;
Christopher F. Bladin, MD, FRACP; P. Alan Barber, PhD, FRACP;
Geoffrey A. Donnan, MD, FRACP; Stephen M. Davis, MD, FRACP; for the EPITHET Investigators
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Background and Purpose—Before Phase III trials of acute stroke therapies, proof-of-concept MRI trials are increasingly
used to gauge the likelihood of success. Given that animal models use infarct volume as the end point, Phase II trials
have aimed to translate the findings using infarct growth. These trials could be expedited if subacute diffusion-weighted
imaging lesion volume replaced late T2-weighted lesion volume as the primary end point.
Methods—In the Echoplanar Imaging Thrombolytic Evaluation Trial, patients with acute ischemic stroke presenting within
3 to 6 hours were randomized to tissue plasminogen activator or placebo. We assessed correlations between acute (Day
1), subacute (Day 3 to 5) as well as late (Day 90) lesion volumes and clinical outcome (National Institutes of Health
Stroke Scale). We compared lesion growth between placebo- and tissue plasminogen activator-treated patients.
Results—All 3 scans were performed in 72 of 101 patients (32 tissue plasminogen activator, 40 placebo). Median time to
subacute imaging was 3 days (interquartile range, 2 to 4) and 90 days (interquartile range, 90 to 95) for the late scan.
Increase in lesion volume from acute to subacute scans was smaller in the tissue plasminogen activator group compared
with the placebo group (6.77 mL; interquartile range, 2.30 to 49.10; versus 30.00 mL; interquartile range, 7.19 to 85.93;
P⫽0.03). Subsequent shrinkage did not reveal significant treatment effects. Correlation coefficient between acute and
late lesion volumes was 0.81 (P⬍0.01). Subacute and late lesion volumes were strongly correlated (rho⫽0.94, P⬍0.01).
Correlation coefficient for acute, subacute, and late lesion volume and late National Institutes of Health Stroke Scale
score was 0.64 (P⬍0.01), 0.81 (P⬍0.01), and 0.77 (P⬍0.01), respectively.
Conclusions—These findings suggest that subacute imaging at Day 3 after thrombolysis is an appropriate imaging end point
for proof-of-concept MRI-based stroke treatment trials and can replace later MRI measurements. (Stroke. 2009;40:1353-1358.)
Key Words: MRI 䡲 plasminogen activator 䡲 stroke 䡲 timing 䡲 tissue plasminogen activator
C
linical end points in acute stroke studies are traditionally
assessed on Day 90, because the bulk of neurological
recovery has occurred by this time point.1,2 One of the biggest
challenges in stroke research is the translation of findings
from animal models to human studies. Although clinical outcome is the most important end point in Phase III stroke studies,
surrogate measures derived from imaging techniques can facilitate study design.3–7 The most commonly used imaging end
point is infarct growth, ideally assessed with serial MRI. This
surrogate has been chosen because it facilitates translation from
preclinical models, in which infarct volume is traditionally used
as the primary end point. Before pivotal Phase III trials of acute
stroke therapies, proof-of-concept studies using this end point
can be used to estimate the likelihood of success of putative
therapeutic interventions.8 At present, however, the optimal time
point for outcome imaging is unknown.
Previous studies indicate that lesions grow during the acute
and subacute periods up to 3 to 4 days before gradually
decreasing in size.9 –15 To date, most studies have used a late
scan performed concomitantly with clinical assessments.
Typically, final infarct volume is measured on a T2-weighted
image between Days 30 and 90.10,16,17 This can be problematic because patients may be lost to follow-up or die before
these time points.
Surrogate MRI stroke trials could be expedited if subacute
diffusion-weighted imaging (DWI) lesion volume could be
used to replace late T2-weighted lesion volume as the
primary end point. We used the data set of the Echoplanar
Received July 24, 2008; final revision received October 9, 2008; accepted October 21, 2008.
From the Department of Neurology (M.E., S.C., D.A.D.S., S.M.D.), The Royal Melbourne Hospital, Parkville, Australia; the Department of Neurology
and Hunter Medical Research Institute (M.W.P., C.R.L.), John Hunter Hospital, University of Newcastle, Australia; the Faculty of Medicine and Dentistry
(K.S.B.), University of Alberta, Edmonton, Canada; the Department of Neurology (C.F.B.), Box Hill Hospital, Monash University, Melbourne, Australia;
the Department of Neurology (P.A.B.), Auckland Hospital, Auckland, New Zealand; and the Department of Neurology (G.A.D.), Austin Hospital,
Melbourne, Australia.
Correspondence to Stephen M. Davis, MD, FRACP, Department of Neurology, The Royal Melbourne Hospital, Grattan Street, 3050 Parkville,
Australia. E-mail [email protected]
© 2009 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.108.532622
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Table. Baseline Characteristics of Patients Included in This Substudy
All (n⫽72)
Placebo (n⫽40)
tPA (n⫽32)
Mean age, years (SD)
Characteristics
71 (14)
71 (13)
71 (14)
P Value
0.966
Male sex, no. of patients (%)
34 (47)
19 (48)
19 (59)
0.315
0.152
Hypertension, no. of patients (%)
50 (69)
25 (63)
25 (78)
Diabetes mellitus, no. of patients (%)
12 (17)
7 (18)
5 (16)
0.832
Hyperlipidemia, no. of patients (%)
27 (38)
14 (35)
13 (41)
0.624
Atrial fibrillation, no. of patients (%)
26 (36)
13 (33)
13 (41)
0.476
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Current/past smoker, no. of patients (%)
42 (58)
16 (40)
11 (34)
0.624
Median NIHSS at presentation (IQR)
12 (9)
10 (9)
14 (18)
0.343
Median time from stroke onset to emergency
department presentation, minutes (IQR)
136 (79)
121 (75)
146 (88)
0.489
Median time from stroke onset to MRI scan,
minutes (IQR)
263 (78)
245 (89)
270 (51)
0.266
Median time from stroke onset to treatment,
minutes (IQR)
308 (69)
309 (80)
307 (48)
0.751
Median time to subacute imaging, days (IQR)
3 (2)
72 (50)
72 (30)
0.799
Median times to late imaging, days (IQR)
90 (5)
92 (4)
91 (8)
0.487
DWI lesion volume on Day 1, mL (IQR)
20 (33)
21 (33)
14 (32)
0.951
Data are mean (SD), no. (%), or median (range).
Imaging Thrombolytic Evaluation Trial (EPITHET) to test
the hypotheses that subacute lesion volumes are sufficient to
demonstrate treatment effects and that the relationship between early lesion evolution and clinical outcome was at least
equivalent to the relationship between later imaging and
clinical outcome. In this substudy, we did not aim to
demonstrate the efficacy of tissue plasminogen activator
(tPA) in the 3- to 6-hour time window. Rather, we investigated whether relevant imaging information is lost when
completing the last scan at 3 to 5 days after stroke onset rather
than reliance on a scan at 90 days.
Methods
EPITHET was a prospective, double-blind, multicenter trial with
acute hemispheric stroke patients randomized to placebo or tPA 3 to
6 hours after symptom onset. Informed consent was obtained from
all subjects. Human research and ethics committees approved study
protocols and informed consent procedures at all recruiting sites.
Methodological details have been reported previously.16 In brief,
patients had acute MRI and clinical assessment through the National
Institutes of Health Stroke Scale (NIHSS) performed before treatment on Day 1 and repeated Days 3 to 5 (subacute) and day 90 (late)
after acute stroke. A baseline screening noncontrast CT scan was
used to exclude patients with acute hemorrhage and major early
ischemic change of more than one third of the territory of the middle
cerebral artery.
Lesion Measurement
All MRI scans were read at the coordinating center by investigators
blinded to treatment assignment and clinical outcomes but not to
time point. DWI at baseline and Days 3 to 5 and T2-weighted lesions
at Day 90 were assessed by 2 independent raters who used standard
planimetric software (Analyze 7.0; Biomedical Imaging Resource,
Mayo Clinic, Rochester, Minn). The mean DWI and T2-weighted
lesion volumes from the 2 raters were used for subsequent analysis.16
Statistical Analysis
Only patients who had all 3 scans were included in this subgroup
analysis. Correlations between lesion volumes (on acute and subacute DWI and late T2) were assessed. Correlations between lesion
volumes and clinical scores (NIHSS) were assessed. The difference
in the median lesion volume changes between tPA- and placebotreated patients was assessed using the nonparametric Mann–
Whitney U test. We fitted an analysis of covariance model that
allowed for an interaction between treatment group and the earlier
scans in the association with the late scan, ie, late scan⫽acute/subacute scan⫹treatment group⫹acute/subacute scan*treatment group.
Data were analyzed using SPSS statistical software Version 15.0.
P⬍0.05 was deemed significant for all analyses.
Results
Patients
Of 101 patients enrolled into EPITHET, one withdrew
consent after randomization to placebo and before treatment.
Of the remaining 100 patients, 91 had a subacute scan,
whereas 72 patients (40 placebo, 32 tPA) had imaging and
clinical outcome assessment at all 3 time points. There were
20 deaths before day 90 (13 tPA, 7 placebo) of whom 7 died
before the subacute scan (6 tPA, one placebo). Two patients
did not have subacute MRI for other reasons. Overall, 7
patients were lost to follow-up and one patient refused
clinical assessment on Day 90. Six further patients did not
receive all planned scans for other reasons. Baseline characteristics of the included patients are shown in the Table. There
were no significant baseline differences between the placebo
group and tPA-treated patients. Comparison of baseline
characteristics of patients included and excluded revealed no
statistical differences except for a higher prevalence of
diabetes among patients excluded from this substudy (17%
of the patients included versus 36% of the patients excluded, P⫽0.04; Supplemental Table I, available online at
http://stroke.ahajournals.org).
Lesion Measurement
Results correlated well between raters for baseline DWI lesion
volume (r2⫽0䡠97), Day 3 to 5 DWI lesion volume (r2⫽0䡠98),
and Day 90 T2-weighted lesion volume (r2⫽0䡠99).16 Median
Ebinger et al
Timing of MRI-Based Proof-of-Concept Stroke Trials
1355
Figure 1. Evolution of the median lesion
volume. Initial growth is significantly smaller
in tPA-treated patients, whereas subsequent
decrease in lesion size is similar in both
groups.
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difference in DWI lesion volume between raters was 0.5 mL
(interquartile range [IQR], ⫺2.1 mL to 3.6 mL). Median
difference in T2 lesion volume was 0.0 mL (IQR, ⫺3.1 mL to
3.6 mL).
Lesion Evolution
Median time to the subacute scan was 3 days (IQR, 2 to 4)
and 90 days to the late scan (IQR, 90 to 95). Median acute
DWI lesion volume was 19.56 mL (IQR, 8.46 to 41.36),
median subacute DWI lesion volume was 45.15 mL (IQR,
15.87 to 125.10), and median late T2-weighted lesion volume
23.01 mL (IQR, 5.39 to 81.91).
Placebo Versus Tissue Plasminogen Activator
In the placebo patients, median lesion volume was 20.51 mL
(IQR, 8.17 to 41.65) on the acute scan, 61.15 mL (IQR, 17.55 to
143.14) on the subacute scan, and 46.43 mL (IQR, 10.15 to
117.73) on the late scan. In patients treated with tPA, median
lesion volume was initially 14.37 mL (IQR, 8.69 to 40.18), grew
to 27.74 mL (IQR, 11.79 to 78.87), and shrank subsequently to
7.62 mL (IQR, 3.79 to 56.62; Figure 1). Thus, acute to subacute
lesion growth was smaller in tPA- compared with placebotreated patients. However, reduction in lesion volume between
subacute and late imaging did not differ significantly between
placebo- and tPA-treated patients.
From acute to late imaging, the median lesion growth was
15.25 mL (IQR, ⫺2.61 to 59.19) in the placebo group and
⫺1.80 mL (IQR, ⫺6.33 to 3.77) in tPA-treated patients
(P⫽0.002).
From acute to subacute imaging, median lesion volume
growth was 30.00 mL (IQR, 7.19 to 85.93) in the placebo
group and 6.77 mL (IQR, 2.30 to 49.10) in tPA-treated
patients (P⫽0.032). In both groups, lesion volume decreased
between subacute and late imaging without significant differ-
ences (placebo: median, ⫺9.92 mL; IQR, ⫺28.23 to 3.66
versus tPA: ⫺11.73 mL; IQR, ⫺43.00 to ⫺3.98; P⫽0.371).
Relationship Between Lesion Volumes at Different
Time Points
Lesion volumes acutely and subacutely correlated with final
infarct volume on Day 90. Overall, Spearman’s correlation
between acute DWI and late T2 was 0.81 (P⬍0.01; n⫽72).
Separated by treatment group, Spearman’s correlation between acute DWI and late T2 was 0.76 (P⬍0.01; n⫽40) for
placebo-treated patients and 0.86 for patients treated with tPA
(P⬍0.01; n⫽32). Analysis of covariance revealed that the
main effects of both acute DWI lesion volume and treatment
group on late DWI volume were statistically significant
(P⬍0.01). The tPA group was associated with a 27.9-mL
smaller volume on Day 90 relative to the control group (95%
CI, 8.6 to 47.2). The interaction between group and acute
DWI lesion volume was not statistically significant
(P⫽0.68).
Overall, Spearman’s correlation between subacute DWI
and T2 was 0.94 (P⬍0.01; n⫽72). This indicated less
variance in lesion volume from subacute to late imaging
compared with lesion volume from acute to late imaging.
Spearman’s correlation between subacute DWI and T2 was
0.97 (P⬍0.01; n⫽40) for placebo-treated patients and 0.83
for patients treated with tPA (P⬍0.01; n⫽32). Analysis of
covariance analysis revealed that the main effect of subacute
lesion volume was statistically significant (P⬍0.01), whereas
the effect of treatment group was not (P⫽0.068). The
interaction between treatment group and subacute DWI lesion
volume was not statistically significant (P⫽0.77; Figure 2).
Relationship Between Lesion Volume and
Clinical Outcome
Subacute lesion volume correlated tightly with final neurological outcome measured with NIHSS. Spearman’s correla-
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Figure 2. Scatterplots of lesion volumes.
Spearman’s correlation between acute DWI
(A) and late T2 was 0.81 (P⬍0.01; n⫽72).
Spearman’s correlation between subacute
DWI (B) and T2 was 0.94 (P⬍0.01; n⫽72).
Circles indicate patients treated with tPA
(Spearman’s correlation between acute and
late lesion volume 0.86, P⬍0.01; n⫽32;
Spearman’s correlation between subacute
and late lesion volume 0.83, P⬍0.01; n⫽32).
Black triangles symbolize patients who
received placebo (Spearman’s correlation
between acute and late lesion volume 0.76,
P⬍0.01; n⫽40; Spearman’s correlation
between subacute and late lesion volume
0.97, P⬍0.01; n⫽40).
tion coefficient of lesion volume and outcome NIHSS score
was 0.64 for acute, 0.81 for subacute, and 0.77 for late
scanning (P⬍0.01; Supplemental Figure I, available online at
http://stroke.ahajournals.org).
Discussion
This substudy of EPITHET shows that ischemic lesion
volume measured by MRI at 3 days after stroke onset is a
suitable imaging surrogate end point. Our results suggest that
imaging patients with stroke 90 days after symptom onset
does not provide additional information over that obtained
from subacute MRI data. This is an important finding given
the logistic and additional financial difficulties associated
with imaging patients with stroke at later time points. For
example, in EPITHET, 30% of patients were unable to have
a Day 90 MRI, which meant that their outcomes were based
on the last observation carried forward method using the
subacute MRI time point. In contrast, only 2 patients in
Ebinger et al
Timing of MRI-Based Proof-of-Concept Stroke Trials
addition to those who died within the first days were not able
to undergo subacute MRI, indicating good feasibility of
imaging at this time point. Adopting a study design based on
subacute imaging would help to eliminate the need to use the
last observation carried forward method in the future.
Lesion Measurement
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To standardize image analysis and eliminate interobserver
variability, all MRI scans were read at the coordinating center
by 2 investigators. Thus far, investigator judgment is needed
for delineation of lesion boundaries. In theory, fully automated software to measure lesion volumes may be able to
reduced sources of errors. However, no such software has
been validated sufficiently. Quantitative volumes by interrater measurements can provide consistent and repeatable
results.4,18 There was good agreement between lesion volumes measured by the 2 raters and the mean of lesion
volumes obtained by the 2 raters was used for further
analyses.
Lesion Evolution
The results of this study suggest that shortening Phase II
MRI-based surrogate end point studies of thrombolytic agents
from 3 months to 3 days could expedite and economize
research progress without loss of essential information. Our
study indicates that the treatment effect of tPA on lesion
growth was observed between the acute and subacute time
points. The subsequent decrease in lesion volume after
subacute MRI did not differ significantly between treatment
groups, suggesting that the effect of reperfusion therapy is
ideally assessed at earlier time points. The excellent correlation indicated that the decrease from subacute to late imaging
was predictable. The infarct dynamics related to the acute
stroke and its treatment had manifested itself by imaging on
Day 3. The natural evolution of cerebral infarct volume in the
placebo group in our study was consistent with a pattern of
initial lesion growth and subsequent shrinkage previously
described.4 – 6,9 –15 This shrinkage is likely to reflect a combination of resolution of edema and later gliosis. Although the
correlation between acute and late lesion volumes was similar
to the correlation between subacute and late lesion volume in
patients treated with tPA (0.86 versus 0.83, respectively),
these correlations differed in patients who received placebo.
The evolution of lesion volumes from the acute to the
subacute scan was variable and less predictable in the placebo
group (Spearman’s rho⫽0.76). However, the correlation
between subacute and late lesion volume was very strong in
patients who received placebo (Spearman’s rho⫽0.97). The
fact that this correlation was stronger than the one observed in
tPA-treated patients may be attributable to the greater lesion
volumes and therefore reduced risk of measurement errors in
the placebo group.
Relationship Between Lesion Volume and
Clinical Outcome
Correlations between clinical scores and lesion volume were
also in accordance with most previously reported studies,
although this has become a recent source of controversy.4 –9,19
Correlations of subacute and late lesion volume with clinical
1357
outcome were similar, indicating that there is no disadvantage in
using the earlier time point as a predictor of clinical outcome.
Thus, subacute lesion volume can predict the neurological deficit
on Day 90 at least as well as the scan on Day 90. Furthermore,
an outcome scan within the first week would also cover safety
aspects such as hemorrhagic transformation occurring most
often within 48 hours after therapy.20
Limitations
The results of this study cannot be generalized to all MRIbased stroke research. Treatment with tPA aims at recanalization ideally assessed within hours.21 Effects on final infarct
volume of thrombolytic-induced reperfusion are expected to
occur early and later lesion evolution appears to be unrelated
to thrombolytic effects. This may not be the case with
neuroprotective drugs, which may potentially require later
scanning times.
Previous studies of DWI lesion evolution have demonstrated that diffusion restriction is relatively stable from 36
hours to 2 weeks after onset.15 Our subacute scans were
completed over a relatively wide time interval (IQR, 2 to 4
days). Additional intermediate time points before and after
the subacute scan were not planned.
The increase in lesion volume at the subacute time is due
not only to an increase in the extent of irreversibly infarcted
tissue, but also to swelling caused by an uptake of water into
the tissue secondary to both ionic and vasogenic edema.22
However, swelling does not necessarily result in infarction.23
The volume analysis performed in this study did not allow for
determination of the relative contributions of swelling versus
infarction. Patients who received tPA are more likely to have
reperfused at an early stage and are therefore less likely to
have severe infarct swelling. Thus, the apparent greater
increase in infarct volume in the placebo group may be due to
an excess of tissue swelling. In general, smaller lesions swell
less. Although there was no significant difference in lesion
size on Day 1, the smaller lesions of tPA-treated patients
could have been expected to have less increase in infarct
volume than the placebo-treated patients.
An acknowledged limitation of this analysis was the
selective nature of the trial in general and in particular the
exclusion of nonsurvivors in this substudy. Of the 1224
patients screened within 6 hours, only 101 were enrolled in
EPITHET.16 Only patients with comparable information on
lesion volume on all 3 points in time were included in this
particular substudy. This likely explains why we found a
significant difference in lesion growth attenuation with tPA in
this substudy, whereas in the full EPITHET trial, previously
only trends had been found that did not achieve formal
statistical significance.16 The design of this analysis therefore
includes a bias in favor of a tPA treatment effect. The
exclusion of the excess deaths related to tPA meant that these
patients could not be studied at the 3 time points. Important
adverse clinical effects may have been missed. For example,
almost twice as many patients who received tPA did not have
the Day 90 scan and this was mostly because they had died,
a substantial excess compared with placebo. By focusing on
imaging surrogates, we can only refer to those patients who
survived and were able to complete scanning at all 3 time
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April 2009
points. However, this substudy was not designed to prove the
efficacy of tPA beyond 3 hours but to demonstrate the
appropriateness of an earlier imaging end point in imaging
based trials, which cannot replace clinical outcomes.
9.
Summary
10.
Our findings suggest completing an outcome scan as early as
3 days after thrombolysis is appropriate for proof-of-concept
stroke treatment trials using infarct growth as the surrogate
end point. Reperfusion and recanalization should be evaluated within hours after treatment. This may lead to more
uniform results and a decrease in lost data. These factors are
to be considered in the design of future MRI-based acute
stroke studies.
Sources of Funding
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EPITHET was an investigator-driven trial supported by academic
grants from the Australian National Health and Medical Research
Council (NHMRC), the National Stroke Foundation, and the Heart
Foundation of Australia. Boehringer Ingelheim supplied matching
alteplase and placebo but was not involved in the study design, data
management, or data analysis. M.E. was supported by The Royal
Melbourne Hospital Neuroscience Foundation.
11.
12.
13.
14.
15.
Disclosures
S.M.D. is a member of the Servier, Novo Nordisk, and Sanofi
Aventis Advisory Boards. G.A.D. is a member of the Boehringer
Ingelheim, PAION, Servier, and Sanofi Aventis Advisory Boards.
16.
References
17.
1. Tissue plasminogen activator for acute ischemic stroke. The National
Institute of Neurological Disorders and Stroke rt-PA stroke study group.
N Engl J Med. 1995;333:1581–1587.
2. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP,
Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR,
Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers
G, Bluhmki E, Wilhelm M, Hamilton S. Association of outcome with
early stroke treatment: pooled analysis of ATLANTIS, ECASS, and
NINDS rt-PA stroke trials. Lancet. 2004;363:768 –774.
3. Barber PA, Parsons MW, Desmond PM, Bennett DA, Donnan GA, Tress
BM, Davis SM. The use of PWI and DWI measures in the design of
‘proof-of-concept’ stroke trials. J Neuroimaging. 2004;14:123–132.
4. Barber PA, Darby DG, Desmond PM, Yang Q, Gerraty RP, Jolley D, Donnan
GA, Tress BM, Davis SM. Prediction of stroke outcome with echoplanar
perfusion- and diffusion-weighted MRI. Neurology. 1998;51:418–426.
5. Lovblad KO, Baird AE, Schlaug G, Benfield A, Siewert B, Voetsch B,
Connor A, Burzynski C, Edelman RR, Warach S. Ischemic lesion
volumes in acute stroke by diffusion-weighted magnetic resonance
imaging correlate with clinical outcome. Ann Neurol. 1997;42:164 –170.
6. Tong DC, Yenari MA, Albers GW, O’Brien M, Marks MP, Moseley ME.
Correlation of perfusion- and diffusion-weighted MRI with NIHSS score
in acute (⬍6.5 hour) ischemic stroke. Neurology. 1998;50:864 – 870.
7. Baird AE, Lovblad KO, Dashe JF, Connor A, Burzynski C, Schlaug G,
Straroselskaya I, Edelman RR, Warach S. Clinical correlations of
diffusion and perfusion lesion volumes in acute ischemic stroke.
Cerebrovasc Dis. 2000;10:441– 448.
8. MR Stroke Collaborative Group, Phan TG, Donnan GA, Davis SM,
Byrnes G. Proof-of-principle phase II MRI studies in stroke: sample size
18.
19.
20.
21.
22.
23.
estimates from dichotomous and continuous data. Stroke. 2006;37:
2521–2525.
Beaulieu C, de Crespigny A, Tong DC, Moseley ME, Albers GW, Marks
MP. Longitudinal magnetic resonance imaging study of perfusion and
diffusion in stroke: evolution of lesion volume and correlation with
clinical outcome. Ann Neurol. 1999;46:568 –578.
Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian
L, Harnett K, Schwiderski U, Gammans R. Effect of citicoline on ischemic
lesions as measured by diffusion-weighted magnetic resonance imaging.
Citicoline 010 investigators. Ann Neurol. 2000;48:713–722.
Rivers CS, Wardlaw JM, Armitage PA, Bastin ME, Carpenter TK, Cvoro
V, Hand PJ, Dennis MS. Do acute diffusion- and perfusion-weighted MRI
lesions identify final infarct volume in ischemic stroke? Stroke. 2006;37:
98 –104.
Schwamm LH, Koroshetz WJ, Sorensen AG, Wang B, Copen WA,
Budzik R, Rordorf G, Buonanno FS, Schaefer PW, Gonzalez RG. Time
course of lesion development in patients with acute stroke: serial
diffusion- and hemodynamic-weighted magnetic resonance imaging.
Stroke. 1998;29:2268 –2276.
Sorensen AG, Buonanno FS, Gonzalez RG, Schwamm LH, Lev MH,
Huang-Hellinger FR, Reese TG, Weisskoff RM, Davis TL, Suwanwela N,
Can U, Moreira JA, Copen WA, Look RB, Finklestein SP, Rosen BR, Koroshetz
WJ. Hyperacute stroke: evaluation with combined multisection diffusionweighted and hemodynamically weighted echo-planar MR imaging. Radiology.
1996;199:391–401.
van Everdingen KJ, van der Grond J, Kappelle LJ, Ramos LM, Mali WP.
Diffusion-weighted magnetic resonance imaging in acute stroke. Stroke.
1998;29:1783–1790.
Lansberg MG, O’Brien MW, Tong DC, Moseley ME, Albers GW. Evolution of cerebral infarct volume assessed by diffusion-weighted magnetic
resonance imaging. Arch Neurol. 2001;58:613– 617.
Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, et
al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging
Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7:299 –309.
Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E,
Bammer R, Kakuda W, Lansberg MG, Shuaib A, Coplin W, Hamilton S,
Moseley M, Marks MP; DEFUSE Investigators. Magnetic resonance
imaging profiles predict clinical response to early reperfusion: the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study. Ann Neurol. 2006;60:508 –517.
Luby M, Bykowski JL, Schellinger PD, Merino JG, Warach S. Intra- and
interrater reliability of ischemic lesion volume measurements on
diffusion-weighted, mean transit time and fluid-attenuated inversion
recovery MRI. Stroke. 2006;37:2951–2956. Erratum in Stroke. 2007;
38:452.
Kane I, Carpenter T, Chappell F, Rivers C, Armitage P, Sandercock P,
Wardlaw J. Comparison of 10 different magnetic resonance perfusion
imaging processing methods in acute ischemic stroke: effect on lesion
size, proportion of patients with diffusion/perfusion mismatch, clinical
scores, and radiologic outcomes. Stroke. 2007;38:3158 –3164.
Moulin T, Crepin-Leblond T, Chopard JL, Bogousslavsky J. Hemorrhagic infarcts. Eur Neurol. 1994;34:64 –77.
Delgado-Mederos R, Rovira A, Alvarez-Sabin J, Ribo M, Munuera J,
Rubiera M, Santamarina E, Maisterra O, Delgado P, Montaner J, Molina
CA. Speed of tPA-induced clot lysis predicts DWI lesion evolution in
acute stroke. Stroke. 2007;38:955–960.
Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V. Brain oedema
in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol. 2007;6:258 –268.
Butcher KS, Lee SB, Parsons MW, Allport L, Fink J, Tress B, Donnan G,
Davis SM; EPITHET Investigators. Differential prognosis of isolated
cortical swelling and hypoattenuation on CT in acute stroke. Stroke.
2007;38:941–947.
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Expediting MRI-Based Proof-of-Concept Stroke Trials Using an Earlier Imaging End
Point
Martin Ebinger, Soren Christensen, Deidre A. De Silva, Mark W. Parsons, Christopher R. Levi,
Kenneth S. Butcher, Christopher F. Bladin, P. Alan Barber, Geoffrey A. Donnan and Stephen
M. Davis
for the EPITHET Investigators
Stroke. 2009;40:1353-1358; originally published online February 26, 2009;
doi: 10.1161/STROKEAHA.108.532622
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