Bridging Intravenous–Intra-Arterial Rescue Strategy

Bridging Intravenous–Intra-Arterial Rescue Strategy
Increases Recanalization and the Likelihood of a Good
Outcome in Nonresponder Intravenous Tissue Plasminogen
Activator-Treated Patients
A Case–Control Study
Marta Rubiera, MD, PhD; Marc Ribo, MD, PhD; Jorge Pagola, MD, PhD; Pilar Coscojuela, MD;
David Rodriguez-Luna, MD; Olga Maisterra, MD; Bernardo Ibarra, MD; Socorro Piñeiro, MD;
Pilar Meler; Francisco J. Romero, MD; Jose Alvarez-Sabin, MD, PhD; Carlos A. Molina, MD, PhD
Downloaded from http://stroke.ahajournals.org/ by guest on March 30, 2017
Background and Purpose—Safety and efficacy of the “bridging therapy” (intra-arterial [IA] reperfusion rescue for
nonresponder intravenous [IV] tissue plasminogen activator [tPA]-treated patients) is a matter of debate. Our aim was
to compare IV and IV–IA thrombolysis using a case– control approach.
Methods—Consecutive patients with proximal intracranial occlusion who received IA reperfusion procedures after
unsuccessful IV tPA (lack of clinical improvement and arterial recanalization 1 hour after tPA bolus) were studied
(IV–IA group). They were compared with occluded vessel, clot location, stroke severity, and time to treatment-matched
1 to 2 historical patients from our prospective IV tPA database with persistent occlusion 1 hour after IV tPA (IV-NR
group). Arterial occlusion and recanalization were assessed with transcranial Doppler. Clinical evaluation was assessed
by National Institutes of Health Stroke Scale at baseline, 24 hours, and at discharge. Symptomatic intracranial
hemorrhage was defined according to the National Institute of Neurological Disorders and Stroke trial. Functional
evaluation was determined by modified Rankin Scale, being functional independency defined by modified Rankin Scale
score ⱕ2.
Results—Forty-two IV–IA patients were compared with 84 matched IV-NR. Mean age was 71.5⫾2.9 years, 58 (46%) were
women, and baseline median National Institutes of Health Stroke Scale score was 20 (interquartile range, 5). Mean time
from symptoms to IV tPA was 176.9⫾113 minutes. On transcranial Doppler, complete recanalization was significantly
higher in IV–IA than control subjects (12 hours: 45.2% versus 18.1%, P⫽0.002; 24 hours: 46.3% versus 25.3%,
P⫽0.016) with nonsignificant better clinical evolution at 24 hours (40.5% versus 30.1%, P⫽0.169) and discharge
(52.5% versus 39.5%, P⫽0.123). Symptomatic intracranial hemorrhage was similar (IV–IA 11.9% versus IV-NR 6%,
P⫽0.205). Mortality at 3 months was 50% in the IV–IA group and 35.8% in the IV-NR (P⫽0.154). Forty percent of
IV–IA patients were functionally independent at 3 months and only 14.9% IV-NR (P⫽0.012).
Conclusions—Bridging IV–IA treatment may improve recanalization and clinical outcome in nonresponder IV tPA-treated
patients. (Stroke. 2011;42:00-00.)
Key Words: acute stroke 䡲 Doppler 䡲 thrombolysis 䡲 thrombolytic Rx
R
lization in only 40% of the cases.4 This rate is even lower in
occlusions of the M1 segment of the middle cerebral artery or
the intracranial internal carotid artery, where the rate of
recanalization is approximately 20% and 10%,5 respectively.
Therefore, advanced strategies for increasing recanalization
in acute stroke are being developed in the last years.1
Pharmacological and mechanical endovascular strategies are
very promising techniques that have shown recanalization
rates of 66% to 81% depending on the series and methods.6 – 8
eperfusion of the ischemic tissue before irreversible
damage is the main objective of acute ischemic stroke
treatment.1 The only accepted pharmacological treatment for
acute ischemic stroke is intravenous (IV) tissue plasminogen
activator (tPA), which aim is to recanalize an occluded
intracranial artery.2 Moreover, recanalization has been shown
to be the most important predictor of good clinical outcome
after thrombolysis in stroke due to large vessel occlusion.3
However, in the best case scenario, IV tPA induces recana-
Received July 20, 2010; final revision received September 15, 2010; accepted October 6, 2010.
From the Stroke Unit (M. Rubiera, M. Ribo, J.P., D.R.-L., O.M., S.P., P.M., J.A.-S., C.A.M.), Neurology Department, and the Neuroradiology Section
(P.C., B.I., F.J.R.), Hospital Vall d’Hebron, Universidad Autonoma de Barcelona, Barcelona, Spain.
Correspondence to Marta Rubiera, MD, PhD, Stroke Unit, Neurology Department, Hospital Vall d’Hebron, Ps. Vall d’Hebron, 119-29,
08035-Barcelona, Spain. E-mail [email protected]
© 2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.110.597104
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April 2011
However, whether the higher recanalization rate is translated
into a better clinical outcome of these patients is still a matter
of debate.1 To date, there is no robust evidence of the benefit
of endovascular rescue procedures over conventional IV tPA
treatment.8,9
The “bridging” approach consists of the use of endovascular mechanical or pharmacological thrombolytic strategies
to rescue a patient with lack of recanalization after IV tPA
treatment. Several previous reports have shown the safety of
this rescue strategy in patients with an acute ischemic
stroke8,10 and clinical trials are currently being pursued to set
scientific evidence. However, there is still controversy about
the real efficacy of rescue procedures according to enhancement of recanalization and especially clinical improvement.11
Therefore, we designed a case– control study comparing
patients treated with IV tPA alone with matched patients
receiving bridging therapy.
Table 1.
Baseline Clinical Characteristics
IV–IA Group
(n⫽42)
IV-NR Group
(n⫽84)
P
Age, years
70.1⫾11.3
72.2⫾13.6
0.388
Gender, female
58 (46%)
68 (54%)
0.141
Diabetes mellitus
10 (23.8%)
18 (21.4%)
0.464
Hypertension
26 (63.4%)
49 (59%)
0.394
Baseline NIHSS
20 (IQR, 3)
20 (IQR, 5)
0.771
Glucose, mg/dL
144.7⫾45.7
140.6⫾51.9
0.693
Systolic blood pressure, mm Hg
147.7⫾27.9
154.4⫾27.5
0.263
Diastolic blood pressure, mm Hg
77.5⫾14.9
81.4⫾16.5
0.237
Atrial fibrillation
16 (38.1%)
29 (34.5%)
0.420
22 (53.7%)
38 (45.2%)
0.603
0.083
Stroke subtypes
Cardioembolic
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Atherothrombotic
8 (19.5%)
26 (31%)
Undetermined
8 (19.5%)
15 (17.9%)
Patients and Methods
Dissection
3 (7.3%)
From February 2009 to January 2010, all consecutive patients with
acute stroke admitted within 4.5 hours from symptoms onset to our
university hospital were evaluated (and until 8 hours with basilar
artery occlusions). After ruling out hemorrhage and early signs of
infarction larger than one third of the middle cerebral artery territory
on baseline CT or MRI, those patients without contraindication were
treated with the standard dose of 0.9 mg/kg of IV tPA according to
current guidelines. All patients received carotid and transcranial
Doppler (TCD) ultrasound examination before tPA bolus, and those
with an intracranial occlusion were monitored with continuous TCD
(Power-Mode 100; Spencer Technologies) during tPA infusion. If
the patient did not experience clinical improvement and a persistent
occlusion was documented on TCD at the end of infusion, the patient
was transferred to the neuroangiography suite, where endovascular
reperfusion procedures were started after confirmation of occlusion
by the digital angiography. The neurointerventionalist, according to
his preferences and patient characteristics, used intra-arterial (IA)
tPA at a maximum dose of 20 mg and/or microwire mechanic
disruption and/or a Merci retriever. The endovascular procedure was
stopped when recanalization was achieved or after 6 hours from
symptoms onset (12 hours in basilar occlusions). Those patients
receiving bridging therapy constitute our IV–IA case group.
Each patient in the case group was matched with 2 historic control
subjects treated exclusively with standard IV tPA with similar
occluded vessel and clot location on TCD, stroke severity measured
by the National Institute of Health Stroke Scale Score (NIHSS), and
time to IV tPA treatment, who did not experience recanalization on
TCD after 1 hour from tPA bolus. These patients were treated in our
institution before January 2009 when the endovascular rescue
protocol was implemented and would have received bridging therapy
if available at that time. They constitute the IV nonresponders
(IV-NR) control group and were individually selected from the 511
patients prospectively included in our IV tPA database in which
clinical outcome data were blinded. All patients with an intracranial
occlusion treated in our institution with IV tPA from October 2002
to January 2009 were prospectively recorded in this database. During
this time period, no patient was treated with endovascular reperfusion therapies in our institution.
Arterial occlusion and recanalization were determined by TCD
according to the Thrombolysis In Brain Ischemia flow grading
system.12 In IV–IA group, arterial patency was also determined by
the angiographic Thrombolysis In Myocardial Infarction (TIMI)
scale.13 Complete recanalization was defined as TIMI IIb or III or
Thrombolysis In Brain Ischemia 4 or 5. TCD was repeated at the end
of endovascular procedure, after 12 and 24 hours, to evaluate
recanalization.
All patients received a CT scan at 24 to 36 hours from symptom
onset. Intracranial hemorrhage was defined and classified according
Time to IV tPA
165.1⫾144.9
5 (6%)
182.1⫾96.2
0.558
0.506
0.444
IQR indicates interquartile range.
to the European Cooperative Acute Stroke Study (ECASS) in
hemorrhagic infarction and parenchymal hemorrhage.14 When
the hemorrhage was accompanied by an increase ⬎4 points on the
NIHSS and the hemorrhage was thought to be the cause of the
neurological deterioration, it was classified as symptomatic intracranial hemorrhage.15
Clinical severity was scored by the NIHSS, which was performed
at baseline, before the endovascular procedure, after 24 hours, and at
discharge. Clinical improvement was defined as a decrease in ⬎4
points on the NIHSS. At 3 months, functional outcome was evaluated by the modified Rankin Scale and functional independency was
defined by modified Rankin Scale score ⱕ2.16
The study was approved by the local ethics committee and an
informed consent was obtained from the patient or surrogates in each
case.
Statistical Analyses
Continuous variables are presented as mean and SDs or as median
and range values. Noncontinuous variables are presented as percentages. Statistical significance for intergroup differences was assessed
by the 2-tailed Fisher exact test and Pearson ␹2 test for categorical
variables and Student t test, Mann-Whitney U test, and KruskalWallis test for continuous variables. The Statistical Package for
Social Science (SPSS Inc, Version 17.0 for Windows) was used for
statistical analyses. A level of P⬍0.05 was accepted as statistically
significant.
Results
During the study period, 42 IV–IA patients were included in
the study and were matched with 84 IV-NR control patients.
Mean age of the series was 71.5⫾12.9 years, 58 (46%) were
women, and median baseline NIHSS score was 20 (interquartile range, 5). Mean time from symptoms to IV tPA was
176.9⫾113.3 minutes. The baseline clinical characteristics of
the series are described in Table 1.
The occluded vessels were as follows: middle cerebral
artery 60 (47.6%), intracranial internal carotid artery 39
(31%), basilar artery 24 (19%), and posterior cerebral artery
3 (2.4%). On TCD, 120 (95.2%) patients had a proximal
(Thrombolysis In Brain Ischemia 0 to 1) occlusion and 6
patients had a distal (Thrombolysis In Brain Ischemia 2 to 3)
Rubiera et al
Figure 1. Complete recanalization (REC12 hours), early clinical
improvement (Imp-24 hours), dramatic recovery at discharge
(DDR), and symptomatic intracranial hemorrhage (SICH) in both
IV–IA and IV-NR groups. *Statistically significant. IV, intravenous;
IA, intra-arterial; IV-NR, IV nonresponders.
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occlusion. The digital angiography showed TIMI 0 to 1 in 39
patients (92.8%), TIMI 2a in 2 patient (4.7%), and TIMI 2b
in 1 patient (2.4%). The digital angiography did not confirm
the vessel occlusion in 1 additional patient (2.4%) who was
excluded from this study.
In the IV–IA group, median time from tPA bolus to groin
puncture was 60.3⫾36.3 minutes. Twenty-seven (67.5%)
patients received IA tPA, 28 (70%) received microwire
mechanical disruption, 22 (55%) were treated with both tPA
and microwire disruption, and 3 (7.3%) patients received
Merci retriever thrombectomy after unsuccessful IA tPA.
During endovascular reperfusion therapies, the following
complications occurred: impossible access to the occlusion
site in 4 patients (9.5%), arterial dissection in 1 (2.4%),
subarachnoidal hemorrhage/vessel perforation in 2 (4.8%),
embolization to an unoccluded vascular territory in 2 (4.8%),
and puncture site complications (1 local hematoma, 1 pseudoaneurysm) in 2 (4.8%).
On TCD, complete recanalization (Thrombolysis In Brain
Ischemia 4 to 5) was significantly more frequent in IV–IA
patients than control subjects after 12 (IV–IA 45.2 versus
IV-NR 18.1%, P⫽0.002) and 24 hours (IV–IA 46.3 versus
IV-NR 25.3%, P⫽0.016). Angiographically, 60% of patients
achieved some degree of recanalization; 8 (19%) achieved
TIMI 2a, 7 (16.7%) TIMI 2b, and 10 (23.8%) TIMI 3.
There was a trend toward a better clinical course in patients
receiving bridging therapy as compared with IV-NR patients,
but this did not reach statistical significance (clinical improvement after 24 hours: IV–IA 40.5% versus IV-NR
30.1%, P⫽0.169; at discharge: IV–IA 52.5% versus IV-NR
39.5%, P⫽0.123). However, the rate of dramatic recovery at
discharge (defined as a decrease ⱖ10 points on the NIHSS or
a final NIHSS score of 0 or 1) was significantly higher in the
IV–IA group (40% versus 23.6%, P⫽0.048; Figure 1).
Intracranial hemorrhages in both groups are represented in
Figure 1. IV–IA patients had a nonsignificant higher rate of
parenchymal hemorrhage (26.2% versus 13.1% in IV-NR,
P⫽0.060). However, the rate of symptomatic intracranial
hemorrhage was similar in both groups (11.9% versus 6%,
P⫽0.205).
Bridging IV–IA Versus Nonresponder IV
3
Figure 2. Modified Rankin Scale score (mRS) in IV–IA and IV-NR
groups at 3 months. *Statistically significant. IV, intravenous; IA,
intra-arterial; IV-NR, IV nonresponders.
At 3 months, 40% of patients who received bridging
therapy were functionally independent, as compared with
only 14.9% of IV tPA nonresponders (P⫽0.012; Figure 2).
Mortality at 3 months was numerically higher in the IV–IA
group (50% versus 35.8%), but this did not reach statistical
significance (P⫽0.154).
The bridging IV–IA rescue (OR, 4.4; 95% CI, 1.2 to 15.1)
was the only independent predictor of functional independency defined as modified Rankin Scale score ⱕ2. Conversely, the presence of an intracranial internal carotid artery
occlusion (OR, 0.1; 95% CI, 0.01 to 0.7) independently
predicted the lack of a good functional outcome.
A subgroup analysis was performed according to the
location of the arterial occlusion (Table 2). In patients with an
anterior circulation stroke (middle cerebral artery and intracranial internal carotid artery occlusions), IV–IA therapy was
significantly associated with higher recanalization than isolated IV treatment. In the posterior circulation stroke (basilar
Table 2. Subgroup Analysis According to Location
of Occlusion*
Anterior Circulation
IV–IA Group
(n⫽33)
IV-NR Group
(n⫽66)
P
Complete 12 hours-REC
14 (42.4%)
10 (15.4%)
0.004†
24-hour improvement
14 (42.4%)
18 (27.7%)
0.108
4 (12.1%)
5 (7.6%)
0.345
3-month mortality
13 (39.4%)
49 (30.3%)
0.285
mRS ⱕ2
16 (48.5%)
8 (12.1%)
0.001†
Posterior Circulation
IV–IA Group
(n⫽9)
IV-NR Group
(n⫽18)
P
Complete 12 hours-REC
5 (55.6%)
5 (27.8%)
0.162
24-hour improvement
3 (33.3%)
7 (38.9%)
0.561
SICH
1 (11.1%)
0 (0%)
0.333
3-month mortality
6 (66.6%)
9 (50%)
0.392
mRS ⱕ2
2 (22.2%)
6 (33.3%)
0.406
SICH
*Complete recanalization after 12 hours, early clinical improvement (24-hour
decrease in ⱖ4 on the NIHSS), symptomatic intracranial hemorrhage (SICH),
3-month mortality and functional independency (mRS ⱕ2) in patients receiving
IV-IA therapy and IV nonresponder patients according to anterior (middle
cerebral artery and intracranial internal carotid artery) or posterior circulation
occlusion (basilar artery and posterior cerebral artery).
†Statistically significant.
4
Stroke
April 2011
artery, vertebral artery, and posterior cerebral artery occlusions), the recanalization rate was numerically higher for
IV–IA treatment but did not reach statistical significance.
Patients with anterior stroke who received bridging therapy
were significantly more prone to have a good functional
outcome at 3 months than IV-NR patients (modified Rankin
Scale score ⱕ2: IV–IA 48.5% versus IV-NR 12.1%,
P⫽0.001). Conversely, patients with a posterior circulation
stroke experienced similar long-term outcome independent of
the reperfusion treatment used.
Discussion
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The evolution of ischemic stroke treatment in the last few
years has changed from a contemplative attitude toward an
active, vessel-focused, and sometimes aggressive therapy.
Clinical trials showed improvement of functional outcome of
patients with stroke treated with IV tPA, pointing to recanalization as the main determinant of this improvement.17,18
Therefore, endovascular approaches seem particularly attractive, because they increase recanalization rates from 30% to
40% with IV tPA up to 70% to 80%.1
However, endovascular reperfusion strategies have been
criticized because of the lack of randomized clinical trials
comparing IA therapies against IV tPA.9,11,19 Moreover,
recent studies with endovascular procedures did not show the
expected rates of clinical improvement despite achieving high
recanalization rates.7,20 A clear example is the Penumbra
pivotal trial with 82% of TIMI 2 to 3 results but only 25% of
functionally independent patients. This percentage of good
outcome, comparable with the control group in the National
Institute of Neurological Disorders and Stroke trial, has raised
concerns about the efficacy of endovascular treatments.19
This fact may be explained by the lack of a comparable control
group with similar baseline characteristics, including location
of vessel occlusion. Recently, the REcanalisation using
Combined intravenous Alteplase and Neurointerventional
ALgorithm for acute Ischemic StrokE (RECANALISE)
study17 compared patients receiving bridging rescue therapy with historic IV tPA patients with confirmed arterial
occlusion. The authors found an increased recanalization
in the endovascular rescue group but failed to demonstrate
an improvement in early and long-term outcome of the
bridging therapy. This study, however, did not compare
patients with similar baseline characteristics. The IV tPA
group could be favored by the fact that some of the patients
may have achieved early recanalization.3 Those patients
would have not been suitable to be treated with endovascular procedures. The Interventional Management of
Stroke (IMS) III trial that is currently randomizing patients
to either IV tPA treatment or IV tPA plus reperfusion
rescue strategies will answer the question about the beneficial clinical impact of the bridging approach in patients
with persistent intracranial artery occlusion.11
In the meantime, our study was designed to evaluate IV–IA
patients who received bridging therapy and compare them
with the most similar historic controls, those who would have
received IA rescue treatment if available after an unsuccessful IV tPA. To make them even more comparable, we
established a case– control approach, matching patients ac-
cording to factors potentially able to modify the response to
IV tPA and outcome as vessel and site of arterial occlusion,
time to treatment, and stroke severity. Our results showed not
only a significant increase in the recanalization rate with the
endovascular rescue strategy as expected, but also a significantly better early clinical course and higher rates of favorable long-term outcome with a 25% absolute increase in the
likelihood of functional independency at 3 months.
The subgroup analysis showed that patients with an anterior circulation stroke may benefit more from the bridging
IV–IA therapy than those with a posterior stroke. These
results are comparable with previous studies that have shown
similar efficacy with isolated IV tPA, bridging therapy, or
primary intraarterial reperfusion treatment in acute basilar
occlusions.21,22 In our case, however, the number of patients
with posterior circulation is scarce, and probably the results
should be confirmed with a longer series.
The safety of the endovascular rescue strategies has also
been a matter of debate. Whether the IV tPA dose should be
⬍0.9 mg/kg if a possible IA rescue is planned is still
controversial.10 In our series, we used the standard full dose
of 0.9 mg/kg. Although there was a trend toward a higher rate
of hemorrhagic transformation, symptomatic intracranial
hemorrhage was comparable in both groups. The rate of
mortality in the series is high, especially in the IV–IA patients
(without statistical significance between both groups), but the
severity of stroke at baseline may justify these percentages.
Whether this difference in mortality could be a consequence
of the endovascular procedure complications and whether this
difference could be significant with a longer series is not
known. However, safety and efficacy of bridging IV–IA
treatment will be properly addressed in ongoing randomized
trials.
Our study has some limitations. The fact that this is not a
randomized study may induce some bias; however, the
case– control approach with matching blinded to vascular and
clinical outcomes seems a reasonable alternative. Also, our
patients received continuous TCD monitoring during IV tPA
treatment, and in some cases, monitoring was maintained
during the endovascular procedure. Thus, extended
ultrasound-enhanced thrombolysis may potentially influence
recanalization rates in the bridging group.4 Finally, with
the control group being an historical one, a general
improvement in acute stroke care and experience over time
may have influenced clinical outcomes and should be
taken into account.
In conclusion, the IV–IA bridging reperfusion rescue
strategies may improve the recanalization rate and the clinical
outcome of patients with an acute ischemic stroke who do not
respond to IV tPA. Current clinical trials may further confirm
this hypothesis.
Disclosures
None.
References
1. Broderick JP. Endovascular therapy for acute ischemic stroke.
Stroke. 2009;40:S103–106.
Rubiera et al
Downloaded from http://stroke.ahajournals.org/ by guest on March 30, 2017
2. Tissue plasminogen activator for acute ischemic stroke. The National
Institute of Neurological Disorders and Stroke rtPA stroke study group.
N Engl J Med. 1995;333:1581–1587.
3. Ribo M, Alvarez-Sabin J, Montaner J, Romero F, Delgado P, Rubiera M,
Delgado-Mederos R, Molina CA. Temporal profile of recanalization after
intravenous tissue plasminogen activator: selecting patients for rescue
reperfusion techniques. Stroke. 2006;37:1000 –1004.
4. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR,
Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill
MD, Wojner AW. Ultrasound-enhanced systemic thrombolysis for acute
ischemic stroke. N Engl J Med. 2004;351:2170 –2178.
5. Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S,
Akhtar N, Orouk FO, Salam A, Shuaib A, Alexandrov AV. Site of arterial
occlusion identified by transcranial Doppler predicts the response to
intravenous thrombolysis for stroke. Stroke. 2007;38:948 –954.
6. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin
M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial
prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. PROlyse in Acute Cerebral Thromboembolism.
JAMA. 1999;282:2003–2011.
7. Penumbra Pivotal Stroke Trial Investigators. The Penumbra Pivotal
Stroke Trial: safety and effectiveness of a new generation of mechanical
devices for clot removal in intracranial large vessel occlusive disease.
Stroke. 2009;40:2761–2768.
8. IMS II Trial Investigators. The Interventional Management of Stroke
(IMS) II study. Stroke. 2007;38:2127–2135.
9. Fields JD, Lindsay K, Liu KC, Nesbit GM, Lutsep HL. Mechanical
thrombectomy for the treatment of acute ischemic stroke. Expert Rev
Cardiovasc Ther. 8:581–592.
10. Shaltoni HM, Albright KC, Gonzales NR, Weir RU, Khaja AM, Sugg
RM, Campbell MS III, Cacayorin ED, Grotta JC, Noser EA. Is intra-arterial thrombolysis safe after full-dose intravenous recombinant tissue
plasminogen activator for acute ischemic stroke? Stroke. 2007;38:80 – 84.
11. Khatri P, Hill MD, Palesch YY, Spilker J, Jauch EC, Carrozzella JA,
Demchuk AM, Martin R, Mauldin P, Dillon C, Ryckborst KJ, Janis S,
Tomsick TA, Broderick JP. Methodology of the Interventional Management of Stroke III trial. Int J Stroke. 2008;3:130 –137.
12. Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD,
Alexandrov AV. Thrombolysis In Brain Ischemia (TIBI) transcranial
Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator.
Stroke. 2001;32:89 –93.
13. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge
HT, Francis CK, Hillis D, Ludbrook P. Thrombolysis In Myocardial
Infarction (TIMI) trial, Phase I: a comparison between intravenous tissue
14.
15.
16.
17.
18.
19.
20.
21.
22.
Bridging IV–IA Versus Nonresponder IV
5
plasminogen activator and intravenous streptokinase. Clinical findings
through hospital discharge. Circulation. 1987;76:142–154.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R,
Boysen G, Bluhmki E, Hoxter G, Mahagne MH, Hennerici M. Intravenous thrombolysis with recombinant tissue plasminogen activator for
acute hemispheric stroke. The European Cooperative Acute Stroke Study
(ECASS). JAMA. 1995;274:1017–1025.
Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W,
Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO,
Soinne L, Toni D, Vanhooren G. Thrombolysis with alteplase for acute
ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMOnitoring STudy (SITS-MOST): an observational study. Lancet. 2007;
369:275–282.
The Dutch TIA trial: protective effects of low-dose aspirin and atenolol in
patients with transient ischemic attacks or nondisabling stroke. The Dutch
TIA study group. Stroke. 1988;19:512–517.
Mazighi M, Serfaty JM, Labreuche J, Laissy JP, Meseguer E, Lavallee
PC, Cabrejo L, Slaoui T, Guidoux C, Lapergue B, Klein IF, Olivot JM,
Abboud H, Simon O, Niclot P, Nifle C, Touboul PJ, Raphaeli G, Gohin
C, Claeys ES, Amarenco P. 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.
Molina CA, Alexandrov AV, Demchuk AM, Saqqur M, Uchino K,
Alvarez-Sabin J. Improving the predictive accuracy of recanalization on
stroke outcome in patients treated with tissue plasminogen activator.
Stroke. 2004;35:151–156.
Cloft HJ, Rabinstein A, Lanzino G, Kallmes DF. Intra-arterial stroke
therapy: an assessment of demand and available work force. AJNR Am J
Neuroradiol. 2009;30:453– 458.
Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS,
Lutsep HL, Rymer MM, Higashida RT, Starkman S, Gobin YP, Frei D,
Grobelny T, Hellinger F, Huddle D, Kidwell C, Koroshetz W, Marks M,
Nesbit G, Silverman IE. Mechanical thrombectomy for acute ischemic
stroke: final results of the Multi MERCI trial. Stroke. 2008;39:
1205–1212.
Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis.
Stroke. 2006;37:922–928.
Schonewille WJ, Wijman CA, Michel P, Rueckert CM, Weimar C, Mattle
HP, Engelter ST, Tanne D, Muir KW, Molina CA, Thijs V, Audebert H,
Pfefferkorn T, Szabo K, Lindsberg PJ, de Freitas G, Kappelle LJ, Algra
A. Treatment and outcomes of acute basilar artery occlusion in the Basilar
Artery International Cooperation Study (BASICS): a prospective registry
study. Lancet Neurol. 2009;8:724 –730.
Downloaded from http://stroke.ahajournals.org/ by guest on March 30, 2017
Bridging Intravenous−Intra-Arterial Rescue Strategy Increases Recanalization and the
Likelihood of a Good Outcome in Nonresponder Intravenous Tissue Plasminogen
Activator-Treated Patients: A Case−Control Study
Marta Rubiera, Marc Ribo, Jorge Pagola, Pilar Coscojuela, David Rodriguez-Luna, Olga
Maisterra, Bernardo Ibarra, Socorro Piñeiro, Pilar Meler, Francisco J. Romero, Jose
Alvarez-Sabin and Carlos A. Molina
Stroke. published online March 3, 2011;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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26
Stroke
Vol. 4, No. 3
Abstract 4
27
6
Stroke 日本語版 Vol. 6, No. 2
Full Article
静脈内‐動脈内ブリッジング療法は静脈内組織プラス
ミノゲン活性化因子投与による治療に反応しない患
者の再開通および良好な転帰の可能性を増加させる
— 症例対照研究
Bridging Intravenous–Intra-Arterial Rescue Strategy Increases Recanalization and
the Likelihood of a Good Outcome in Nonresponder Intravenous Tissue Plasminogen
Activator-Treated Patients ― A Case-Control Study
Marta Rubiera, MD, PhD1; Marc Ribo, MD, PhD1; Jorge Pagola, MD, PhD1; Pilar Coscojuela, MD2;
David Rodriguez-Luna, MD1; Olga Maisterra, MD1; Bernardo Ibarra, MD2; Socorro Piñeiro, MD1; Pilar
Meler1; Francisco J. Romero, MD2; Jose Alvarez-Sabin, MD, PhD1; Carlos A. Molina, MD, PhD1
1
Stroke Unit, Neurology Department, and 2 Neuroradiology Section, Hospital Vall d’Hebron, Universidad Autonoma de Barcelona,
Barcelona, Spain.
背景および目的：「 ブリッジング療法 」
［ 静脈内（ IV ）組織
プラスミノゲン活性化因子（ tPA ）投与による治療に反応
しない患者に対する動脈内（ IA ）再灌流救済療法 ］の安全
性および有効性は議論の的となっている。本研究の目的
は，症例対照法を用いて IV 血栓溶解療法と IV-IA 血栓溶
解療法を比較することであった。
方法：IV tPA が無効（ tPA ボーラス投与の 1 時間後に臨
床的改善および動脈再開通がみられない ）の後に IA 再灌
流法を受けた近位頭蓋内閉塞を有する連続患者を調査し
た（ IV-IA 群 ）。これらの患者と比較するため，当施設の
前向き IV tPA データベース内から，閉塞血管，血塊の
位置，脳卒中の重症度，および治療までの時間が一致し，
IV tPA 投与の 1 時間後に閉塞が持続していた 1 ～ 2 例の
患者を歴史的対照とした（ IV-NR 群 ）
。動脈閉塞および再
開通を経頭蓋超音波ドプラ検査により評価した。ベース
ライン，24 時間時，および退院時に NIHSS スコアによ
り臨床評価を行った。症候性頭蓋内出血は米国国立神経
疾患・脳卒中研究所（ National Institute of Neurological
Disorders and Stroke ）の臨床試験に従って定義した。機
能評価は改変 Rankin 尺度（ mRS ）により決定し，mRS ス
コアが 2 またはそれ以下を身体機能の自立と定義した。
結果：42 例の IV-IA 群患者を，84 例の対応する IV-NR
群患者と比較した。全体の平均年齢は 71.5 ± 12.9 歳，58
例（ 46％）が女性であり，ベースラインの NIHSS スコアの
中央値は 20（ 四分位範囲：5 ）であった。症状発現から IV
tPA 投与までの平均時間は 176.9 ± 113 分であった。経
頭蓋超音波ドプラ検査では，IV-IA 群で完全な再開通の
割合が対照群被験者と比べて有意に高く（ 12 時間：45.2％
対 18.1 ％，p ＝ 0.002；24 時 間：46.3 ％ 対 25.3 ％，p ＝
0.016），臨床経過は 24 時間時（ 40.5％ 対 30.1％，
p ＝ 0.169 ）
および退院時（ 52.5％ 対 39.5％，p ＝ 0.123 ）
で有意ではな
いがより良好であった。症候性頭蓋内出血は同様であっ
た（ IV-IA 群 11.9 ％ 対 IV-NR 群 6 ％，p ＝ 0.205 ）
。3 カ
月時の死亡率は IV-IA 群では 50％であり，IV-NR 群では
35.8％であった（p ＝ 0.154 ）。IV-IA 群患者の 40％で 3 カ
月時に身体機能の自立が認められたのに対し，IV-NR 群
ではわずかに 14.9％であった（p ＝ 0.012）。
結論：IV-IA ブリッジング療法は IV tPA 投与による治療
に反応しない患者における再開通および臨床転帰を改善
する可能性がある。
Stroke 2011; 42: 993-997
KEYWORDS 急性脳卒中，ドプラ検査，血栓溶解療法，血栓溶解薬
不可逆的損傷に至る前に虚血組織の再灌流を行うこと
起こるのは症例の 40％にすぎない 4。この割合は，中大脳
が，急性虚血性脳卒中治療の主要な目的である 1。急性
動脈の M1 セグメントの閉塞または頭蓋内内頸動脈閉塞
虚血性脳卒中の薬理学的治療として唯一認められている
ではさらに低く，再開通の割合はそれぞれおよそ 20％お
ものは静脈内（IV ）組織プラスミノゲン活性化因子（tissue
よび 10％である 5。このため，ここ数年，急性脳卒中に
plasminogen activator: tPA）
であり，その目的は閉塞した
おける再開通の割合を増加させるための高度な治療法が
頭蓋内動脈の再開通である 。さらに，再開通は，大血管
開発されている 1。薬理学的および機械的な血管内治療は
閉塞による脳卒中における血栓溶解療法後の良好な臨床
非常に有望な手法であり，シリーズおよび方法により 66
転帰の最も重要な予測因子であることが示されている 。
～ 81％の再開通率が示されている 6-8。しかし，高い再開
しかし，最良のシナリオでも IV tPA 投与により再開通が
通率がこれらの患者の臨床転帰の向上につながるかどう
2
3
stroke6-2.indb 6
11.9.27 10:53:38 AM
静脈内‐動脈内ブリッジング療法は静脈内 tPA 投与による治療に反応しない患者の再開通および良好な転帰の可能性を増加させる
7
かは依然として議論の分かれるところである 1。今日まで，
以前に当施設で治療を受けており，当時ブリッジング療
血管内救済療法の方が従来の IV tPA 療法に比べて有益で
法が利用可能であればブリッジング療法を受けていただ
あることを示す確固たる証拠は得られていない
ろうと思われる患者である。これらの患者を IV ノンレス
。
8,9
「ブリッジング」法では，IV tPA 療法後に再開通がみら
ポンダー（IV-NR）対照群とし，臨床転帰データが盲検化
れない患者を救済するために，血管内の機械的または薬
された当施設の IV tPA データベースに前向きに登録され
理学的血栓溶解療法が使用される。以前のいくつかの報
た 511 例の患者から個別に選択した。2002 年 10 月から
告で，急性虚血性脳卒中患者におけるこの救済療法の安
2009 年 1 月までに当施設で IV tPA 投与による治療を受
全性が示されており
，科学的証拠を示すために臨床試
けた頭蓋内閉塞を有するすべての患者が，このデータベー
験が現在行われている。しかし，再開通の増加および特
スに前向きに記録された。この期間中，当施設で血管内
に臨床的改善を基準とした救済法の真の有効性に関して
再灌流療法を受けた患者はいなかった。
8,10
は依然として議論がある 。このため我々は，IV tPA 単
動脈閉塞および再開通を，Thrombolysis In Brain Ischemia
独の治療を受けた患者と，ブリッジング療法を受けた対
の血流分類に従って TCD で判定した 12。IV-IA 群では，
照患者を比較する症例対照研究を計画した。
血管造影 Thrombolysis In Myocardial Infarction（ TIMI）ス
11
ケールによっても動脈開存の判定も行った 13。TIMI IIb
患者および方法
2009 年 2 月から 2010 年 1 月までの期間に，症状の発
現から 4.5 時間以内に当大学病院に入院した連続するす
または III，もしくは Thrombolysis In Brain Ischemia 4 ま
たは 5 を完全な再開通と定義した。血管内治療の終了時，
12 時間後および 24 時間後に TCD を再度行い，再開通を
評価した。
べての急性脳卒中患者を評価した（脳底動脈閉塞症では 8
症状発現から 24 ～ 36 時間の時点ですべての患者の
時間まで）
。出血ならびにベースラインの CT または MRI
CT スキャンを行った。頭蓋内出血は，出血性梗塞および
で中大脳動脈領域の 3 分の 1 より大きい梗塞の初期徴候
実質性出血に関する European Cooperative Acute Stroke
が認められる患者を除外した後で，禁忌のない患者に対
Study（ECASS）
の定義と分類に従った 14。出血が NIHSS
し，現行ガイドラインに従って標準用量である 0.9 mg/kg
の 4 ポイント超の上昇を伴い，出血が神経症状の悪化の
の IV tPA を投与した。すべての患者に対して tPA ボー
原因であると考えられる場合は，症候性頭蓋内出血に分
ラス投与の前に頸動脈および経頭蓋超音波ドプラ検査
類した 15。
（ transcranial Doppler: TCD）
を行い，頭蓋内閉塞が認め
臨床的重症度は NIHSS によりスコア化し，ベースライ
られた患者については tPA 注入中に連続的 TCD（Power-
ン時，血管内治療の前，24 時間後，および退院時に実施
Mode 100; Spencer Technologies）
によるモニタリングを
した。臨床的改善は，NIHSS の 4 ポイント超の低下と定
行った。患者に臨床的改善がみられず，注入終了時の
義した。3 カ月時に機能的転帰を改変 Rankin 尺度（ mRS）
TCD で閉塞の持続が記録された場合，その患者を脳血管
により評価し，mRS スコアが 2 またはそれ以下を身体機
造影検査室に移し，そこで，デジタル血管造影により閉
能の自立と定義した 16。
塞を確認した後で血管内再灌流法を開始した。脳血管内
本研究は当施設の倫理委員会による承認を受け，各症
治療専門医が，自らの選択と患者の特性に応じて，最大
例について患者または代理人からインフォームドコンセ
用量 20 mg の動脈内（IA ）tPA および／またはマイクロワ
ントを取得した。
イヤーによる機械的破壊および／または Merci リトリー
バーを使用した。再開通が得られた時点，もしくは症状
統計解析
発現から 6 時間（脳底動脈閉塞症では 12 時間）
が経過した
連続変数は平均値と標準偏差または中央値と範囲とし
時点で血管内治療を中止した。ブリッジング療法を受け
て表わした。非連続変数はパーセンテージとして表わし
た患者を IV-IA 症例群とする。
た。群間差の統計学的有意性は，カテゴリ変数について
症例群の各患者に，
2 例の歴史的対照患者を対応させた。
は Fisher の両側直接確率検定および Pearson の χ 2 検定に
歴史的対照患者は，TCD での閉塞血管および血塊の位
より評価し，連続変数については Student t 検定，Mann-
置，NIHSS スコアを指標とする脳卒中の重症度，および
Whitney U 検定，および Kruskal-Wallis 検定により評価
IV tPA 療法までの時間が同様であり，標準的な IV tPA
した。統計解析には Statistical Package for Social Science
のみによる治療を受けた患者で，tPA ボーラス投与 1 時
（SPSS Inc, Version 17.0 for Windows）
を使用した。p ＜
間後の TCD で再開通が認められなかった患者とした。こ
0.05 の水準を統計学的に有意とした。
れらの患者は，血管内救済療法が導入された 2009 年 1 月
stroke6-2.indb 7
11.9.27 10:53:39 AM
8
Stroke 日本語版 Vol. 6, No. 2
結　果
表 1 ベースラインの臨床的特徴
研究期間中，42 例の IV-IA 患者が本研究に組み入れら
れ，84 例の IV-NR 対照患者と対応させた。本シリーズ全
年齢（歳）
体の平均年齢は 71.5 ± 12.9 歳，
58 例
（46％）
が女性であり，
性別（女性）注）
ベースラインの NIHSS スコアの中央値は 20
（ 四分位範囲：
糖尿病
5）
であった。症状発現から IV tPA 投与までの平均時間は
176.9 ± 113.3 分であった。本シリーズのベースラインの
臨床的特徴を表 1 に示す。
閉塞血管は，中大脳動脈 60 例（47.6％）
，頭蓋内内頸
p値
70.1 ± 11.3
72.2 ± 13.6
0.388
―
―
―
10 (23.8%)
18 (21.4%)
0.464
高血圧
26 (63.4%)
49 (59%)
0.394
20 (IQR, 3)
20 (IQR, 5)
0.771
グルコース（mg/dL）
144.7 ± 45.7
140.6 ± 51.9
0.693
収縮期血圧（mm Hg）
147.7 ± 27.9
154.4 ± 27.5
0.263
拡張期血圧（mm Hg）
77.5 ± 14.9
81.4 ± 16.5
0.237
16 (38.1%)
29 (34.5%)
0.420
動脈 39 例（31％）
，脳底動脈 24 例（19％）
，後大脳動脈 3
例（ 2.4％）であった。TCD では，120 例（95.2％）に近位
脳卒中サブタイプ
れ，6 例に遠位（Thrombolysis In Brain Ischemia 2 ～ 3）
の
IV-NR 群
（84 例 ）
ベースラインの NIHSS
心房細動
（ Thrombolysis In Brain Ischemia 0 ～ 1）
の閉塞が認めら
IV-IA 群
（42 例）
心原性
22 (53.7%)
38 (45.2%)
0.603
アテローム血栓性
08 (19.5%)
26 (31%)
0.083
閉塞が認められた。デジタル血管造影では 39 例（92.8％）
不明
08 (19.5%)
15 (17.9%)
0.558
解離
03 (7.3%)
05 (6%)
0.506
が TIMI 0 ～ 1 であり，2 例（4.7％）
が TIMI 2a であり，1
IV tPA までの時間
例（ 2.4％）
が TIMI 2b であった。また，デジタル血管造影
IQR は四分位範囲を示す。
注：各群の女性数と割合が正確に示されていないため，Stroke 日本語版には記載
しないが，性別以外の臨床的特徴には影響はない。
では，別の 1 例（2.4％）
には血管閉塞が確認されなかった
165.1 ± 144.9
182.1 ± 96.2
0.444
ため，本研究から除外された。
IV-IA 群では，tPA ボーラス投与から鼠径部穿刺まで
の時間の中央値は 60.3 ± 36.3 分であった。27 例
（67.5％）
は IV-IA 群で有意に高かった
（40％ 対 23.6％，p ＝ 0.048；
図 1）
。
が IA tPA の投与を受け，28 例
（70％）
がマイクロワイヤー
両群における頭蓋内出血を図 1 に示す。IV-IA 群の
による機械的破壊を受け，22 例（ 55％）が tPA と機械的
患者では実質性出血の割合が有意ではないが高かった
破壊の両方による治療を受け，3 例（7.3％）が IA tPA が
（26.2 ％ 対 IV-NR 群 13.1 ％，p ＝ 0.060）
。 し か し， 症
無効であった後に Merci リトリーバーによる血栓除去を
候性頭蓋内出血の割合は両群で同様であった（ 11.9％ 対
受けた。血管内再灌流療法中，以下の合併症が発生した：
6％，p ＝ 0.205）
。
4 例（ 9.5％）に閉塞部位へのアクセス不能，1 例（ 2.4％）
3 カ月時には，ブリッジング療法を受けた患者の 40％
に動脈解離，2 例（4.8％）にくも膜下出血／血管穿孔，2
で身体機能の自立が認められたのに対し，IV tPA ノンレ
例（ 4.8％）に閉塞していない血管領域の塞栓形成，2 例
スポンダーでは身体機能の自立が認められたのは 14.9％
（ 4.8％）
に穿刺部位の合併症（1 例は局所的血腫，1 例は偽
にすぎなかった（p ＝ 0.012；図 2 ）
。3 カ月時の死亡率は
動脈瘤）
。
TCD では，完全な再開通
（Thrombolysis In Brain Ischemia
4 ～ 5）
は 12 時間後（IV-IA 群 45.2％ 対 IV-NR 群 18.1％，
数値的には IV-IA 群で高かったが（50％ 対 35.8％）
，これ
は統計学的に有意には達しなかった
（p ＝ 0.154）
。
IV-IA ブリッジング療法（OR ＝ 4.4，95％ CI：1.2 ～
p ＝ 0.002）および 24 時間後（IV-IA 群 46.3％ 対 IV-NR
15.1）
は，mRS スコア 2 以下と定義した身体機能の自立の
群 25.3％，p ＝ 0.016 ）に IV-IA 群患者で対照患者より有
唯一の独立した予測因子であった。逆に，頭蓋内内頸動
意に多く認められた。血管造影では，60％の患者である
脈閉塞の存在（OR ＝ 0.1，95％ CI：0.01 ～ 0.7）
は良好な
程度の再開通が得られた。すなわち，8 例（ 19％）
が TIMI
機能的転帰の欠如を独立して予測した。
2a に達し，7 例（16.7％）
が TIMI 2b に，10 例（23.8％）
が
TIMI 3 に達した。
動脈閉塞の位置によるサブグループ解析を行った（表
2）
。前方循環脳卒中（中大脳動脈および頭蓋内内頸動脈
ブリッジング療法を受けた患者では IV-NR 患者と比べ
の閉塞）の患者では，IV-IA 療法は IV 単独療法と比べて
て臨床経過が良好である傾向がみられたが，これは統計
高い再開通率と有意に関連していた。後方循環脳卒中（脳
学的に有意には達しなかった（24 時間後の臨床的改善：
底動脈，椎骨動脈，後大脳動脈の閉塞）
では，再開通率は
IV-IA 群 40.5％ 対 IV-NR 群 30.1％，p ＝ 0.169；退院時：
数値的には IV-IA 療法で高かったが，統計学的に有意に
IV-IA 群 52.5％ 対 IV-NR 群 39.5％，p ＝ 0.123）
。しか
は達しなかった。ブリッジング療法を受けた前方循環脳
し，退院時の劇的な回復（NIHSS が 10 ポイント以上低下
卒中患者は IV-NR 患者と比べて 3 カ月時の機能的転帰が
もしくは最終 NIHSS スコアが 0 または 1 と定義）
の割合
良好である傾向が有意に高かった（mRS スコア 2 以下：
stroke6-2.indb 8
11.9.27 10:53:40 AM
9
静脈内‐動脈内ブリッジング療法は静脈内 tPA 投与による治療に反応しない患者の再開通および良好な転帰の可能性を増加させる
IV-IA 群
％
50
45
40
35
30
25
20
15
10
5
0
mRS 0
mRS 1
mRS 2
mRS 3
mRS 4
mRS 5
mRS 6
45,2
40,5
40
IV-IA
19,2
15,4
3,8
11,5
0,1
50
30,1
23,6
18,1
IV-NR
3
9
3
13,4
19,4
16,4
35,8
11,9
6
0%
REC12h
図1
IV-NR 群
Imp-24h
DDR
SICH
IV-IA 群と IV-NR 群の完全な再開通（ REC12h ），早期の
臨床的改善（ Imp-24h ），退院時の劇的な回復（ DDR ），お
よび症候性頭蓋内出血（ SICH ）。* 統計学的に有意。IV：
静脈内，IA：動脈内，IV-NR：IV ノンレスポンダー。
20%
40%
60%
80%
100%
3 カ月時の IV-IA 群と IV-NR 群の改変 Rankin 尺度（ mRS ）
図 2 ス コ ア。* 統 計 学 的 に 有 意。IV： 静 脈 内，IA： 動 脈 内，
IV-NR：IV ノンレスポンダー。
ング救済療法を受けた患者と動脈閉塞が確認され IV tPA
療法を受けた歴史的対照患者とを比較した。著者らは血
IV-IA 群 48.5％ 対 IV-NR 群 12.1％，p ＝ 0.001）
。逆に，
管内救済群における再開通の増加を認めたが，ブリッジ
後方循環脳卒中患者では，使用した再灌流療法に関係な
ング療法による早期および長期的転帰の改善を実証する
く長期的転帰は同様であった。
ことはできなかった。しかし，この研究では，同様のベー
スライン特性をもつ患者を比較したわけではなかった。
考　察
この数年間の虚血性脳卒中治療は，静観的態度から，
IV tPA 群は，患者の一部で早期再開通が得られたことに
よる恩恵を受けた可能性がある 3。これらの患者は血管内
治療には適さなかったであろうと思われる。Interventional
能動的で，血管に焦点をあてた，時には積極的な治療法
Management of Stroke (IMS) III 試験は，患者を IV tPA 療
へと方向を変えて発展してきた。臨床試験の結果，IV
法または IV tPA ＋再灌流救済療法のいずれかに無作為に
tPA による治療を受けた脳卒中患者の機能的転帰の改善
割り付けている段階であるが，この試験により，頭蓋内
が示され，この改善の主要決定要因として再開通が指摘
動脈閉塞が持続する患者に対するブリッジング療法の臨
されている
。再開通率が IV tPA の 30 ～ 40％から 70
17,18
～ 80％に上昇することから，血管内治療は特に魅力的と
思われる 1。
しかし，IA 療法を IV tPA と比較した無作為臨床試験
が行われていないため，血管内再灌流法は批判を受けて
きた 9,11,19。さらに，血管内治療の最近の研究では，高い
再開通率が得られたものの，期待された臨床的改善率が
表 2 閉塞の部位によるサブグループ解析 *
前方循環
IV-IA 群
（33 例）
IV-NR 群
（66 例 ）
p値
12 時間後の完全な再開通
14 (42.4%)
10 (15.4%)
0.004†
24 時間後の改善
14 (42.4%)
18 (27.7%)
0.108
認められなかった 7,20。明らかな例として Penumbra 主要
SICH
04 (12.1%)
05 (7.6%)
0.345
試験があり，この試験では 82％で TIMI 2 ～ 3 の結果が
3 カ月時の死亡率
13 (39.4%)
49 (30.3%)
0.285
得られたが身体機能の自立が得られた患者は 25％にすぎ
mRS ≦ 2
16 (48.5%)
08 (12.1%)
0.001†
なかった。良好な転帰のこの割合は，米国国立神経疾患・
後方循環
IV-IA 群
（9 例）
IV-NR 群
（18 例 ）
p値
脳卒中研究所（National Institute of Neurological Disorders
12 時間後の完全な再開通
05 (55.6%)
05 (27.8%)
0.162
and Stroke）の臨床試験と同等であり，血管内治療の有
24 時間後の改善
03 (33.3%)
07 (38.9%)
0.561
効性に関する懸念を引き起こした 19。この事実は，血管
SICH
01 (11.1%)
00 (0%)
0.333
3 カ月時の死亡率
06 (66.6%)
09 (50%)
0.392
mRS ≦ 2
02 (22.2%)
06 (33.3%)
0.406
閉塞の位置を含め，同様のベースライン特性を有する比
較可能な対照群がないことにより説明できる可能性が
ある。最近，REcanalisation using Combined intravenous
Alteplase and Neurointerventional ALgorithm for acute
Ischemic StrokE（RECANALISE ）研究 17 では，ブリッジ
stroke6-2.indb 9
*閉
塞部位が前方循環（中大脳動脈および頭蓋内内頸動脈）か後方循環（脳底動脈
および後大脳動脈）かによる，IV-IA 療法を受けた患者と IV ノンレスポンダー
患者の 12 時間後の完全な再開通，早期の臨床的改善（24 時間時に NIHSS の 4
ポイント以上の低下）
，症候性頭蓋内出血（ SICH ）
，3 カ月時の死亡率および身
体機能の自立
（mRS ≦ 2）
。
† 統計学的に有意。
11.9.27 10:53:41 AM
case– control approach with matching blinded to vascular and
ALgorithm for acute Ischemic StrokE (RECANALISE)
clinical outcomes seems a reasonable alternative. Also, our
study17 compared patients receiving bridging rescue therpatients received continuous TCD monitoring during IV tPA
apy with historic IV tPA patients with confirmed arterial
treatment, and in some cases, monitoring was maintained
occlusion. The authors found an increased recanalization
during the endovascular procedure. Thus, extended
in the endovascular rescue group but failed to demonstrate
ultrasound-enhanced thrombolysis may potentially influence
an
early
10 improvement
6, No.and
2 long-term outcome of the
Stroke 日本語版inVol.
recanalization rates in the bridging group.4 Finally, with
bridging therapy. This study, however, did not compare
the control group being an historical one, a general
patients with similar baseline characteristics. The IV
tPA
11
長期にわたる経験が臨床転帰に影響を及ぼした可能性が
床的に有益な影響に関する疑問に答えが出るだろう
。
improvement
in acute stroke care and experience over time
group could be favored by the fact that some of the patients
may
have influenced clinical outcomes and should be
あり，このことを考慮に入れるべきである。
その間，我々の研究は，ブリッジング療法を受けた
may
have achieved early recanalization.3 Those patients
taken into account.
would患者を評価し，最も類似した歴史的対照患者，すな
have not been suitable to be treated with endovas結論として，IV-IA ブリッジング再灌流救済療法は，
IV-IA
In conclusion, the IV–IA bridging reperfusion rescue
cular procedures. The Interventional Management of
IV tPA に反応しない急性虚血性脳卒中患者の再開通率お
わち IV tPA が無効な場合に，利用可能であれば IA 救済
strategies
may improve the recanalization rate and the clinical
Stroke (IMS) III trial that is currently randomizing patients
よび臨床転帰を改善する可能性がある。現在の臨床試験
療法を受けていたであろう患者と比較することを目的と
outcome
of patients with an acute ischemic stroke who do not
to either IV tPA treatment or IV tPA plus reperfusion
respond
to IV tPA. Current clinical trials may further confirm
rescue strategies will answer the question about the beneにより，この仮説がさらに立証される可能性がある。
してデザインされた。さらに両群を同等にするため，血
this
hypothesis.
ficial clinical impact of the bridging approach in patients
管と閉塞部位，治療までの時間，脳卒中の重症度のよう
with persistent intracranial artery occlusion.11
情報開示
に In
IVthe
tPA
に対する反応と転帰を修飾する可能性がある要
meantime,
our study was designed to evaluate IV–IA
Disclosures
なし。
因に従って症例を釣り合わせるよう，症例対照の方法を
patients who received bridging therapy and compare them
None.
with the most similar historic controls, those who would have
設定した。本研究の結果，予想通り血管内救済療法で再
received IA rescue treatment if available after an unsuccessRubiera et al
References
開通率が有意に上昇しただけでなく，早期臨床経過が有
ful IV tPA. To make them even more comparable, we
1. Broderick JP. Endovascular therapy for acute ischemic stroke.
意に良好であり，3
カ月後に身体機能の自立の
25％増加
established a case– control
approach, matching patients
acStroke. 2009;40:S103–106.
2. Tissue plasminogen activator for acute ischemic stroke. The National
を伴う良好な長期的転帰が示された。
Downloaded from http://stroke.ahajournals.org/ by MICHAEL BRUNKE on July 29, 2011
サブグループ解析では，前方循環脳卒中患者は後方循
環脳卒中患者と比べて IV-IA ブリッジング療法の恩恵が
3.
より多く得られる可能性があることが示された。これら
の結果は，急性脳底動脈閉塞症の治療において IV tPA
4.
単独，ブリッジング療法，または動脈内再灌流単独療法
で同程度の有効性が示された以前の研究とほぼ同様であ
る 21,22。しかし，本研究では後方循環脳卒中患者の数が少
5.
なく，おそらくより長期のシリーズで結果を確認する必
要がある。
6.
また，血管内救済療法の安全性も議論の的となってい
る。IA 救済療法の可能性が予定される場合に IV tPA の
用量を 0.9 mg/kg 未満とすべきかどうかについても依然と
7.
して議論が分かれている 10。本シリーズでは，標準用量
である 0.9 mg/kg を使用した。出血性変化の割合が高く
なる傾向が認められたが，症候性頭蓋内出血は両群で同
程度であった。本シリーズにおける死亡率は高く，特に
IV-IA 群患者で高かったが（両群間に統計学的有意差はな
し）
，これらの割合はベースラインでの脳卒中の重症度に
8.
9.
10.
より説明できる可能性がある。この死亡率の差が血管内
治療の合併症の結果であるのか，また，より長期のシリー
11.
ズでこの差が有意となり得るのかについては不明である。
しかし，IV-IA ブリッジング療法の安全性および有効性は
12.
現在進行中の無作為試験で正しく評価されるだろう。
本研究にはいくつかの限界がある。無作為試験ではな
Rubiera et al 13.
いという事実によりいくらかのバイアスが生じた可能性
がある。しかしながら，血管および臨床的転帰について
2. Tissue plasminogen activator for acute ischemic stroke. The National
盲検化して対応させた症例対照法は妥当な代替策である
Institute of Neurological Disorders and Stroke rtPA stroke study group.
と思われる。また，本研究の患者は
IV tPA 療法中に連続
N Engl J Med. 1995;333:1581–1587.
3. Ribo
M, Alvarez-Sabin
J, Montaner J, Romero F, Delgado P, Rubiera M,
的な
TCD
モニタリングを受け，場合によっては血管内治
14.
Delgado-Mederos R, Molina CA. Temporal profile of recanalization after
intravenous tissue plasminogen activator: selecting patients for rescue
療中もモニタリングが持続された。したがって，長時間
reperfusion techniques. Stroke. 2006;37:1000 –1004.
の超音波併用血栓溶解療法がブリッジング療法群の再開
4. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR,
4
Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk
AM, Moye LA, Hill
通率に影響を及ぼした可能性がある
。最後に，対照群が
15.
MD, Wojner AW. Ultrasound-enhanced systemic thrombolysis for acute
歴史的対照であるため，急性脳卒中ケアの全般的改善や
ischemic stroke. N Engl J Med. 2004;351:2170 –2178.
5. Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S,
Akhtar N, Orouk FO, Salam A, Shuaib A, Alexandrov AV. Site of arterial
occlusion identified by transcranial Doppler predicts the response to
intravenous thrombolysis for stroke. Stroke. 2007;38:948 –954.
6. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin
M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial
prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. PROlyse in Acute Cerebral Thromboembolism.
JAMA. 1999;282:2003–2011.
stroke6-2.indb 10
7. Penumbra Pivotal Stroke Trial Investigators. The Penumbra Pivotal
16.
17.
Institute of Neurological Disorders and Stroke rtPA stroke study group.
N Engl J Med. 1995;333:1581–1587.
Ribo M, Alvarez-Sabin J, Montaner J, Romero F, Delgado P, Rubiera M,
Delgado-Mederos R, Molina CA. Temporal profile of recanalization after
intravenous tissue plasminogen activator: selecting patients for rescue
reperfusion techniques. Stroke. 2006;37:1000 –1004.
Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR,
Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill
MD, Wojner AW. Ultrasound-enhanced systemic thrombolysis for acute
ischemic stroke. N Engl J Med. 2004;351:2170 –2178.
Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S,
Akhtar N, Orouk FO, Salam A, Shuaib A, Alexandrov AV. Site of arterial
occlusion identified by transcranial Doppler predicts the response to
intravenous thrombolysis for stroke. Stroke. 2007;38:948 –954.
Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin
M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial
prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. PROlyse in Acute Cerebral Thromboembolism.
JAMA. 1999;282:2003–2011.
Penumbra Pivotal Stroke Trial Investigators. The Penumbra Pivotal
Stroke Trial: safety and effectiveness of a new generation of mechanical
devices for clot removal in intracranial large vessel occlusive disease.
Stroke. 2009;40:2761–2768.
IMS II Trial Investigators. The Interventional Management of Stroke
(IMS) II study. Stroke. 2007;38:2127–2135.
Fields JD, Lindsay K, Liu KC, Nesbit GM, Lutsep HL. Mechanical
thrombectomy for the treatment of acute ischemic stroke. Expert Rev
Cardiovasc Ther. 8:581–592.
Shaltoni HM, Albright KC, Gonzales NR, Weir RU, Khaja AM, Sugg
RM, Campbell MS III, Cacayorin ED, Grotta JC, Noser EA. Is intra-arterial thrombolysis safe after full-dose intravenous recombinant tissue
plasminogen activator for acute ischemic stroke? Stroke. 2007;38:80 – 84.
Khatri P, Hill MD, Palesch YY, Spilker J, Jauch EC, Carrozzella JA,
Demchuk AM, Martin R, Mauldin P, Dillon C, Ryckborst KJ, Janis S,
Tomsick TA, Broderick JP. Methodology of the Interventional Management of Stroke III trial. Int J Stroke. 2008;3:130 –137.
Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD,
Alexandrov AV. Thrombolysis In Brain Ischemia (TIBI) transcranial
Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator.
Stroke. 2001;32:89 –93.
Bridging IV–IA Versus Nonresponder IV
997
Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge
HT, Francis CK, Hillis D, Ludbrook P. Thrombolysis In Myocardial
Infarction (TIMI) trial, Phase I: a comparison between intravenous tissue
plasminogen activator and intravenous streptokinase. Clinical findings
through hospital discharge. Circulation. 1987;76:142–154.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R,
Boysen G, Bluhmki E, Hoxter G, Mahagne MH, Hennerici M. Intravenous thrombolysis with recombinant tissue plasminogen activator for
acute hemispheric stroke. The European Cooperative Acute Stroke Study
(ECASS). JAMA. 1995;274:1017–1025.
Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W,
Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO,
Soinne L, Toni D, Vanhooren G. Thrombolysis with alteplase for acute
ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMOnitoring STudy (SITS-MOST): an observational study. Lancet. 2007;
369:275–282.
The Dutch TIA trial: protective effects of low-dose aspirin and atenolol in
patients with transient ischemic attacks or nondisabling stroke. The Dutch
TIA study group. Stroke. 1988;19:512–517.
Mazighi M, Serfaty JM, Labreuche J, Laissy JP, Meseguer E, Lavallee
PC, Cabrejo L, Slaoui T, Guidoux C, Lapergue B, Klein IF, Olivot JM,
Abboud H, Simon O, Niclot P, Nifle C, Touboul PJ, Raphaeli G, Gohin
C, Claeys ES, Amarenco P. Comparison of intravenous alteplase with
a
11.9.27
combined intravenous– endovascular approach in patients with stroke and
Bridging
14.
15.
16.
17.
18.
19.
20.
21.
22.
plasminogen a
through hospita
Hacke W, Kas
Boysen G, Blu
nous thrombol
acute hemisphe
(ECASS). JAM
Wahlgren N, A
Hennerici MG,
Soinne L, Toni
ischaemic strok
MOnitoring ST
369:275–282.
The Dutch TIA
patients with tra
TIA study grou
Mazighi M, Se
PC, Cabrejo L,
Abboud H, Sim
C, Claeys ES,
combined intra
confirmed arter
study. Lancet N
Molina CA, A
Alvarez-Sabin
stroke outcome
Stroke. 2004;35
Cloft HJ, Rabi
therapy: an ass
Neuroradiol. 2
Smith WS, Su
Lutsep HL, Ry
Grobelny T, He
Nesbit G, Silv
stroke: final
1205–1212.
Lindsberg PJ,
tematic analysi
Stroke. 2006;37
Schonewille W
HP, Engelter S
Pfefferkorn T,
A. Treatment an
Artery Internat
study. Lancet N
10:53:43 AM
stroke study group.
gado P, Rubiera M,
recanalization after
patients for rescue
ami Z, Ford SR,
M, Moye LA, Hill
ombolysis for acute
8.
arami Z, Calleja S,
AV. Site of arterial
ts the response to
948 –954.
H, Kase C, Pessin
era F. Intra-arterial
CT II study: a ranThromboembolism.
Penumbra Pivotal
ation of mechanical
occlusive disease.
agement of Stroke
p HL. Mechanical
stroke. Expert Rev
, Khaja AM, Sugg
ser EA. Is intra-arrecombinant tissue
ke. 2007;38:80 – 84.
C, Carrozzella JA,
kborst KJ, Janis S,
nterventional Man–137.
arber PA, Hill MD,
(TIBI) transcranial
recovery, and morminogen activator.
LS, Dalen J, Dodge
ysis In Myocardial
n intravenous tissue
domizedhospital
controlled
trial. PROlyse
in Acute
Cerebral Thromboembolism.
Abboud H, Simon O, Niclot P, Nifle C, Touboul PJ, Raphaeli G, Gohin
through
discharge.
Circulation.
1987;76:142–154.
JAMA.W,
1999;282:2003–2011.
C, Claeys ES, Amarenco P. Comparison of intravenous alteplase with a
14. Hacke
Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R,
7. Boysen
Penumbra
Pivotal Stroke
Trial
Penumbra
Pivotal
combined intravenous– endovascular approach in patients with stroke and
G, Bluhmki
E, Hoxter
G, Investigators.
Mahagne MH, The
Hennerici
M. IntraveStroke
Trial: safetywith
and effectiveness
a new
generation of
mechanical
confirmed arterial occlusion (RECANALISE study): a prospective cohort
nous
thrombolysis
recombinant of
tissue
plasminogen
activator
for
devices
for clot removal
in intracranial
large vesselAcute
occlusive
study. Lancet Neurol. 2009;8:802– 809.
acute
hemispheric
stroke. The
European Cooperative
Strokedisease.
Study
Stroke. 2009;40:2761–2768.
18. Molina CA, Alexandrov AV, Demchuk AM, Saqqur M, Uchino K,
(ECASS).
JAMA. 1995;274:1017–1025.
IMS II Trial
Investigators.
The Interventional
of Stroke
Alvarez-Sabin J. Improving the predictive accuracy of recanalization on
15.8. Wahlgren
N, Ahmed
N, Davalos
A, Ford GA, Management
Grond M, Hacke
W,
(IMS) II study.
Stroke.
stroke outcome in patients treated with tissue plasminogen activator.
Hennerici
MG, Kaste
M,2007;38:2127–2135.
Kuelkens S, Larrue V, Lees KR, tPA
Roine
RO,
静脈内‐動脈内ブリッジング療法は静脈内
投与による治療に反応しない患者の再開通および良好な転帰の可能性を増加させる
11
9. Soinne
Fields L,
JD,Toni
Lindsay
K, Liu KC,
Nesbit GM, Lutsep
HL. Mechanical
Stroke. 2004;35:151–156.
D, Vanhooren
G. Thrombolysis
with alteplase
for acute
thrombectomy
the Safe
treatment
of acute ischemic
stroke. Expert
Rev
19. Cloft HJ, Rabinstein A, Lanzino G, Kallmes DF. Intra-arterial stroke
ischaemic
strokefor
in the
Implementation
of Thrombolysis
in StrokeCardiovasc STudy
Ther. 8:581–592.
therapy: an assessment of demand and available work force. AJNR Am J
MOnitoring
(SITS-MOST): an observational study. Lancet. 2007;
10. 369:275–282.
Shaltoni HM, Albright KC, Gonzales NR, Weir RU, Khaja AM, Sugg
Neuroradiol. 2009;30:453– 458.
RM,Dutch
Campbell
MS III,
Cacayorin
ED,ofGrotta
JC,aspirin
Noser and
EA.atenolol
Is intra-ar20. Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS,
16. The
TIA trial:
protective
effects
low-dose
in
terial thrombolysis
after attacks
full-dose
intravenous recombinant
tissue
Lutsep HL, Rymer MM, Higashida RT, Starkman S, Gobin YP, Frei D,
patients
with transientsafe
ischemic
or nondisabling
stroke. The Dutch
plasminogen
activator
for1988;19:512–517.
acute ischemic stroke? Stroke. 2007;38:80 – 84.
Grobelny T, Hellinger F, Huddle D, Kidwell C, Koroshetz W, Marks M,
TIA
study group.
Stroke.
11. Mazighi
Khatri P,M,Hill
MD, JM,
Palesch
YY, Spilker
J, Jauch
EC, Carrozzella
JA,
Nesbit G, Silverman IE. Mechanical thrombectomy for acute ischemic
17.
Serfaty
Labreuche
J, Laissy
JP, Meseguer
E, Lavallee
Demchuk
MartinT,R,Guidoux
MauldinC,P,Lapergue
Dillon C,B,Ryckborst
Janis
stroke: final results of the Multi MERCI trial. Stroke. 2008;39:
PC,
CabrejoAM,
L, Slaoui
Klein IF, KJ,
Olivot
JM,S,
TomsickH,TA,
Broderick
JP.P,Methodology
of the
Man1205–1212.
Abboud
Simon
O, Niclot
Nifle C, Touboul
PJ, Interventional
Raphaeli G, Gohin
agement
III trial.
Int J Stroke. of
2008;3:130
–137.
21. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a sysC,
Claeys of
ES,Stroke
Amarenco
P. Comparison
intravenous
alteplase with a
12. combined
Demchukintravenous–
AM, Burgin endovascular
WS, Christouapproach
I, FelberginRA,
Barber
PA,
Hill MD,
tematic analysis comparing intra-arterial and intravenous thrombolysis.
patients
with
stroke
and
Alexandrov
AV. occlusion
Thrombolysis
In Brain Ischemia
(TIBI) transcranial
Stroke. 2006;37:922–928.
confirmed
arterial
(RECANALISE
study): a prospective
cohort
Doppler
flowNeurol.
grades 2009;8:802–
predict clinical
22. Schonewille WJ, Wijman CA, Michel P, Rueckert CM, Weimar C, Mattle
study.
Lancet
809.severity, early recovery, and mortality inCA,
patients
treated with
tissueSaqqur
plasminogen
activator.
HP, Engelter ST, Tanne D, Muir KW, Molina CA, Thijs V, Audebert H,
18. Molina
Alexandrov
AV, intravenous
Demchuk AM,
M, Uchino
K,
Stroke. 2001;32:89
–93.
Pfefferkorn T, Szabo K, Lindsberg PJ, de Freitas G, Kappelle LJ, Algra
Alvarez-Sabin
J. Improving
the predictive accuracy of recanalization on
13. stroke
Chesebro
JH, Knatterud
G, Roberts
Borer
J, Cohen
LS, Dalenactivator.
J, Dodge
A. Treatment and outcomes of acute basilar artery occlusion in the Basilar
outcome
in patients
treated R,
with
tissue
plasminogen
HT, Francis
CK, Hillis D, Ludbrook P. Thrombolysis In Myocardial
Artery International Cooperation Study (BASICS): a prospective registry
Stroke.
2004;35:151–156.
Infarction
(TIMI) trial,A,Phase
I: a comparison
intravenousstroke
tissue
study. Lancet Neurol. 2009;8:724 –730.
19. Cloft
HJ, Rabinstein
Lanzino
G, Kallmesbetween
DF. Intra-arterial
therapy: an assessment of demand and available work force. AJNR Am J
Neuroradiol. 2009;30:453– 458.
20. Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS,
Lutsep HL, Rymer MM, Higashida RT, Starkman S, Gobin YP, Frei D,
Grobelny T, Hellinger F, Huddle D, Kidwell C, Koroshetz W, Marks M,
Nesbit G, Silverman IE. Mechanical thrombectomy for acute ischemic
stroke: final results of the Multi MERCI trial. Stroke. 2008;39:
1205–1212.
21. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis.
Stroke. 2006;37:922–928.
22. Schonewille WJ, Wijman CA, Michel P, Rueckert CM, Weimar C, Mattle
HP, Engelter ST, Tanne D, Muir KW, Molina CA, Thijs V, Audebert H,
Pfefferkorn T, Szabo K, Lindsberg PJ, de Freitas G, Kappelle LJ, Algra
A. Treatment and outcomes of acute basilar artery occlusion in the Basilar
Artery International Cooperation Study (BASICS): a prospective registry
study. Lancet Neurol. 2009;8:724 –730.
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