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n engl j med 372;1 nejm.org january 1, 2015
11
The new england
journal of medicine
established in 1812
january 1, 2015
vol. 372 no. 1
A Randomized Trial of Intraarterial Treatment for Acute
Ischemic Stroke
O.A. Berkhemer, P.S.S. Fransen, D. Beumer, L.A. van den Berg, H.F. Lingsma, A.J. Yoo, W.J. Schonewille, J.A. Vos,
P.J. Nederkoorn, M.J.H. Wermer, M.A.A. van Walderveen, J. Staals, J. Hofmeijer, J.A. van Oostayen,
G.J. Lycklama à Nijeholt, J. Boiten, P.A. Brouwer, B.J. Emmer, S.F. de Bruijn, L.C. van Dijk, L.J. Kappelle, R.H. Lo,
E.J. van Dijk, J. de Vries, P.L.M. de Kort, W.J.J. van Rooij, J.S.P. van den Berg, B.A.A.M. van Hasselt, L.A.M. Aerden,
R.J. Dallinga, M.C. Visser, J.C.J. Bot, P.C. Vroomen, O. Eshghi, T.H.C.M.L. Schreuder, R.J.J. Heijboer, K. Keizer,
A.V. Tielbeek, H.M. den Hertog, D.G. Gerrits, R.M. van den Berg-Vos, G.B. Karas, E.W. Steyerberg, H.Z. Flach,
H.A. Marquering, M.E.S. Sprengers, S.F.M. Jenniskens, L.F.M. Beenen, R. van den Berg, P.J. Koudstaal,
W.H. van Zwam, Y.B.W.E.M. Roos, A. van der Lugt, R.J. van Oostenbrugge, C.B.L.M. Majoie, and D.W.J. Dippel,
for the MR CLEAN Investigators*
ABSTR ACT
The authors’ full names, academic de-
grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
Dippel at the Department of Neurology
H643, Erasmus MC University Medical
Center, PO Box 2040, Rotterdam 3000
CA, the Netherlands, or at d.dippel@
erasmusmc.nl.
Drs. Berkhemer, Fransen, and Beumer and
Drs. van Zwam, Roos, van der Lugt, van
Oostenbrugge, Majoie, and Dippel con-
tributed equally to this article.
* A complete list of investigators in the
Multicenter Randomized Clinical Trial
of Endovascular Treatment for Acute
Ischemic Stroke in the Netherlands
(MR CLEAN) is provided in the Supple-
mentary Appendix, available at NEJM.org.
This article was published on December 17,
2014, and updated on January 1, 2015, at
NEJM.org.
N Engl J Med 2015;372:11-20.
DOI: 10.1056/NEJMoa1411587
Copyright © 2014 Massachusetts Medical Society.
Background
In patients with acute ischemic stroke caused by a proximal intracranial arterial
occlusion, intraarterial treatment is highly effective for emergency revasculariza-
tion. However, proof of a beneficial effect on functional outcome is lacking.
Methods
We randomly assigned eligible patients to either intraarterial treatment plus usual
care or usual care alone. Eligible patients had a proximal arterial occlusion in the
anterior cerebral circulation that was confirmed on vessel imaging and that could
be treated intraarterially within 6 hours after symptom onset. The primary out-
come was the modified Rankin scale score at 90 days; this categorical scale mea-
sures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death).
The treatment effect was estimated with ordinal logistic regression as a common
odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds
ratio measured the likelihood that intraarterial treatment would lead to lower mod-
ified Rankin scores, as compared with usual care alone (shift analysis).
Result s
We enrolled 500 patients at 16 medical centers in the Netherlands (233 assigned to in-
traarterial treatment and 267 to usual care alone). The mean age was 65 years (range,
23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before ran-
domization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to
intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence
interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points
(95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score,
0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differ-
ences in mortality or the occurrence of symptomatic intracerebral hemorrhage.
Conclusions
In patients with acute ischemic stroke caused by a proximal intracranial occlusion
of the anterior circulation, intraarterial treatment administered within 6 hours af-
ter stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and
others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current
Controlled Trials number, ISRCTN10888758.)
The New England Journal of Medicine
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The
new england journal
of
medicine
n engl j med 372;1 nejm.org january 1, 2015
12
I
ntravenous alteplase administered
within 4.5 hours after symptom onset is the
only reperfusion therapy with proven efficacy
in patients with acute ischemic stroke.
1
However,
well-recognized limitations of this therapy in-
clude the narrow therapeutic time window and
contraindications such as recent surgery, coagu-
lation abnormalities, and a history of intracrani-
al hemorrhage.
2
Moreover, intravenous alteplase
appears to be much less effective at opening
proximal occlusions of the major intracranial ar-
teries, which account for more than one third of
cases of acute anterior-circulation stroke.
3,4
Early
recanalization after intravenous alteplase is seen
in only about one third of patients with an occlu-
sion of the internal-carotid-artery terminus,
5
and
the prognosis without revascularization is gener-
ally poor for such patients.
6
For these reasons,
intraarterial treatment is regarded as a poten-
tially important component of the therapeutic
armamentarium.
Intraarterial therapy can be broadly divided
into chemical dissolution of clots with locally
delivered thrombolytic agents and clot retrieval
or thrombectomy with mechanical devices. Al-
though early randomized trials and subsequent
meta-analyses
7
showed a benefit of treatment with
prourokinase
8,9
or urokinase,
10
their results are
not directly applicable to current decision making
about treatment because the control groups did
not include intravenous alteplase, and mechani-
cal approaches have largely replaced locally ap-
plied thrombolytic agents as first-line therapy.
11
The neutral results of the recent randomized,
controlled trials of intraarterial treatment have
contributed to uncertainty regarding the efficacy
of the catheter-based approach.
12-14
Numerous
questions have been raised concerning the design
and conduct of these trials, including a relatively
long interval before intraarterial treatment, the
absence of pretreatment vascular imaging to con-
firm a proximal intracranial occlusion, and the
limited use of third-generation mechanical throm-
bectomy devices such as retrievable stents. In the
Multicenter Randomized Clinical Trial of Endo-
vascular Treatment for Acute Ischemic Stroke in
the Netherlands (MR CLEAN), we assessed wheth-
er intraarterial treatment plus usual care would
be more effective than usual care alone in patients
with a proximal arterial occlusion in the anterior
cerebral circulation that could be treated intra-
arterially within 6 hours after symptom onset.
Methods
Study Design
MR CLEAN was a pragmatic, phase 3, multicenter
clinical trial with randomized treatment-group
assignments, open-label treatment, and blinded
end-point evaluation. Intraarterial treatment (in-
traarterial thrombolysis, mechanical treatment,
or both) plus usual care (which could include in-
travenous administration of alteplase) was com-
pared with usual care alone (control group) in pa-
tients with acute ischemic stroke and a proximal
intracranial arterial occlusion of the anterior cir-
culation that was confirmed on vessel imaging.
The study protocol (available with the full text
of this article at NEJM.org) was approved by a cen-
tral medical ethics committee and the research
board of each participating center. All patients or
their legal representatives provided written in-
formed consent before randomization.
Members of the executive committee and the
local investigators designed the study, collected
and analyzed the data, wrote the manuscript,
and made the decision to submit the manuscript
for publication. The authors vouch for the accu-
racy and completeness of the data and for the fidel-
ity of this report to the study protocol. The study
sponsors were not involved in the study design,
study conduct, protocol review, or manuscript
preparation or review.
Patients and Participating Centers
The study was conducted at 16 centers in the
Netherlands. Patients were 18 years of age or
older (no upper age limit) with acute ischemic
stroke caused by an intracranial occlusion in the
anterior circulation artery. Initiation of intraarte-
rial treatment had to be possible within 6 hours
after stroke onset. Eligible patients had an occlu-
sion of the distal intracranial carotid artery, mid-
dle cerebral artery (M1 or M2), or anterior cere-
bral artery (A1 or A2), established with computed
tomographic (CT) angiography (CTA), magnetic
resonance angiography (MRA), or digital-subtrac-
tion angiography (DSA), and a score of 2 or higher
on the National Institutes of Health Stroke Scale
(NIHSS; range, 0 to 42, with higher scores indi-
cating more severe neurologic deficits). Inclusion
of patients with an additional extracranial inter-
nal-carotid-artery occlusion or dissection was left
to the judgment of the treating physician. Detailed
inclusion and exclusion criteria are listed in the
A Quick Take
is available at
NEJM.org
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Intraarterial Treatment for Acute Ischemic Stroke
n engl j med 372;1 nejm.org january 1, 2015
13
study protocol. We did not keep a log of patients
who were screened for eligibility.
Randomization
The randomization procedure was Web-based, with
the use of permuted blocks. We stratified random-
ization according to medical center, use of intrave-
nous alteplase (yes or no), planned treatment
method (mechanical or other), and stroke sever-
ity (NIHSS score of ≤14 or >14).
Intervention
Intraarterial treatment consisted of arterial cath-
eterization with a microcatheter to the level of
occlusion and delivery of a thrombolytic agent,
mechanical thrombectomy, or both. The method
of intraarterial treatment was left to the discre-
tion of the local interventionist.
The use of alteplase or urokinase for intraar-
terial thrombolysis was allowed in this trial,
with a maximum dose of 90 mg of alteplase or
1,200,000 IU of urokinase. The dose was re-
stricted to 30 mg of alteplase or 400,000 IU of
urokinase if intravenous alteplase was given.
Mechanical treatment could involve thrombus re-
traction, aspiration, wire disruption, or use of a
retrievable stent.
Only devices that had received U.S. Food and
Drug Administration approval or a Conformité
Européenne (CE) marking and were approved by
the steering committee could be used in the
trial. One or more members of each intervention
team had to have completed at least five full
procedures with a particular type of device.
15
Outcome and Safety Measures
The primary outcome was the score on the mod-
ified Rankin scale at 90 days. The modified
Rankin scale is a 7-point scale ranging from 0
(no symptoms) to 6 (death). A score of 2 or less
indicates functional independence.
16
Secondary outcomes included the NIHSS
score at 24 hours and at 5 to 7 days or discharge
if earlier, activities of daily living measured with
the Barthel index, and the health-related quality
of life measured with the EuroQol Group 5-Dimen-
sion Self-Report Questionnaire at 90 days.
17,18
We examined the following prespecified dichoto-
mizations of the modified Rankin score: 0 or 1
versus 2 to 6, 0 to 2 versus 3 to 6, and 0 to 3 versus
4 to 6. Imaging outcomes included arterial re-
canalization measured with CTA or MRA at 24
hours and the final infarct volume on noncon-
trast CT at 5 to 7 days.
Safety variables included hemorrhagic com-
plications, progression of ischemic stroke, new
ischemic stroke into a different vascular territo-
ry, and death. If neurologic deterioration devel-
oped, additional neuroimaging was required.
Symptomatic intracranial hemorrhage was de-
fined as neurologic deterioration (an increase of
4 or more points in the score on the NIHSS) and
evidence of intracranial hemorrhage on imaging
studies. Local neurologists were aware of the
treatment-group assignments and reported seri-
ous adverse events through our Web-based data-
base or by fax or e-mail.
Clinical and Radiologic Assessment
All patients underwent clinical assessment (in-
cluding determination of the NIHSS score) at
baseline, after 24 hours, and at 5 to 7 days or at
discharge if earlier. A single experienced trial in-
vestigator, who was unaware of the treatment-
group assignments, conducted the follow-up in-
terviews at 90 days by telephone with the patient,
proxy, or health care provider. This interview
provided reports for the assessment of the modi-
fied Rankin score by reviewers who remained
unaware of the treatment-group assignments.
16-18
The imaging committee evaluated the find-
ings on baseline noncontrast CT for the Alberta
Stroke Program Early Computed Tomography
Score (ASPECTS; range, 0 to 10, with 1 point
subtracted for any evidence of early ischemic
change in each defined region on the CT scan),
19
baseline vessel imaging (CTA, MRA, or DSA) for
the location of the occlusion, and follow-up CTA
or MRA at 24 hours for vessel recanalization.
Recanalization was classified as complete or not
complete and was further evaluated with the use
of the modified Arterial Occlusive Lesion score
(see the Supplementary Appendix, available at
NEJM.org, for details about scales).
20,21
Follow-
up CT scans obtained at 5 days were assessed for
the presence of intracranial hemorrhage.
22
All
neuroimaging studies were evaluated by two neu-
roradiologists who were unaware of the treat-
ment-group assignments. The final infarct vol-
ume on the follow-up CT scan was assessed with
the use of an automated, validated algorithm.
23
An independent core laboratory assessed angio-
graphic outcomes on DSA imaging, using the
modified Thrombolysis in Cerebral Infarction
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n engl j med 372;1 nejm.org january 1, 2015
14
(TICI) score, which ranges from 0 (no reperfu-
sion) to 3 (complete reperfusion).
21
Statistical Analysis
All analyses were based on the intention-to-treat
principle. The primary effect variable was the ad-
justed common odds ratio for a shift in the direc-
tion of a better outcome on the modified Rankin
scale; this ratio was estimated with multivariable
ordinal logistic regression.
24
We calculated an
adjusted odds ratio for all possible cutoff values
on the modified Rankin scale to assess the con-
sistency of effect and the plausibility of propor-
tionality of the odds ratio. The adjusted common
odds ratio and all secondary effect variables were
adjusted for potential imbalances in the follow-
ing major prognostic variables between the inter-
vention group and the control group: age; stroke
severity (NIHSS score) at baseline; time from
stroke onset to randomization; status with re-
spect to previous stroke, atrial fibrillation, and
diabetes mellitus; and occlusion of the internal-
carotid-artery terminus (yes vs. no).
25
We imput-
ed missing values of baseline variables that were
used to adjust the regression models of treatment
effect on primary and secondary outcomes with
mean or mode, as applicable. No outcomes were
imputed, except for single missing values of
items on the NIHSS at 24 hours and at 5 to 7 days
or discharge. Patients who died were not assigned
NIHSS scores and were not included in analyses
of such scores.
The adjusted and unadjusted common odds ra-
tios are reported with 95% confidence intervals to
indicate statistical precision. Binary outcomes were
analyzed with logistic regression and are reported
as adjusted and unadjusted odds ratios with 95%
confidence intervals. All P values are two-sided.
Treatment-effect modification was explored
in prespecified subgroups of patients, defined by
NIHSS score (2 to 15, 16 to 19, or ≥20), age (≥80
years or <80 years), occlusion of the internal-
carotid-artery terminus (yes or no), additional
extracranial internal-carotid-artery occlusion (yes
or no), time from stroke onset to randomization
(≤120 minutes or >120 minutes), and ASPECTS
(0 to 4, 5 to 7, or 8 to 10). The statistical sig-
nificance of possible differences between sub-
groups in the treatment effect was tested with
interaction terms. No adjustments for multiple
tests were made. All analyses were performed
with the use of the Stata/SE statistical package,
version 13.1 (StataCorp).
Assuming a 10% crossover rate,
26
we calcu-
lated that a sample of 500 patients (250 patients
in each group) would yield a power of 82%, at a
significance level of 0.05, to detect a treatment
effect that resulted in an absolute increase of 10
percentage points in the proportion of patients
with a modified Rankin score of 0 to 3 in the
intervention group as compared with the pro-
portion in the control group.
Results
Randomization and Baseline Characteristics
Between December 2010 and March 2014, a total
of 502 patients underwent randomization in 16
Dutch centers. Two patients, whose representatives
withdrew consent immediately after randomization
and assignment to the control group, could not be
included in the intention-to-treat analysis.
The mean age of the 500 study participants was
65 years (range, 23 to 96); 292 participants
(58.4%) were men. Risk factors for a poor out-
come, clinical risk factors for stroke, and aspects
of prerandomization treatment were evenly dis-
tributed between the two treatment groups (
Table
1
, and Table S1 in the Supplementary Appendix).
Treatment Assignments and Crossovers
In total, 233 patients (46.6%) were assigned to
the intervention group and 267 patients (53.4%)
were assigned to the control group. One patient
received intraarterial treatment after being as-
signed to the control group. Intraarterial treat-
ment was never initiated in 17 patients (7.3%)
assigned to the intervention group (Fig. S1 in the
Supplementary Appendix).
Intervention Details
Actual intraarterial therapy (with or without me-
chanical thrombectomy) was performed in 196 of
the 233 patients in the intervention group (84.1%).
In 88 patients (37.8%), general anesthesia was used.
A simultaneous second revascularization proce-
dure (acute cervical carotid stenting) was per-
formed in 30 patients (12.9%).
Mechanical treatment was performed in 195
of the 233 patients (83.7%). Retrievable stents were
used in 190 patients (81.5%), and other devices were
used in 5 patients (2.1%) (Table S2 in the Supple-
mentary Appendix). Additional intraarterial throm-
bolytic agents were given to 24 patients (10.3%).
Intraarterial thrombolytic agents were used
as monotherapy in 1 of the 233 patients (0.4%).
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