NEJMoa 1415061

new england
The
journal of medicine
established in 1812 june 11, 2015 vol. 372 no. 24
Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone

in Stroke
Jeffrey L. Saver, M.D., Mayank Goyal, M.D., Alain Bonafe, M.D., Hans-Christoph Diener, M.D., Ph.D., Elad I. Levy, M.D.,
Vitor M. Pereira, M.D., Gregory W. Albers, M.D., Christophe Cognard, M.D., David J. Cohen, M.D.,
Werner Hacke, M.D., Ph.D., Olav Jansen, M.D., Ph.D., Tudor G. Jovin, M.D., Heinrich P. Mattle, M.D.,
Raul G. Nogueira, M.D., Adnan H. Siddiqui, M.D., Ph.D., Dileep R. Yavagal, M.D., Blaise W. Baxter, M.D.,
Thomas G. Devlin, M.D., Ph.D., Demetrius K. Lopes, M.D., Vivek K. Reddy, M.D., Richard du Mesnil de Rochemont, M.D.,
Oliver C. Singer, M.D., and Reza Jahan, M.D., for the SWIFT PRIME Investigators*
A BS T R AC T
BACKGROUND
Among patients with acute ischemic stroke due to occlusions in the proximal ante- The authors’ affiliations are listed in the
rior intracranial circulation, less than 40% regain functional independence when Appendix. Address reprint requests to
Dr. Saver at the UCLA Stroke Center, 710
treated with intravenous tissue plasminogen activator (t-PA) alone. Thrombectomy Westwood Plaza, Los Angeles, CA 90095,
with the use of a stent retriever, in addition to intravenous t-PA, increases reperfu- or at jsaver@mednet.ucla.edu.
sion rates and may improve long-term functional outcome.
Drs. Saver and Goyal contributed equally
METHODS to this article.
We randomly assigned eligible patients with stroke who were receiving or had re- *A complete list of investigators in the
ceived intravenous t-PA to continue with t-PA alone (control group) or to undergo Solitaire with the Intention for Throm-
endovascular thrombectomy with the use of a stent retriever within 6 hours after bectomy as Primary Endovascular Treat-
ment (SWIFT PRIME) trial is provided in
symptom onset (intervention group). Patients had confirmed occlusions in the proxi- the Supplementary Appendix, available at
mal anterior intracranial circulation and an absence of large ischemic-core lesions. NEJM.org.
The primary outcome was the severity of global disability at 90 days, as assessed by
This article was published on April 17, 2015,
means of the modified Rankin scale (with scores ranging from 0 [no symptoms] to at NEJM.org.
6 [death]).
N Engl J Med 2015;372:2285-95.
RESULTS DOI: 10.1056/NEJMoa1415061
The study was stopped early because of efficacy. At 39 centers, 196 patients under- Copyright © 2015 Massachusetts Medical Society.
went randomization (98 patients in each group). In the intervention group, the
median time from qualifying imaging to groin puncture was 57 minutes, and the
rate of substantial reperfusion at the end of the procedure was 88%. Thrombectomy
with the stent retriever plus intravenous t-PA reduced disability at 90 days over the
entire range of scores on the modified Rankin scale (P<0.001). The rate of func-
tional independence (modified Rankin scale score, 0 to 2) was higher in the inter-
vention group than in the control group (60% vs. 35%, P<0.001). There were no
significant between-group differences in 90-day mortality (9% vs. 12%, P = 0.50) or
symptomatic intracranial hemorrhage (0% vs. 3%, P = 0.12).
CONCLUSIONS
In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in
the proximal anterior intracranial circulation, thrombectomy with a stent retriever
within 6 hours after onset improved functional outcomes at 90 days. (Funded by
Covidien; SWIFT PRIME ClinicalTrials.gov number, NCT01657461.)
n engl j med 372;24 nejm.org june 11, 2015 2285

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The n e w e ng l a n d j o u r na l of m e dic i n e
I
ntravenous tissue plasminogen acti- ME THODS
vator (t-PA) administered within 4.5 hours
after the onset of acute ischemic stroke im- TRIAL DESIGN
proves outcomes.1-3 However, intravenous t-PA has In this international, multicenter, prospective,
multiple constraints, including unresponsiveness randomized, open clinical trial, we compared in-
of large thrombi to rapid enzymatic digestion, a travenous t-PA followed by neurovascular throm-
narrow time window for administration, and the bectomy with the use of a stent retriever with
risk of cerebral and systemic hemorrhage. Among intravenous t-PA alone in patients with acute is
patients with occlusions of the intracranial inter- chemic stroke. All the patients had confirmed oc-
nal carotid artery or the first segment of the clusion of the intracranial internal carotid artery,
middle cerebral artery (or both), intravenous t-PA the first segment of the middle cerebral artery, or
results in early reperfusion in only 13 to 50%.4-7 both on vessel imaging and an absence of large
Neurovascular thrombectomy is a reperfusion ischemic-core lesions. Patients were randomly
strategy that is distinct from pharmacologic fibri- assigned in a 1:1 ratio to one of two treatment
nolysis. Endovascular mechanical treatments can groups: intravenous t-PA plus stent retriever (in-
remove large, proximal clots rapidly and result in tervention group) or intravenous t-PA alone (con-
higher rates of reperfusion than intravenous t-PA trol group). Using a minimization algorithm,
alone. Three initial trials of endovascular thera- we balanced the numbers of patients in the two
pies did not show a benefit for thrombectomy treatment groups with respect to four factors:
over intravenous t-PA or supportive medical care, investigational site, baseline severity according
but they were limited by the use of intraarterial to the National Institutes of Health Stroke Scale
delivery of t-PA or the use of early-generation de- (NIHSS) score (≤17 vs. >17, on a scale of 0 to 42,
vices with modest reperfusion efficacy (or both), with higher scores indicating greater severity), age
the failure of two trials to use vessel imaging to (<70 years vs. ≥70 years), and occlusion location
confirm the presence of an appropriate target oc- (middle cerebral artery vs. internal carotid artery).
clusion, and the slow initiation of endovascular Details of the study design have been pub-
intervention.8-10 lished previously.19 The study was conducted and
The Solitaire revascularization device (Covidien) reported with fidelity to the study protocol, avail-
is a self-expanding stent used to retrieve thrombi able with the full text of this article at NEJM.org.
and restore blood flow. In multicenter registries (An overview of the study procedure is provided
and one randomized trial, this stent retriever, in Fig. S1 in the Supplementary Appendix, avail-
as compared with early-generation mechanical able at NEJM.org.)
thrombectomy devices, was associated with fast- The trial was approved by the institutional
er and more frequent reperfusion, reduced intra- review board at each site. Enrolled patients pro-
cranial hemorrhage, and improved disability vided written informed consent, or at select sites,
outcome.11-15 there was an exception from explicit informed
We performed the Solitaire with the Intention consent in emergency circumstances.
for Thrombectomy as Primary Endovascular Treat- The trial was funded by Covidien and designed
ment (SWIFT PRIME) trial to establish the effi- and led by a steering committee that included
cacy and safety of rapid neurovascular throm- academic investigators and representatives of the
bectomy with the stent retriever in conjunction sponsor. The site investigators gathered the data,
with intravenous t-PA versus intravenous t-PA alone with monitoring and database maintenance per-
in patients with acute ischemic stroke. This trial formed by the sponsor. The first and subsequent
was among several contemporaneous trials drafts of the manuscript were written by the
launched worldwide to test new-generation strat- first and second authors, incorporating input
egies for mechanical thrombectomy.16-18 Our from all the authors. The academic authors had
trial was conducted in multiple countries and unrestricted access to the data, performed the
health systems as a registration trial capable of data analysis with the primary and the indepen-
supporting expansion of regulatory labeling. We dent study statisticians, and attest to the integ-
used a uniform device procedure in the interven- rity of the trial and the completeness and accu-
tion group and tested intracranial neurovascular racy of the reported data. The trial was monitored
thrombectomy alone rather than in combination by an independent data and safety monitoring
with cervical stenting. board.
2286 n engl j med 372;24 nejm.org june 11, 2015
Stent Retriever after Intr avenous t -PA vs. t -PA Alone
PATIENTS AND PARTICIPATING CENTERS procedure performance. The study target for the
The study was performed at 39 centers in the time from qualifying imaging to groin puncture
United States and Europe. All study centers were was within 70 minutes.
required to have performed at least 40 mechani-
cal-thrombectomy procedures, including at least OUTCOME MEASURES
20 procedures with the Solitaire stent retriever, The primary study-outcome measure was disabil-
annually. Entry criteria selected patients who had ity at 90 days, as assessed by means of the modi-
acute ischemic stroke with moderate-to-severe fied Rankin scale, a global measure of disability
neurologic deficits; had imaging-confirmed oc- on a seven-level scale, with scores ranging from
clusion of the intracranial internal carotid artery, 0 (no symptoms) to 6 (death) (Fig. 1). (Details on
the first segment of the middle cerebral artery, or the use of this scale are provided in the Supple-
both; met the imaging eligibility requirements; mentary Appendix.)
were receiving or had received intravenous t-PA; Secondary clinical efficacy outcomes were the
and were able to undergo initiation of endovas- rate of death at 90 days, the rate of functional
cular treatment within 6 hours after the time independence (modified Rankin scale score, ≤2)
that they were last known to be well before the at 90 days, and the change in the NIHSS score
onset of acute stroke symptoms. Qualifying im- at 27 hours after randomization. The technical
aging had to be performed at a study hospital; im- efficacy outcomes regarding revascularization were
aging was repeated for patients who were trans- substantial reperfusion, as assessed by means of
ferred from outside hospitals. Detailed study catheter angiography in the intervention group
inclusion and exclusion criteria are provided in and defined as a modified Thrombolysis in Ce-
Table S1 in the Supplementary Appendix.
To identify patients with salvageable tissue, at
Score on Modified Rankin Scale
trial launch the entry criteria regarding imaging
No symptoms Death
selection required patients to have a target-mis-
0 1 2 3 4 5 or 6
match penumbral profile, with a small core of
tissue that was likely to be irreversibly injured
and a large region of hypoperfused tissue that Stent Retriever +
was likely to be salvageable. Penumbral imaging Intravenous t-PA 17 26 17 12 15 12
(N=98)
analysis was performed with the use of RAPID
(iSchemaView), an operator-independent image-
postprocessing system.20 After the enrollment of
Intravenous t-PA
the first 71 patients, these criteria were revised (N=93)
9 11 16 17 22 26
to use a small-to-moderate core-infarct strategy

(Table S1 in the Supplementary Appendix) to ac-
commodate study sites with limited perfusion- Patients (%)
imaging capability and to ensure accelerated treat-
ment delivery. Study sites with advanced imaging Figure 1. Functional Outcomes at 90 Days, According to the Score
on the Modified Rankin Scale.
capability were still encouraged to obtain pen-
Shown are the 90-day scores on the modified Rankin scale for the patients
umbral imaging and to exclude patients who did in the two treatment groups. Scores range from 0 to 6, with 0 indicating no
not meet the target-mismatch profile. symptoms, 1 no clinically significant disability (able to carry out all usual
activities, despite some symptoms), 2 slight disability (able to look after
INTERVENTION own affairs without assistance but unable to carry out all previous activi-
In the intervention group, neurovascular throm- ties), 3 moderate disability (requires some help but able to walk unassist-
ed), 4 moderately severe disability (unable to attend to bodily needs with-
bectomy was performed with the use of the Soli- out assistance and unable to walk unassisted), 5 severe disability (requires
taire FR (Flow Restoration) or Solitaire 2 device. constant nursing care and attention, bedridden, and incontinent), and
Concomitant stenting of the cervical internal ca- 6 death. Persons with a score of 0, 1, or 2 are considered to be independent
rotid artery was not permitted, although angioplas- in daily function. Neurovascular thrombectomy with the use of a stent re-
ty could be performed to permit intracranial access. triever was associated with a significant shift in the distribution of scores
toward lesser disability (P<0.001 by the Cochran–Mantel–Haenszel test),
A studywide continuous quality-improvement including an absolute increase of 25 percentage points in the proportion
program emphasized the speed and quality of the of patients who were functionally independent at 90 days (P<0.001). The
neurointerventional workflow, including rapid pa- term t-PA denotes tissue plasminogen activator.
tient transfer to the neuroangiography suite and

rebral Infarction score of 2b (50 to 99% reperfu- CLINICAL AND RADIOLOGIC ASSESSMENT
sion) or 3 (complete reperfusion)21; and successful Clinical assessments were performed at baseline,
reperfusion at 27 hours in the two study groups, 27 hours after randomization, 7 to 10 days (or at
which was defined as reperfusion of 90% or discharge if earlier), 30 days, and 90 days. Clini-
more of the initial perfusion-lesion volume, as cal evaluations included the score on the modi-
assessed by means of perfusion imaging (com- fied Rankin scale for assessing global disability
puted tomography [CT] or magnetic resonance and the NIHSS score for assessing neurologic
imaging [MRI]) at 27 hours after randomiza- deficit. Entry and outcome neurovascular images
tion. Prespecified safety outcomes were all seri- were assessed in a blinded manner by staff at the
ous adverse events through study completion and core imaging laboratories (iSchemaView for pen-
symptomatic intracranial hemorrhage at 27 hours umbral and volumetric imaging and Synarc for
after randomization. parenchymal and angiographic imaging).
Table 1. Demographic and Clinical Characteristics of the Patients.*
Intravenous Stent Retriever plus

t-PA Alone Intravenous t-PA
Characteristic (N = 98) (N = 98)
Age — yr 66.3±11.3 65.0±12.5
Male sex — no./total no. (%) 45/96 (47) 54/98 (55)
Race — no./total no. (%)†
White 83/92 (90) 79/90 (88)
Black 8/92 (9) 10/90 (11)
Asian or other 1/92 (1) 1/90 (1)
Hispanic ethnic group — no. (%)† 7/92 (8) 8/90 (9)
NIHSS score‡
Median 17 17
Interquartile range 13–19 13–20
Prestroke score of 0 or 1 on modified Rankin scale — no./total 93/94 (99) 96/98 (98)
no. (%)§
Medical history — no./total no. (%)
Hypertension 56/97 (58) 66/98 (67)
Diabetes mellitus 15/97 (15) 12/98 (12)
Current or past tobacco use 39/93 (42) 41/96 (43)
Atrial fibrillation 38/97 (39) 35/98 (36)
Myocardial infarction 11/97 (11) 8/98 (8)
Serum glucose — mg/dl¶ 131±47 131±46
Administration of intravenous t-PA at outside 35/94 (37) 31/98 (32)
hospital — no./total no. (%)
Interval from symptom onset to start of intravenous t-PA — min
Median 117 110.5
Parenchymal imaging variable
ASPECTS value‖
Median 9 9
Penumbral imaging performed — no./total no. (%) 75/97 (77) 83/98 (85)
Target-mismatch profile — no./total no. (%)** 64/75 (85) 69/83 (83)
Table 1 (Continued.)

Characteristic (N = 98) (N = 98)
Site of intracranial-artery occlusion — no./total no. (%)

Internal carotid artery 15/94 (16) 17/93 (18)
Middle cerebral artery
First segment 72/94 (77) 62/93 (67)
Second segment†† 6/94 (6) 13/93 (14)
Process time — min
Stroke onset to randomization
Median 188 190.5
Stroke onset to groin puncture
Median NA 224
Interquartile range NA 165–275
Stroke onset to first deployment of stent
retriever
Median NA 252
Arrival in emergency department to groin
puncture
Median NA 90
Qualifying image to groin puncture
Median NA 57
* Plus–minus values are means ±SD. There were no significant differences between the two groups. One patient in the
group that received intravenous tissue plasminogen activator (t-PA) alone requested the deletion of all data. Three
additional patients in the group that received intravenous t-PA alone (1 patient who died and 2 who withdrew) are
missing some baseline data owing to early study exit, including data on the prestroke modified Rankin Scale score,
the hospital site of intravenous t-PA administration, and site of intracranial-artery occlusion for all 3 patients, and
data on sex, race, and ethnic group for 1. Data on race and ethnic group were missing for all 13 patients in France
owing to national regulations. Data regarding the location of the arterial occlusion were missing for 7 patients be-
cause the core laboratory considered that imaging could not be assessed with complete reliability. Two patients were
deemed by the core laboratory to not have occlusions in the internal carotid artery or the first or second segment of
the middle cerebral artery. A total of 37 patients did not have baseline penumbral imaging performed, after a protocol
amendment making penumbral imaging optional. Data regarding additional baseline characteristics are shown in
Table S4 in the Supplementary Appendix. NA denotes not applicable.
† Race and ethnic group were self-reported.
‡ Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating
more severe neurologic deficit.
§ Scores on the modified Rankin scale for the assessment of global disability range from 0 (no symptoms) to 6 (death).
¶ To convert the values for glucose to millimoles per liter, multiply by 0.05551.
‖ The Alberta Stroke Program Early CT Score (ASPECTS) ranges from 0 to 10, with higher scores indicating a smaller
infarct core.
** The target-mismatch profile was defined as meeting the following criteria as assessed on CT perfusion or diffusion
imaging and perfusion MRI: the core infarct lesion measured 50 ml or less, the volume of tissue with a time to maxi-
mum delay of more than 10 seconds was 100 ml or less, and the mismatch volume was at least 15 ml and the mis-
match ratio was more than 1.8:1.0.
†† These occlusions were classified as first-segment occlusions by the treating site at the time of study entry but as sec-
ond-segment occlusions by the core imaging laboratory.

STATISTICAL ANALYSIS test), so pooled study results are presented. All

For the primary outcome, we analyzed the score P values are two-sided.
on the modified Rankin scale at 90 days using
simultaneous success criteria of the overall dis- R E SULT S
tribution of the score (shift in disability levels)
and the proportion of patients who were function- CHARACTERISTICS OF THE PATIENTS
ally independent. Both criteria needed to be met in From December 2012 through November 2014,
order for the study to be declared positive. The 196 patients underwent randomization (98 in
statistical hypothesis on the scale shift was that each group) at 39 centers in the United States and
the distribution over the entire range of scores Europe. Reasons for exclusion are listed in Table
(except for scores of 5 or 6, which were collapsed S3 in the Supplementary Appendix.
into a single group) among patients in the inter- The demographic and clinical characteristics
vention group would be more favorable than the of the two treatment groups at baseline were
distribution in the control group, as analyzed by well balanced (Table 1, and Table S4 in the
means of the Cochran–Mantel–Haenszel test. Supplementary Appendix). Figure S2 in the Sup-
A simultaneous requirement for success was plementary Appendix shows the enrollment and
that the difference in the proportion of patients follow-up of patients in the trial.
with a score of 0 to 2 nominally meet a pre-
specified minimum, which varied according to INTERVENTION
the final sample size at trial discontinuation or In the intervention group, the time from symp-
completion, with a larger benefit required with tom onset to groin puncture was 224 minutes
a smaller sample size (Table S2 in the Supple- (interquartile range, 165 to 275), the time from
mentary Appendix). Missing final scores on the the start of intravenous t-PA to groin puncture
modified Rankin scale were handled with the was 77 minutes (interquartile range, 50 to 142),
use of the last-observation-carried-forward ap- and the time from study-qualifying brain imag-
proach when a score was available from the 30- ing to groin puncture was 57 minutes (interquar-
day visit or the visit at 7 to 10 days. Power and tile range, 40 to 80). In the intervention group,
sample size were determined with the use of the the stent retriever was deployed in 87 patients
dual success criteria, incorporating a group se- (89%); the reasons for nondeployment are listed
quential-analysis plan with five interim analyses in Table S5 in the Supplementary Appendix. Among
for efficacy, futility, and safety. (Details are pro- these 87 patients, the median time from groin
vided in Table S2 in the Supplementary Appen- puncture to first deployment of the stent retriev-
dix and in the full statistical analysis plan in the er was 24 minutes (interquartile range, 18 to 33).
protocol.) General anesthesia was used in 36 patients (37%)
After the preliminary results of the Multi- in the intervention group.
center Randomized Clinical Trial of Endovascu-
lar Treatment for Acute Ischemic Stroke in the PRIMARY OUTCOME
Netherlands (MR CLEAN) and the Endovascular Treatment with thrombectomy with the use of
Treatment for Small Core and Anterior Circula- the stent retriever met both of the simultaneous
tion Proximal Occlusion with Emphasis on Min- success criteria. Thrombectomy treatment was
imizing CT to Recanalization Times (ESCAPE) associated with a favorable shift in the distribu-
trial were reported,16,18 our data and safety moni- tion of global disability scores on the modified
toring board recommended holding enrollment, Rankin scale at 90 days (P<0.001 by the Cochran–
and the first interim efficacy analysis was per- Mantel–Haenszel test, which was lower than the
formed slightly early (including 196 rather than P value of 0.01 that was specified for early stop-
200 patients). In February 2015, the study was ping; number needed to treat for one additional
halted when the interim efficacy analysis showed patient to have a less-disabled outcome, 2.6). The
that the prespecified stopping-criteria boundary shift toward better outcomes was consistent in
for efficacy had been crossed. A test to determine direction across all the score levels of the modi-
whether the data across clinical sites could be fied Rankin scale (Fig. 1). The proportion of pa-
pooled showed no evidence of heterogeneity of tients who were functionally independent (modi-
treatment effect (P = 0.73 by the Breslow–Day fied Rankin scale score, ≤2) at 90 days was
higher in the intervention group than in the con- Tables S10 and S13 in the Supplementary Appen-
trol group, with an absolute difference of 25 per- dix. The proportion of outcomes indicating func-
centage points, which exceeded the 12-percent- tional independence at 90 days was significantly
age-point boundary that was prespecified for higher in the intervention group than in the con-
early stopping. Results remained significant in trol group, with an absolute difference of 25 per-
sensitivity analyses that used multiple imputa- centage points (95% confidence interval [CI], 11 to
tion and worst-case and best-case scenarios to 38) and a risk ratio of 1.70 (95% CI, 1.23 to 2.33;
account for missing data (Table S6 in the Supple- P<0.001; number needed to treat for one addi-
mentary Appendix) and in analyses that were ad- tional patient to be functionally independent,
justed for imbalances in baseline prognostic fea- 4.0). Mortality at 90 days did not differ signifi-
tures (Table S7 and Fig. S3 in the Supplementary cantly between the intervention group and the
Appendix). control group (9% and 12%, respectively; P = 0.50).
In the intervention group, substantial reper-
SECONDARY OUTCOMES fusion (50 to 99%) or complete reperfusion (100%)
Prespecified secondary clinical efficacy outcomes at the end of the procedure occurred in 73 of the
and technical efficacy outcomes regarding revas- 83 patients (88%) who underwent placement of
cularization are shown in Table 2; additional pre- the stent retriever (Table S9 in the Supplementary
specified and post hoc outcomes are shown in Appendix). A total of 4 additional patients who
Table 2. Primary and Secondary Outcomes.*

t-PA Alone Intravenous t-PA Risk Ratio
Outcome (N = 98) (N = 98) (95% CI) P Value
Primary outcome: score on modified Rankin <0.001

scale at 90 days†
No. of patients with data 93 98
Median score 3 2
Secondary outcomes
Clinical efficacy outcome
Functional independence at 90 days 33/93 (35) 59/98 (60) 1.70 (1.23–2.33) <0.001
— no./total no. (%)‡
Change in NIHSS score at 27 hr
No. of patients with data 92 97
Mean change −3.9±6.2 −8.5±7.1 <0.001
Death at 90 days — no./total no. (%)§ 12/97 (12) 9/98 (9) 0.74 (0.33–1.68) 0.50
Revascularization outcome¶
Substantial reperfusion immediately NA 73/83 (88) NA NA
after thrombectomy — no./
total no. (%)
Successful reperfusion at 27 hr — 21/52 (40) 53/64 (83) 2.05 (1.45–2.91) <0.001
no./total no. (%)
* Plus–minus values are means ±SD. CI denotes confidence interval, and NA not applicable.
† Shown are the results of the prespecified Cochran–Mantel–Haenszel test for the shift in disability score. Similar results
were found in the analysis of the common odds ratio (odds ratio, 2.63; 95% CI, 1.57 to 4.40; P<0.001).
‡ Functional independence was defined as a score of 0, 1, or 2 on the modified Rankin scale.
§ One patient in the group that received intravenous t-PA alone requested the deletion of all data, including vital status.
¶ Substantial reperfusion was defined as reperfusion of at least 50% and a modified Thrombolysis in Cerebral Infarction
score of 2b (50 to 99% reperfusion) or 3 (complete reperfusion). Successful reperfusion was defined as reperfusion of
at least 90%, as assessed with the use of perfusion CT or MRI. Data on successful reperfusion were not obtained for all
the patients after the adoption of the protocol amendment making penumbral imaging optional.

underwent the intervention did not have a final was detected in any of the eight prespecified sub-
angiogram that could be assessed. Successful groups (Fig. 2, and Fig. S4 in the Supplementary
reperfusion (≥90%) at 27 hours, assessed by means Appendix). The benefit of thrombectomy with the
of perfusion CT or MRI, was more frequent in the stent retriever plus intravenous t-PA over intrave-
intervention group than in the control group (53 nous t-PA alone was also observed in the pre-
of 64 patients [83%] vs. 21 of 52 [40%], P<0.001). specified subgroup of patients who received in-
travenous t-PA within 3 hours after symptom
SAFETY onset (P<0.001) (Table S8 in the Supplementary
The rates of serious adverse events (36% in the Appendix).
intervention group and 31% in the control group,
P = 0.54) and symptomatic intracranial hemor- DISCUSSION
rhage (0% and 3%, respectively; P = 0.12) did not
differ significantly between the treatment groups Our study showed that in patients with acute
(Table 3, and Table S11 in the Supplementary Ap- ischemic stroke with confirmed large-vessel oc-
pendix). There was no significant between-group clusions of the anterior circulation who were
difference in the rate of all intracranial hemor- treated with intravenous t-PA, treatment with the
rhage subtypes that were assessed radiologically, stent retriever within 6 hours after symptom on-
but there were numerically more subarachnoid set improved functional outcomes at 90 days. For
hemorrhages in the intervention group than in every 2.6 patients who were treated, 1 additional
the control group (four patients and one patient, patient had an improved disability outcome; for
respectively; P = 0.37). No serious adverse events every 4.0 patients who were treated, 1 additional
and seven nonserious adverse events were adjudi- patient was functionally independent at 90-day
cated to be device-related (Table S12 in the Sup- follow-up.
plementary Appendix). These findings confirm and extend those of
recent trials.16-18 Our trial emphasized speedy en-
SUBGROUP ANALYSES dovascular therapy in patients selected by means
Within the constraints of the study sample size, of imaging, similar to the protocol used in the
no evidence of heterogeneity of treatment effect ESCAPE trial,18 and achieved onset-to-reperfusion
Table 3. Safety Outcomes.*

t-PA Alone Intravenous t-PA Risk Ratio
Outcome (N = 97) (N = 98) (95% CI) P Value
no. of patients (%)

Primary safety outcomes
Any serious adverse event at 90 days† 30 (31) 35 (36) 1.15 (0.78–1.72) 0.54
Symptomatic intracranial hemorrhage at 27 hr 3 (3) 0 0.00 (NA) 0.12
Additional safety outcomes at 27 hr
Parenchymal hematoma 7 (7) 5 (5) 0.71 (0.23–2.15) 0.57
Type 1 3 (3) 4 (4) 1.32 (0.30–5.74) 1.00
Type 2 4 (4) 1 (1) 0.25 (0.03–2.17) 0.21
Subarachnoid hemorrhage 1 (1) 4 (4) 3.96 (0.45–34.79) 0.37
* NA denotes not applicable.

† A serious adverse event was an adverse event that led to death, a life-threatening illness or injury, permanent impair-
ment of a body structure or a body function, inpatient or prolonged hospitalization, medical or surgical intervention to
prevent permanent life-threatening illness or injury or permanent impairment to a body structure or a body function, or
fetal distress, fetal death or a congenital anomaly or birth defect. Serious adverse events that are classified according to
organ system are shown in Table S11 in the Supplementary Appendix. None of the serious adverse events were adjudi-
cated by the clinical-events committee to be device-related. Nonserious adverse events that were deemed to be device-
related are shown in Table S12 in the Supplementary Appendix.
Subgroup No. of Patients Relative Risk (95% CI) P Value

Sex 0.78
Male 97 1.75 (1.11–2.78)
Female 93 1.61 (1.03–2.50)
Age 0.88
≥70 yr 83 1.78 (1.03–3.09)
<70 yr 106 1.67 (1.13–2.47)
NIHSS score 0.55
≤17 110 1.49 (1.05–2.11)
>17 80 2.21 (1.17–4.19)
Occlusion location 0.87
Internal carotid artery 30 2.04 (0.67–6.21)
M1 133 1.74 (1.23–2.46)
M2 18 1.35 (0.41–4.41)
Geographic location 0.66
United States 129 1.63 (1.11–2.39)
Europe 62 1.85 (1.05–3.24)
ASPECTS 0.94
6 or 7 43 1.98 (0.73–5.33)
8–10 142 1.62 (1.17–2.24)
Site of initial administration of t-PA 0.87
Study hospital 126 1.61 (1.13–2.30)
Outside hospital 64 1.77 (0.91–3.45)
Time from onset to randomization 0.97
<189 min 96 1.62 (1.08–2.42)
≥189 min 94 1.77 (1.07–2.93)
Overall 191 1.70 (1.23–2.33)
0.3 1.0 3.0 9.0
Intravenous Stent Retriever +

Better Better
Figure 2. Analysis of Functional Independence at 90 Days in Prespecified Subgroups.

Functional independence was defined as a score on the modified Rankin scale of 0, 1, or 2. P values were based on
the Breslow–Day test for homogeneous odds ratios across subgroups. Squares indicate point estimates for treat-
ment effects, and the size of the square is proportional to the precision of the estimate. Scores on the National In-
stitutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic
deficits. The threshold of 17 was the threshold used in stratifying randomization. The Alberta Stroke Program Early
CT Score (ASPECTS) ranges from 0 to 10, with higher scores indicating a smaller infarct core; a score of 6 or 7 indi-
cates moderate infarct core, and a score of 8 or higher small infarct core. For the time from stroke onset to ran-
domization, the median value was prespecified as the cutoff point for analysis and was found to be 189 minutes.
M1 denotes first segment of the middle cerebral artery, and M2 second segment of middle cerebral artery.
times that were faster than those in MR CLEAN16 retriever deployment could take place while
and in studies of early-generation interven- t-PA was infusing.
tions.8-10 The median time from arrival in the Several aspects of the treatment and treat-
emergency department to groin puncture of ment response were distinctive in our study. The
90 minutes was faster than the 120-minute rate of substantial or complete reperfusion (88%)
target that is recommended in current multiso- among patients undergoing intracranial inter-
ciety guidelines.22 In our trial, study sites were vention was higher in this trial than in previous
provided with a prespecified efficiency target of trials. The high reperfusion rate is probably due
performing groin puncture within 70 minutes in part to the more homogeneous patient popula-
after qualifying imaging, and continuous cen- tion (more occlusions in the first segment of the
tral review encouraged rapid workflow. For middle cerebral artery and fewer intracranial or
patients with intravenous t-PA that was initiat- cervical occlusions of the internal carotid artery)
ed at study centers, groin puncture and stent- and the more homogeneous intervention (an ef-

fective stent retriever and no other device classes tomatic hemorrhage were low and did not differ
and no intraarterial fibrinolytic agent) in this significantly between the two treatment groups.
trial than in earlier trials. The frequency of func- Subarachnoid hemorrhage and intracerebral he-
tional independence in the intervention group matomas as assessed radiologically were also un-
was high in our trial (60%) and was greater than common.
that observed in MR CLEAN (33%) and similar Our study has several limitations. First, we
to that observed in the ESCAPE trial (53%) and studied a homogeneous cohort of patients treat-
the Extending the Time for Thrombolysis in ed with intravenous t-PA; additional trials are
Emergency Neurological Deficits — Intra-Arteri- needed to delineate the effects of stent-retriever
al (EXTEND IA) trial (71%).17 The high frequency therapy in other populations of patients with
of this outcome probably reflects the earlier start acute ischemic stroke, including those who are
of the intervention,23-26 the exclusion of patients ineligible for intravenous t-PA, those who pres-
with large core infarcts on the basis of imag- ent more than 6 hours after symptom onset
ing,27,28 and the greater reperfusion rate in our (including those who awaken after having had a
trial, as compared with the other trials. stroke), and those with occlusions in the second
No significant differences in treatment effect segment of the middle cerebral artery or the
were detected across all the prespecified sub- posterior circulation. Second, study conduct in-
groups, including such factors as age, sex, degree cluded a continuous quality-improvement pro-
of neurologic deficit, site of occlusion, and size gram to improve endovascular workflow effi-
of infarct core on qualifying imaging, although ciency at the participating sites. Implementation
the moderate sample size limited the power of of similar quality-improvement programs in rou-
this analysis. We also performed a prespecified tine care settings,29 as has been done on a broad
analysis comparing patients who received intra- scale for intravenous t-PA,30 would be required
venous t-PA at an outside hospital and were trans- to ensure similar stent-retriever outcomes in reg-
ferred to a study center for thrombectomy with ular practice. Finally, all the enrolling sites were
those who received both the intravenous t-PA and tertiary care centers with established stroke-inter-
the endovascular intervention at the study center. vention programs staffed by experienced neuro-
One third of the patients were treated with intra- interventionalists. These results may not be
venous t-PA at an outside hospital. These patients generalizable to clinical sites without requisite
had less favorable outcomes overall; however, neurointerventional expertise.
their relative benefit from endovascular therapy In conclusion, we found that in patients with
did not differ significantly from that observed in acute ischemic stroke due to large-vessel occlu-
patients who received intravenous t-PA at the sion who had small or moderate ischemic cores,
study site (Fig. 2, and Fig. S4 in the Supplemen- emergency neurovascular thrombectomy with the
tary Appendix). stent retriever was safe and effective in achieving
The rates of serious adverse events did not dif- reperfusion and substantially reduced the degree
fer significantly between the study groups over- of disability and increased the proportion of pa-
all or within major organ categories, and no de- tients with functional independence 3 months
vice-specific serious adverse events were observed. after stroke.
The most common nonserious device-specific
Supported by Covidien.
adverse event was transient, intraprocedural vaso- Disclosure forms provided by the authors are available with
spasm without clinical sequelae. Rates of symp- the full text of this article at NEJM.org.
APPENDIX
The authors’ affiliations are as follows: the Department of Neurology and Comprehensive Stroke Center, David Geffen School of
Medicine (J.L.S.), and the Division of Interventional Neuroradiology (R.J.), University of California, Los Angeles (UCLA), Los Angeles,
and the Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford (G.W.A.) — both in
California; the Departments of Radiology and Clinical Neurosciences, University of Calgary, Calgary, AB (M.G.), and the Division of
Neuroradiology and Division of Neurosurgery, Departments of Medical Imaging and Surgery, Toronto Western Hospital, University
Health Network, University of Toronto, Toronto (V.M.P.) — both in Canada; the Department of Neuroradiology, Hôpital Gui-de-
Chauliac, Montpellier (A.B.), and the Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Toulouse,
Toulouse (C.C.) — both in France; the Department of Neurology, University Hospital of University Duisburg–Essen, Essen (H.-C.D.),
the Department of Neurology, University of Heidelberg, Heidelberg (W.H.), the Department of Radiology and Neuroradiology, Chris-
tian–Albrechts–University Kiel, Kiel (O.J.), and the Institute of Neuroradiology (R.M.R.) and Department of Neurology (O.C.S.), Klini-
kum der Goethe–Universität, Frankfurt — all in Germany; the Department of Neurosurgery (E.I.L., A.H.S.) and Toshiba Stroke and
Vascular Research Center (A.H.S.), State University of New York at Buffalo, Buffalo; Saint Luke’s Mid America Heart Institute and
University of Missouri–Kansas City School of Medicine, Kansas City (D.J.C.); the Department of Neurology, University of Pittsburgh
Medical Center, Pittsburgh (T.G.J., V.K.R.); the Department of Neurology, Inselspital, University of Bern, Bern, Switzerland (H.P.M.);
the Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Department of Neurology, Emory University School of Medicine,
Atlanta (R.G.N.); the Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine–Jackson Memorial
Hospital, Miami (D.R.Y.); the Department of Radiology (B.W.B.) and Division of Neurology (T.G.D.), Erlanger Hospital at the Univer-
sity of Tennessee, Chattanooga; and the Department of Neurosurgery, Rush University Medical Center, Chicago (D.K.L.).
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new england

Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone

n engl j med 372;24 nejm.org june 11, 2015 2285

2286 n engl j med 372;24 nejm.org june 11, 2015

to use a small-to-moderate core-infarct strategy

n engl j med 372;24 nejm.org june 11, 2015 2287

Table 1. Demographic and Clinical Characteristics of the Patients.*

Intravenous Stent Retriever plus

2288 n engl j med 372;24 nejm.org june 11, 2015

Intravenous Stent Retriever plus

Site of intracranial-artery occlusion — no./total no. (%)

n engl j med 372;24 nejm.org june 11, 2015 2289

STATISTICAL ANALYSIS test), so pooled study results are presented. All

2290 n engl j med 372;24 nejm.org june 11, 2015

Table 2. Primary and Secondary Outcomes.*

Intravenous Stent Retriever plus

Primary outcome: score on modified Rankin <0.001

n engl j med 372;24 nejm.org june 11, 2015 2291

Table 3. Safety Outcomes.*

Intravenous Stent Retriever plus

no. of patients (%)

* NA denotes not applicable.

2292 n engl j med 372;24 nejm.org june 11, 2015

Subgroup No. of Patients Relative Risk (95% CI) P Value

Intravenous Stent Retriever +

Figure 2. Analysis of Functional Independence at 90 Days in Prespecified Subgroups.

n engl j med 372;24 nejm.org june 11, 2015 2293

2294 n engl j med 372;24 nejm.org june 11, 2015

n engl j med 372;24 nejm.org june 11, 2015 2295

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