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Effect of Intra-arterial Alteplase vs Placebo Following Successful
Thrombectomy on Functional Outcomes in Patients
With Large Vessel Occlusion Acute Ischemic Stroke
The CHOICE Randomized Clinical Trial
Arturo Renú, MD; Mónica Millán, MD; Luis San Román, MD; Jordi Blasco, MD; Joan Martí-Fàbregas, MD; MikelTerceño, MD; Sergio Amaro, MD;
Joaquín Serena, MD; Xabier Urra, MD; Carlos Laredo, PhD; Roger Barranco, MD; PolCamps-Renom, MD; Federico Zarco, MD; Laura Oleaga, MD;
Pere Cardona, MD; Carlos Castaño, MD; Juan Macho, MD; Elisa Cuadrado-Godía, MD; Elio Vivas, MD; Antonio López-Rueda, MD;
Leopoldo Guimaraens, MD; Anna Ramos-Pachón, MD; Jaume Roquer, MD; Marian Muchada, MD; Alejandro Tomasello, MD; Antonio Dávalos, MD;
Ferran Torres, MD; Ángel Chamorro, MD; for the CHOICE Investigators
IMPORTANCE It is estimated that only 27% of patients with acute ischemic stroke and large
vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are
disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to
these suboptimal clinical benefits.
OBJECTIVE To investigate whether treatment with adjunct intra-arterial alteplase after
thrombectomy improves outcomes following reperfusion.
DESIGN, SETTING, AND PARTICIPANTS Phase 2b randomized, double-blind, placebo-controlled
trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia,
Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke
treated with thrombectomy within 24 hours after stroke onset and with an expanded
Treatment in Cerebral Ischemia angiographic score of 2b50 to 3.
INTERVENTIONS Participants were randomized to receive intra-arterial alteplase (0.225
mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52).
MAIN OUTCOMES AND MEASURES The primary outcome was the difference in proportion of
patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no
symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate
of symptomatic intracranial hemorrhage and death.
RESULTS The study was terminated early for inability to maintain placebo availability and
enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic
stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the
angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57
women [47%]), and 113 (6%) were treated as randomized. The proportion of participants
with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and
40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P= .047).
The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was
0% with alteplase and 3.8% with placebo (risk difference, −3.8%; 95% CI, −13.2% to 2.5%).
Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, −7.2%;
95% CI, −19.2% to 4.8%).
CONCLUSIONS AND RELEVANCE Among patients with large vessel occlusion acute ischemic
stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial
alteplase compared with placebo resulted in a greater likelihood of excellent neurological
outcome at 90 days. However, because of study limitations, these findings should be
interpreted as preliminary and require replication.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03876119;
EudraCT Number: 2018-002195-40
JAMA. doi:10.1001/jama.2022.1645
Published online February 10, 2022.
Visual Abstract
Editorial
Supplemental content
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Ángel
Chamorro, MD, Department of
Neuroscience, Hospital Clinic
of Barcelona, 170 Villarroel,
08036 Barcelona, Spain (achamorro
@clinic.cat).
Research
JAMA | Preliminary Communication
(Reprinted) E1
© 2022 American Medical Association. All rights reserved.
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Endovascular thrombectomy is the optimal treatment
option across a wide range of patients with large ves-
sel occlusion acute ischemic stroke.
1
In these patients,
the extent of reperfusion is evaluated on digital subtraction
angiography using the modified Treatment in Cerebral Ische-
mia (mTICI) score.
2
Reperfusion is typically considered suc-
cessful if at the end of the procedure there is an antegrade
reperfusion of more than 50% to 100% of the initially
affected arterial territory, corresponding with an expanded
TICI (eTICI) score of 2b50 or greater. Although 71% of
patients achieved successful reperfusion scores in previous
randomized trials, only 27% of the patients treated were dis-
ability free at 90 days.
3
It is possible that a substantial vol-
ume of brain tissue could have been already irreversibly
injured in some patients by the time reperfusion occurred.
However, impaired reperfusion of the microcirculation
despite complete recanalization could have also contributed
to the less than desired clinical outcomes,
4
for it has been
estimated that nearly every neuron in a human brain has its
own capillary, and capillaries account for more than 90% of
the total intracerebral vascular volume.
5
Digital subtraction angiography remains the gold stan-
dard to assess reperfusion during thrombectomy,
6
but
normal cerebral angiogram findings after thrombectomy
are not necessarily indicative of an effective perfusion of
the microvascular bed.
7
Therefore, it was postulated that
thrombi persist within the microcirculation in patients with
normal or nearly normal cerebral angiograms at the end of
thrombectomy,
8
and it was hypothesized that these smaller
thrombi would be more suitable to dissolve than more proxi-
mal thrombi because the efficacy of thrombolysis is related
to the extent of clot burden.
9
The Chemical Optimization of Cerebral Embolectomy
(CHOICE) trial assessed the preliminary efficacy and safety of
adjunct intra-arterial alteplase treatment compared with pla-
cebo in patients with large vessel occlusion acute ischemic
stroke treated with thrombectomy that resulted in successful
reperfusion on digital subtraction angiography.
Methods
Trial Design
The trial was a multicenter, phase 2b, randomized, double-
blind, placebo-controlled trial performed in Catalonia, Spain.
Intra-arterial alteplase was compared with intra-arterial pla-
cebo in patients with acute ischemic stroke secondary to a
proximal large vessel occlusion treated with thrombectomy
that resulted in angiographic findings of success, defined as
an eTICI score of 2b50 or greater.
An independent data and safety monitoring board con-
ducted the study monitoring with the assistance of a clinical
research organization.
The original version of the study protocol
10
and its modi-
fications were approved by a central medical ethics commit-
tee and by the research board at each participating center.
A detailed description of the trial protocol is provided in
Supplement 1. All patients or their surrogates provided
written informed consent before the endovascular procedure
was started.
The study was conducted in adherence to Spanish regu-
lations of clinical drug trials, the Declaration of Helsinki,
11
and the good clinical practice guidelines of the International
Conference on Harmonization.
Participants and Study Sites
In this study, patients were screened at all 7 of the stroke
centers that have uninterrupted access to performance of
thrombectomy in Catalonia, Spain. Eligible patients had a
large vessel occlusion in the anterior, middle, or posterior
cerebral artery, were treated with thrombectomy within
24 hours after the point when they were last seen well, and
had a postthrombectomy eTICI score of 2b50 or greater as
judged by local investigators. Participants were aged 18 years
or older and had been able to carry out usual activities in
their daily life without support before the stroke. The race
and ethnicity of the patients was classified according to
their chosen nationality; Hispanic patients were individuals
from Mexico/South America/Central America and White
individuals were from Europe. The decision to perform
thrombectomy followed the current local treatment guide-
lines, including an Alberta Stroke Program Early CT Score
(ASPECTS) of at least 6 on noncontrast computed tomogra-
phy (NCCT) if symptoms lasted less than 4.5 hours
(ASPECTS range, 0-10, with 1 point subtracted for any evi-
dence of early ischemic change in each defined region on the
CT scan), or on CT perfusion or diffusion-weighted magnetic
resonance imaging (MRI) if symptoms lasted 4.5 hours
or longer. Other exclusion criteria to participate in the
trial were any contraindication to the use of intravenous
alteplase per local and national guidelines (except time to
therapy) and a National Institutes of Health Stroke Scale
(NIHSS) score on admission of greater than 25, (range, 0-42,
with higher values indicating more severe deficit). Complete
clinical recovery in the angiography suite during the proce-
dure was also an exclusion criterion. Nonanesthetized
patients were evaluated by a neurologist to identify possible
Key Points
Question Does the use of adjunct intra-arterial thrombolysis
following an angiographically successful thrombectomy improve
functional outcomes in patients with large vessel occlusion acute
ischemic stroke?
Findings In this randomized clinical trial that included 121
adults, treatment with intra-arterial alteplase compared with
placebo resulted in a modified Rankin Scale score of 0 or 1i
n 59.0% vs 40.4% of patients at 90 days. This difference was
statistically significant.
Meaning Among patients with large vessel occlusion acute
ischemic stroke and successful reperfusion following
thrombectomy, the use of adjunct intra-arterial alteplase
compared with placebo resulted in a greater likelihood of excellent
neurological outcome at 90 days; however, the findings should be
considered preliminary until replicated.
Research Preliminary Communication Intra-arterial Alteplase After Successful Thrombectomy and Functional Outcomes in Large Vessel Occlusion Stroke
E2 JAMA Published online February 10,2022 (Reprinted) jama.com
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full recovery. Detailed clinical and imaging criteria for inclu-
sion and exclusion and the study procedures and their tim-
ing are provided in eTable 1 and eTable 2 in Supplement 2.
Randomization
Patients were randomly assigned in the angiographysuite using
PROC PLAN in SAS software (SAS Institute Inc) with a 1:1 ratio
between active treatment with intra-arterial alteplaseand pla-
cebo, stratifying by center and use of intravenousalteplase be-
fore thrombectomy (no or yes), in blocks of 4 elements, once
the angiographic eTICI score had been obtained following stan-
dard thrombectomy.
Intervention
Endovascular treatment was carried out according to the
usual practice of each center. If intravenous alteplase was
used before the onset of thrombectomy, local investigators
were allowed to decide when to stop the intravenous infu-
sion. Patients were considered having received intravenous
alteplase if at least half of the corresponding weight-
adjusted dose was administered. Patients randomized
to intra-arterial alteplase received a dose of 0.225 mg/kg
(maximum dose, 22.5 mg) infused over 30 minutes (at trial
onset) or over 15 minutes (after approval of protocol amend-
ment number 3 on November 28, 2019). Patients random-
ized to intra-arterial placebo received a 15-minute infusion
of a lyophilized white powder containing 0.2 mol/L arginine
phosphate and 0.01% polysorbate 80, at a pH of 7.4 after
reconstitution in sterile water for injection. The active treat-
ment and the placebo solutions were limpid, transparent,
and colorless and were injected distally to the origin of the
lenticulostriate branches.
Outcome Measures
The primary efficacy outcome measure was the proportion of
patients with a score of 0 or 1 on the modified Rankin Scale at
90 days. The modified Rankin Scale is an ordered scale coded
from 0 (no symptoms at all) to 5 (severe disability) and 6
(death). A score of 1 or less indicates an excellent (disability-
free) outcome.
The secondary efficacy outcomes included the propor-
tion of patients with improved angiographic findings; a shift
analysis of the modified Rankin Scale score at day 90 in which
severe disability (score of 5) and death (score of 6) were com-
bined into a single “worst” category; the proportion of pa-
tients with a modified Rankin Scale score of 0 to 2 at day 90;
the infarct expansion ratio of final infarct to initial ischemic
tissue volumes; the proportion of patients with an infarct ex-
pansion ratio greater than 1; and the infarction volume at 24
to 48 hours after stroke onset.
The tertiary efficacy outcomes included the proportion of
patients with a Barthel Scale score of 95 to 100 at day 90; the
proportion of ischemic worsening (≥4-point increase on the
NIHSS score) within 48 hours to 72 hours of stroke onset; and
quality of life as measured with the EuroQol 5-Dimension
3-Level Self-Report Questionnaire (EQ-5D-3L) at 90 days.
Scores on the EQ-5D-3L range from −0.33 to 1, with higher
scores indicating better quality of life.
The adverse events measured included incidence of symp-
tomatic intracranial hemorrhage, defined as neurological de-
terioration (≥4-point increase on the NIHSS score) within 24
hours after treatment and evidence of intracranial hemor-
rhage on imaging studies, and death at 90 days. An indepen-
dent clinical events committee adjudicated safety outcomes
and serious adverse events.
Clinical and Radiologic Assessment
Clinical assessments were performed at baseline, at 24 hours
and 48 hours after randomization, at 5 to 7 days (or at dis-
charge if earlier), and at 90 days by certified investigators and
included modified Rankin Scale scores for assessing global
disability and NIHSS scores for assessing neurological deficit.
The primary modified Rankin Scale outcome was assessed by
local raters via a face-to-face visit using a validated struc-
tured interview.
12
Entry and outcome neurovascular images were assessed
in a blinded manner by 2 senior neuroradiologists at a central
core imaging laboratory and included admission baseline NCCT,
admission CT perfusion, 24-hour NCCT, 48-hour brain MRI or
NCCT, and pretreatment and posttreatment angiograms using
the eTICI score
13
(see details in the eAppendix in Supple-
ment 2). At 1 study site, perfusion-weighted MRI and MR spec-
troscopy were also performed at 48 hours after therapy.
Sample Size Calculation
Based on previous data,
14
it was calculated that the enroll-
ment of 100 patients per treatment group would provide a
power of at least 80% to detect a difference in the primary out-
come (modified Rankin Scale score of 0 or 1) assuming a treat-
ment response rate up to approximately 40% in the control
group and a 21% absolute benefit in the interventiongroup for
a 0.05 2-sided type I error. No study losses were accounted
for since all treated randomized patients were to be included
in the analysis.
Statistical Analysis
A detailed description of the analytic approach is provided in
the statistical analysis plan (Supplement 3). The main analy-
sis was conducted in all participants treated as randomized.
The main efficacy variable, the adjusted risk difference of the
proportions of participants with a modified Rankin Scale score
of 0 to 1 at 90 days, was estimated using a binomial regres-
sion model adjusted for the stratification variable of previous
alteplase use, with the link function set to identity.
Secondary outcomes included the shift in the modified
Rankin Scale score at day 90, estimated by means of an odds
ratio using a proportional odds logistic regression model com-
bining the highest 2 scores of 5 and 6 into a single “worst” rank,
with the proportional odds assumption assessed using a score
test, which was not statistically significant (P= .08). The ad-
justed van Elteren test was used as a sensitivity analysis (pro-
portional odds not required). The risk difference for mortal-
ity at 90 days was analyzed as described for the primary end
point, and exact 95% confidence intervals were calculated for
symptomatic intracranial hemorrhage at 24 hours due to lack
of model convergence. As predefined, all risk differences, odds
Intra-arterial Alteplase After Successful Thrombectomy and Functional Outcomes in Large Vessel Occlusion Stroke Preliminary Communication Research
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ratios, and the van Elteren test were adjusted by the stratifi-
cation variable of previous alteplase use for all analyses ex-
cept the subgroup analyses. The rest of the categorical vari-
ables were compared using the Fisher exact test and continuous
variables by means of the Mann-Whitney test. Because of the
potential for type I error due to multiple comparisons, find-
ings for analyses of secondary and tertiary end points should
be interpreted as exploratory.
Treatment effect modification was explored in prespeci-
fied subgroups of patients predicted to have a greater treat-
ment response owing to being at greater risk of poor out-
comes, possibly due to microvascular clogging, such as patients
not receiving intravenous alteplase before thrombectomy
(vs those receiving it), women (vs men),
15
patients with ad-
mission serum glucose concentrations greater than 100 mg/dL
(vs lower values),
16
patients with time from stroke onset to
groin puncture greater than 7.3hours (vs lower values).
17
Higher
study drug concentrations in the microcirculation and, thus,
a greater treatment response were predicted in patients with
an angiographic eTICI score of 2c/3 (vs an eTICI score of
2b50/2b67).
14
Subgroups were analyzed using the same bino-
mial model as for the primary outcome but without the ran-
domization stratum covariate. The subgroup-by-treatment in-
teraction significance was calculated by including that term
in an additional model.
Two post hoc sensitivity analyses were conducted for the
primary end point. First, study site was added to the primary
model as a random effect. Second, a series of models consid-
ered imbalances in baseline variables.
No missing data imputation was conducted in this study
since there were no missing data for the baseline and primary
end points, missing data rates for secondary end points were
trivial (<2%), and tertiary end points (<14%) were considered
of minor relevance.
The statistical significance of possible differences be-
tween subgroups in the treatment effect was tested with in-
teraction terms. No adjustments for multiple tests were made.
All analyses were performed using SAS version 9.4, and the
level of significance was established at P= .05 (2-sided).
Results
Patients
The inability to maintain placebo availability and a slow en-
rollment rate, both affected by the COVID-19pandemic, led to
a premature discontinuation of the trial when 60% of the cal-
culated sample size had been enrolled (n = 121 participants).
The decision to terminate the trial early was made by the steer-
ing committee and the chosen date was that of the expiration
of the placebo, without performing an interim analysis.
From December 2018 through May 2021, 1825 patients
with acute ischemic stroke were treated with thrombectomy
at the 7 study sites, including 121 patients (7%) who were
randomized in the trial, of whom 113 (6%) received their
randomized study treatment. Based on local investigator
assessment, 65 (58%) had an eTICI score of 2b50/67 and 48
(42%) had an eTICI score of 2c/3 at the time of randomiza-
tion. The flow diagram with reasons for exclusion is shown in
Figure 1. Among all thrombectomies performed at the study
centers during the study period, 802 patients (44%) with an
eTICI score of 3 were not eligible for inclusion in the study
because they were treated before the amendment of the ini-
tial angiographic criteria that restricted the inclusion to
patients with an eTICI score of 2b50. All patients had an
available evaluation at 90 days for the primary outcome.
Eight randomized patients were not included in the treated-
as-randomized population because the study treatment was
not started for various reasons, including early reocclusion of
the treated vessel (n = 4), periprocedural complications
(n = 2), and COVID-19 infection diagnosed immediately after
randomization (n = 2). The treated-as-randomized analysis
included 61 patients in the intra-arterial alteplase group and
52 in the placebo group.
Baseline Characteristics
Baseline characteristics were similar in the 2 study groups
(Table 1;eTable3inSupplement 2). The median NIHSS score
was 14 (IQR, 9-20), the median ASPECTS was 9 (IQR, 8-10), in-
travenous alteplase was administered to 69 patients(57 %), and
the median time from stroke onset to randomization was 306
(IQR, 228-609) minutes.
The median time from symptom onset to randomization
was 318 (IQR, 229-641) minutes and from symptom onset to
start of the study treatment was 328 (IQR, 240-676) minutes,
without significant differences between the groups. General
anesthesia was used in 5 patients (9.6%) in the placebo group
and in 4 patients (8.0%)in the alteplase group (Table 1; eTable 3
in Supplement 2).
Intra-arterial alteplase was administered in 30 minutes to
19 patients (31%) and placebo to 19 patients (37%). The infu-
sion was interrupted at 20 minutes because of angiographic
improvement in 1 patient in each treatment group. Under
amendment 3, the study treatment was administered in 15 min-
utes to 42 patients (69%) in the alteplase group and 33 pa-
tients (63%) in the placebo group.
Primary Efficacy Outcome
Treatment with intra-arterial alteplase was associated with a
favorable outcome (a score of 0 or 1 on the modified Rankin
Scale) at 90 days in 36 of 61 patients (59.0%) in the alteplase
group and in 21 of 52 patients (40.4%) in the placebo group
(adjusted risk difference, 18.4%; 95%CI, 0.3%-36.4%; P= .047)
(Table 2 and Figure 2).
Results of analyses of randomized patients regardless of
treatment and analyses regardless of protocol adherence
are presented in eTable 4 in Supplement 2. The findings
of the additional analyses were consistent with the results of
the primary analysis, showing a more favorable outcome
in the alteplase group.
Secondary and Tertiary Outcomes
Predefined secondary and tertiary clinical efficacy outcomes
are shown in Table 2. According to core laboratory assess-
ments, the overall proportion of participants with angio-
graphic improvement in the eTICI score was 8.5% with
Research Preliminary Communication Intra-arterial Alteplase After Successful Thrombectomy and Functional Outcomes in Large Vessel Occlusion Stroke
E4 JAMA Publishedonline February 10, 2022 (Reprinted) jama.com
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alteplase and 7.7% with placebo (risk difference, 0.6%; 95%
CI, −9.5% to 10.7%) and was 11.4% with alteplase and 9.3%
with placebo (risk difference, 1.8%; 95% CI, −11.0% to 14.5%)
after exclusion of patients with a pretreatment eTICI score of
3. There was no significant difference between treatment
with intra-arterial alteplase vs placebo in the shift in the dis-
tribution of global disability scores on the modified Rankin
Scale at 90 days (odds ratio, 1.54; 95% CI, 0.79-2.94), the
infarct expansion ratio, the proportion of patients with
infarct expansion, or the infarction volume at 48 hours after
stroke onset. Also, there was no significant difference
between treatment with intra-arterial alteplase vs placebo in
the tertiary outcomes: the proportion of patients with a
Barthel Scale score of 95 to 100 at day 90 (risk difference,
6.4%; 95% CI, −12.3% to 25.0%); the proportion with ische-
mic worsening (≥4-point increase in NIHSS score) within 48
to 72 hours of stroke onset (risk difference, −4.9%; 95% CI,
−18.0% to 8.3%); and quality of life as measured with the
EQ-5D-3L at 90 days (P= .88 and P= .38 for the visual analog
scale score and the overall score, respectively).
The treatment effects on secondary brain imaging and clini-
cal outcomes are shown in Table 2.
Subgroup and Sensitivity Analyses
Subgroup analyses are shown in the eFigure in Supple-
ment 2. There were no statistically significant interactions in
any of the tested subgroups.
The first sensitivity analysis (post hoc) for the primary
outcome using other study populations and including center
as a random effect and unadjusted models (eTable 4 in
Supplement 2) showed that treatment with intra-arterial
alteplase was associated with a favorable outcome compared
with placebo, although some of the models did not reach sta-
tistical significance. The second post hoc sensitivity analysis
Figure 1. Flow of Patients Through the CHOICE Trial
1825 Patients with acute ischemic stroke treated
with thrombectomy assessed for eligibility
1704 Excludeda
802 mTICI score of 3 prior to protocol amendment
275 mTICI score of 0, 1, or 2a
215 Contraindication to alteplase
108 Stenting requiring dual antiplatelet therapy
80 Consent unavailable
46 Modified Rankin scale score >1
37 More than 6 thrombectomy passes
27 ASPECTS <6
18 Perforation or intracranial bleeding during procedure
16 Admission NIHSS score >24
12 Established infarct in territory of occlusion
11 Stroke symptom onset >24 h prior
10 Clinically unstable
8Enrolled in another clinical trial
8Full recovery at end of thrombectomy
8Diagnostic procedure and/or distal migration of thrombus
8Severe comorbidity
7Carotid dissection
7No angiography suite available
6Technical issues
6Basilar artery occlusion
4Likely unavailable for follow-up
4More than 70 min elapsed from diagnostic imaging
to thrombectomy
20 Other reasons
121 Randomized
65 Randomized to intra-arterial alteplase
61 Received alteplase as randomized
4Did not receive alteplase
2Early reocclusion
1Procedural reasonb
1COVID-19 positive result after
randomizationc
56 Randomized to intra-arterial placebo
52 Received placebo as randomized
4Did not receive placebo
2Early reocclusion
1Procedural reasonb
1COVID-19 positive result after
randomizationc
61 Included in primary analysis 52 Included in primary analysis
59 Patients treated as randomized with
protocol adherence
2Received <50% of study treatment
(prior anticoagulation found after
randomization)
2Received <50% of study treatment
1Severe agitation
1Reocclusion
50 Patients treated as randomized with
protocol adherence
ASPECTS indicates Alberta Stroke
Program Early CT Score;
mTICI, modified Treatment in
Cerebral Ischemia; NIHSS, National
Institutes of Health Stroke Scale.
a
Patients could have more than 1
exclusion.
b
Misplacement of balloon-guided
catheter.
c
Excluded to limit exposure of the
interventionalist team.
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using a series of models considering baseline covariates that
by chance might have some unbalance (eTable 5 in Supple-
ment 2) showed similar results and conclusions.
Adverse Events
At 90 days, death (modified Rankin Scale score of 6) occurred
in 5 of 61 patients (8.2%) in the alteplase group and in 8 of 52
patients (15.4%) in the placebo group (risk difference, −7.3%;
95% CI, −19.3% to 4.6%) (Table 3).
Overall, any type of cerebral hemorrhage occurred in 19
of 61 patients (31.1%) in the alteplase group and in 18 of 52
patients (34.6%) in the placebo group (risk difference, −3.9%;
95% CI, −21.2% to 13.4%) (Table 3). Symptomatic intracranial
hemorrhage (≥4-point increase in the NIHSS score) occurred
Table 1. Baseline Characteristics of Patientsin the CHOICE Trial of Intra-arterial Alteplase
Characteristics Alteplase (n = 61) Placebo (n = 52)
Age, median (IQR), y 73 (71-76) 73 (69-67)
Race and ethnicity, No. (%)
White 59 (97) 48 (92)
Hispanic 2 (3) 3 (6)
Other
a
0 1 (2)
Sex, No. (%)
Female 28 (46) 24 (46)
Male 33 (54) 28 (54)
Medical history, No. (%)
Hypertension 39 (64) 34 (65)
Diabetes 19 (31) 11 (21)
Atrial fibrillation 10 (16) 9 (17)
Ischemic stroke or transient ischemic attack 5 (8) 4 (8)
NIHSS score at hospital arrival, median (IQR)
b
14 (8-20) 14 (10-20)
Blood pressure at hospital arrival,
median (IQR), mm Hg
Systolic 139 (121-156) 136 (113-155)
Diastolic 73 (65-83) 70 (61-78)
Glucose level at hospital arrival, median (IQR), mg/dL 134 (108-164) 119 (103-143)
Treatment with intravenous alteplase
before randomization, No. (%)
c
38 (62) 31 (60)
ASPECTS value, median (IQR)
d
9.0 (9.0-10.0) 10.0 (8.0-10.0)
Baseline modified Rankin Scale score of 1, No. (%) 9 (15) 9 (17)
Location of intracranial occlusion on angiography, No. (%)
e
Terminal internal carotid artery 7 (12) 4 (8)
Proximal, middle, or distal M1 19 (31) 20 (39)
Proximal or distal M2 33 (54) 28 (54)
Ipsilateral cervical carotid occlusion, No. (%) 6 (10) 4 (8)
Angiographic eTICI scores according to local investigators
at randomization, No. (%)
f
2b50/67: 50%-89% reperfusion 34 (56) 31 (60)
2c/3: 90%-100% reperfusion 27 (44) 21 (40)
Workflow times, median (IQR), min
Time from stroke onset to randomization 306.0 (208.0-672.0) 345.0 (237.0-609.0)
Time from stroke onset to start of study treatment 315.0 (218.0-680.0) 356.0 (260.5-635.0)
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; eTICI,
expanded Treatment in CerebralIschemia; NIHSS, National Institutes of Health
Stroke Scale; M1, main trunk of the middle cerebral artery; M2, first-order
branch of the main trunk of the middle cerebral artery.
SI conversion factor: Toconvert the values for glucose to mmol/L, multiply by
0.0555.
a
The “other” category includes Asian and Black.
b
Scores on the NIHSS range from 0 to 42, with higher scores indicating more
severe neurological deficits.
c
Intravenous alteplase was administered if indicated before randomization.
Main contraindications were stroke onset more than 4.5 hours prior and intake
of oral anticoagulants. Eleven patients received less than 50% of the
estimated weight-adjusted dose (dose range, 5-35mg ).
d
ASPECTS is an imaging measure of the extent of ischemic stroke. Scores range
from 0 to 10, with higher scores indicating a smaller infarct core. Valuesshown
are as recalculated at the central core laboratory.
e
The location of the occlusion was not available for 2 patients in the alteplase
group.
f
eTICI score ranges from 0 (0% reperfusion) to 3 (100% reperfusion).
Investigators used the modified TICI (mTICI) scale for clinical decision making
because it is easier to use; the core laboratory reanalyzed all mTICI scores and
relabeled them according to the eTICI scale. Both scales lead to similar
estimations of the degree of perfusion as used in the trial. For example, an
mTICI score of 2b to 3 corresponds to an eTICI score of 2b50 to 3.
Research Preliminary Communication Intra-arterial Alteplase After Successful Thrombectomy and Functional Outcomes in Large Vessel Occlusion Stroke
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in 0 of 61 patients (0%) in the alteplase group and in 2 of 52
patients (3.8%) in the placebo group (risk difference, −3.8%;
95% CI, −13.2% to 2.5%) (Table 3).
Serious adverse events during the 90-day follow-up pe-
riod were numerically more frequent in the alteplase group
than in the placebo group (Table 3). A complete list of adverse
events is provided in eTables 6 and 7 in Supplement 2.
Discussion
In this trial of patients with large vessel occlusion acute ische-
mic stroke and successful reperfusion following thrombec-
tomy, the use of adjunct intra-arterial alteplase resulted in a
greater likelihood of excellentneurologic al outcome at 90 days
compared with placebo. However, because of study limita-
tions, these findings should be interpreted as preliminary and
require replication.
Adjunct administration of intra-arterial alteplase at the end
of the endovascular procedure resulted in improved clinical
outcome despite only minor differences between the treat-
ment groups in angiographic scores or in other surrogate
imaging. This suggests that the improved functional out-
come may be explained by an amelioration in the microcircu-
latory reperfusion.
18
Recently, perfusion imaging studies per-
formed in patients with large vessel occlusion acute ischemic
stroke at the end of successful thrombectomies showed a high
prevalence of around 40% of areas of hypoperfusion in pa-
tients with normal angiogram findings,
19,20
highlighting the
limitations of conventional angiography to ensure the ad-
equacy of perfusion in the microcirculation. In these studies,
the identification of areas of hypoperfusion was clinically
relevant,
20
as patients with areas of hypoperfusion had a more
limited functional recovery than patients with normal perfu-
sion imaging findings at the end of thrombectomy.
Possible explanations for the findings in the current trial
include easier access of the drug and more effective throm-
bolytic activity within the microcirculation, not impeded by
the coexistence of more proximal occlusions, as would be ex-
pected to occur in patients with worse angiographic scores after
Table 2. Primary and Secondary Outcomes of the CHOICE Trialof Intra-arterial Alteplase
Outcomes Alteplase (n = 61) Placebo (n = 52) Absolute risk difference, % (95% CI) Pvalue
a
Primary outcome
Score of 0 or 1 on modified Rankin Scale at 90 d, No. (%) 36 (59.0) 21 (40.4) 18.4 (0.3 to 36.4) .047
Secondary outcomes
Improved angiographic eTICI score, No. (%) [n = 111]
b
5 (8.5) 4 (7.7) 0.6 (−9.5 to 10.7) .91
Excluding baseline eTICI scores of 3 5/44 (11.3) 4/43 (9.3) 1.8 (−11.0 to 14.5) .78
Modified Rankin Scale score at 90 d, No. (%)
c
1.54 (0.79 to 2.94)
d
.38
e
0 21 (34.4) 12 (23.1)
.18
f
1 15 (24.6) 9 (17.3)
2 5 (8.2) 12 (23.1)
3 4 (6.6) 5 (9.6)
4 8 (13.1) 6 (11.5)
5-6 8 (13.1) 8 (15.4)
Infarct expansion ratio, median (IQR) [n = 111]
g
2.0 (0.5-2.03) 4.2 (0.8-46.1) .27
h
Patients with infarct expansion, No. (%) [n = 110] 39 (63.9) 38 (74.5) −8.9 (−25.6 to 7.9) .31
Infarct volume at 48 h, median (IQR), mL [n = 110] 7.7 (3.7-29.3) 12.7 (3.1-35.5) .79
h
Tertiary outcomes
Barthel Index of 95-100 at 90 d, No. (%) [n = 100]
i
38 (67.9) 27 (61.4) 6.4 (−12.3 to 25.0) .60
Ischemic worsening, No. (%) [n = 111]
j
1 (1.6) 3 (5.8) −4.9 (−18.0 to 8.3) .32
EQ-5D-3L score at 90 d, median (IQR)
Visual analog scale [n = 97]
k
80 (60-90) 80 (50-90) .88
h
Overall [n = 97]
l
0.73 (0.49-1.00) 0.74 (0.51-1.00) .38
h
Abbreviations: EQ-5D-3L, EuroQol Group 5-Dimension 3-LevelSelf-Report
Questionnaire; eTICI, expanded Treatment in CerebralIschemia.
a
Pvalues are from binomial regression model unless otherwise specified.
b
Score ranges from 0 (0% reperfusion) to 3 (100% reperfusion).
c
The modified Rankin Scale of functional disability ranges from 0
(no symptoms) to 6 (death). The primary analysis was adjusted by previous
use of alteplase as predefined.
d
Odds ratio (95% CI) indicating the odds of a 1-point worsening on the modified
Rankin Scale.
e
Shift analysis. For odds proportionality test, P= .08.
f
Van Elteren test.
g
Infarct expansion ratio refers to the ratio of final infarct volume to initial
ischemic tissue volume.
h
Mann-Whitney test.
i
Scores on the Barthel Index range from 0 to 100, with higher values indicating
good performance on activities of daily living. A score between 95 and 100
indicates no disability that interferes with daily activities. Included are patients
who were alive at 90 days.
j
Ischemic worsening was defined as an increment of at least 4 points on the
NIHSS at 48 to 72 hours.
k
The visual analog scale comprises a 100-mm line anchored at the opposing
ends of perceived health-related quality of life.
l
Scores on the EQ-5D-3L have 3 levelsof self-reported quality of life
corresponding to no problems, some problems, and extreme problems.
Intra-arterial Alteplase After Successful Thrombectomy and Functional Outcomes in Large Vessel Occlusion Stroke Preliminary Communication Research
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thrombectomy. The results of an ancillary study with perfu-
sion-weighted MRI and MR spectroscopy at 48 hours after
therapy may provide insights into the effects of alteplase on
the microcirculation and on surrogate imaging biomarkers.
The study supports the safety of intra-arterial alteplase in-
fusion for 15 to 30 minutes at a dose of 0.225 mg/kg (maxi-
mum dose, 22.5 mg) and including patients who, unlikein pre-
vious observational nonrandomized studies,
21,22
could also
have received preceding intravenous thrombolysis. There are
no clear predictors for postthrombectomy symptomatic intra-
cranial hemorrhage,
23
and the low rate of bleeding complica-
tions in both treatment groups precluded analysis. The find-
ing of a low bleeding rate was reassuring and consistent with
recent randomized clinical trials
24,25
and case series
26,27
sup-
porting that pharmacological thrombolysis did not increase the
risk of hemorrhagic complications after thrombectomy.
Current guidelines recommend that all eligible patients
receive intravenous alteplase before thrombectomy,
1
and the
results of this trial do not contradict this recommendation.
The study results support the safety of adjunct intra-arterial
alteplase in patients with successful reperfusion at the end of
thrombectomy, including in patients treated previously with
intravenous alteplase, although the findings on effectiveness
should be interpreted as preliminary, requiring replication
before any recommendations for practice change.
Limitations
This trial has several limitations. First, the study was termi-
nated early because the COVID-19 pandemic reduced the ad-
mission of eligible patients at the study sites,
28
and the pla-
cebo could not be restocked after its shelf-life expiration.
Because of this, the sample size was only 60% of what had been
planned. This likely led to a loss of power to assess secondary
and tertiary outcomes as well as interactions in the subgroup
analyses. It rendered the study more vulnerable to the poten-
tial imbalance of prognostic factors. Randomized clinical trials
stopped early for benefit systematically overestimate treat-
ment effects
29
; while that is possible in the current study, the
trial was not stopped early for clinical benefit but instead for
logistic reasons.
Second, any conclusions about benefit should not be based
solely on the point estimate for the effect size, but need to con-
sider the very wide confidence interval, with a lower confi-
dence limit for the adjusted absolute risk difference of 0.3%.
Third, the population included in the study represented
only 7% of the total population treated with thrombectomy in
Figure 2. Distribution of Functional Scores at 90 Days in the CHOICE Trial of Intra-arterial Alteplase
8060 1004020
Modified Rankin Scale score at 90 d
01 2 3 4 5-6
0
Patients, %
Intra-arterial alteplase
(n
=
61) 15 521 4 88
Intra-arterial placebo
(n
=
52) 91212 5 86
Scores on the modified Rankin Scale for patients in the intra-arterial alteplase
group (n = 61) and the placebo group (n = 52) who were evaluated by local
investigators via face-to-face interview. Scores range from 0 to 6, with 0
indicating no symptoms; 1, no clinically significant disability; 2, slight disability
(able to handle own affairs without assistance but unable to carry out all
previous activities); 3, moderate disability (requiring some help, but able to walk
unassisted); 4, moderately severe disability (unable to attend body needs and
unable to walk); 5, severe disability (requiring constant nursing care and
attention); and 6, death. Scores of 5 and 6 were combined for the analysis.
Treatment with intra-arterial alteplase was associated with a favorable outcome
(a score of 0 or 1 on the modified Rankin Scale) at 90 days, with an adjusted risk
difference of 18.4%(95% CI, 0.3%-36.4%;P= .047). The difference between
the intra-arterial alteplase group and the placebo group in the overall
distribution of scores was not statistically significant (shift analysis, adjusted
common odds ratio for worsening of 1 point on the modified Rankin Scale, 1.54;
95% CI, 0.79-2.94).
Table 3. AdverseEvents in the CHOICE Trial of Intra-arterial Alteplase
Outcomes
No. (%) of participants
Alteplase
(n = 61)
Placebo
(n = 52)
Primary safety outcomes
Symptomatic intracranial hemorrhage
at 24 h
0 2 (3.8)
Death at 90 d 5 (8.2) 8 (15.4)
Additional safety outcomes
Any serious adverse events
a
10 (16.4) 15 (28.8)
Any cerebral hemorrhage 19 (31.1) 18 (34.6)
Hemorrhagic infarction
Type 1
b
11 (18.0) 8 (15.4)
Type 2
c
1 (1.6) 0
Parenchymal hematoma
Type 1
d
00
Type 2
e
2 (3.2) 4 (7.7)
Remote 1 (1.6) 0
Subarachnoid hemorrhage 4 (6.6) 6 (11.5)
a
A serious adverse event was defined as an adverse event that leads to death
or permanent impairment, is life-threatening, or causes or prolongs
hospitalization.
b
Hemorrhagic infarction type 1: petechial hemorrhages at the infarct margins.
c
Hemorrhagic infarction type 2: petechial hemorrhages throughout the infarct
and no mass effect.
d
Parenchymal hematoma type 1: 30% or less of the infarcted area and minor
mass effect.
e
Parenchymal hematoma type 2: more than 30% of infarct zone and
substantial mass effect.
Research Preliminary Communication Intra-arterial Alteplase After Successful Thrombectomy and Functional Outcomes in Large Vessel Occlusion Stroke
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© 2022 American Medical Association. All rights reserved.
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Catalonia during the study period, raising a concern about gen-
eralizability of the findings. A major reason for exclusion from
the study was contraindication to use of alteplase, usually due
to recent intake of oral anticoagulants.Fourth, although it has
been suggested that shift analysis improves the overall study
power compared with a dichotomized analysis, this is true
when treatment effects are small and, in particular, uni-
formly distributed over all respective ranges of stroke
severity.
30
Dichotomization at excellent outcome levels was
a more powerful approach in early recanalization trials.
30
A
large effect size concentrated on the milder range of the scale
(score of 0 or 1) was consistent with the hypothesis of restor-
ing microvascular patency to induce secondary parenchymal
neuroprotection, unlike a major neurological improvement
(Lazarus effect), which would be associated with recanaliza-
tion of large proximal vessels. Larger studies are needed tore-
fine the true effect of adjunct intra-arterial thrombolysis and
also to assess efficacy in secondary clinical outcomes and sur-
rogate imaging end points.
Conclusions
Among patients with large vessel occlusion acute ischemic
stroke and successful reperfusion following thrombectomy,
the use of adjunct intra-arterial alteplase compared with pla-
cebo resulted in a greater likelihood of excellent neurological
outcome at 90 days. However, because of study limitations,
these findings should be interpreted as preliminary and
require replication.
ARTICLE INFORMATION
Accepted for Publication: January 29, 2022.
Published Online: February 10, 2022.
doi:10.1001/jama.2022.1645
Author Affiliations: Department of Neuroscience,
Comprehensive Stroke Center,Hospital Clinic of
Barcelona, Barcelona, Spain (Renú, Amaro, Urra,
Laredo, Chamorro); Institut d’Investigacions
Biomèdiques Agustí Pi i Sunyer (IDIBAPS),
Barcelona, Spain (Renú, Amaro, Urra, Laredo,
Chamorro); Stroke Unit, Department of
Neuroscience, Hospital Universitari Germans Trias i
Pujol, Badalona, Spain (Millán, Ramos-Pachón,
Dávalos); Neuroradiology Service, Hospital Clinic of
Barcelona, Barcelona, Spain (San Román, Blasco,
Zarco, Oleaga, Macho, López-Rueda); Department
of Neurology, StrokeUnit , Hospital de la Santa Creu
i Sant Pau, Barcelona, Spain (Martí-Fàbregas,
Camps-Renom, Dávalos); Neuroradiology Service,
Hospital Universitari de Girona Doctor Josep
Trueta, Girona, Spain (Terceño); School of Medicine,
University of Barcelona, Barcelona, Spain (Amaro,
Urra, Chamorro); Neurology Service, Stroke Unit,
Institut d’Investigació Biomèdica de Girona
(IDIBGI), Hospital Universitari de Girona Doctor
Josep Trueta, Girona, Spain (Serena); Department
of Interventional Neuroradiology, Bellvitge
University Hospital, Hospitalet de Llobregat,
Barcelona, Spain (Barranco); Department of
Neurology, Bellvitge UniversityHospital, Barcelona,
Spain (Cardona); Interventional Neuroradiology
Unit, Department of Neuroscience, Hospital
Universitari Germans Trias i Pujol, Badalona, Spain
(Castaño); Department of Neurology, Institut
Hospital del Mar d’Investigacions Mèdiques,
Universitat Autònoma de Barcelona, Barcelona,
Spain (Cuadrado-Godía, Roquer); Department of
Neuroradiology, Hospital del Mar, Barcelona, Spain
(Vivas, Guimaraens); Stroke Unit, Department of
Neurology, Hospital Universitari Vall d’Hebron,
Barcelona, Spain (Muchada); Department of
Neuroradiology, Hospital Vall d’Hebron, Universitat
Autònoma de Barcelona, Barcelona, Spain
(Tomasello); Medical Statistics Core Facility,Clinical
Pharmacology Service, IDIBAPS, Hospital Clínic
Barcelona, Barcelona, Spain (Torres); Biostatistics
Unit, Faculty of Medicine, Universitat Autònoma de
Barcelona, Barcelona, Spain (Torres).
Author Contributions: Drs Torres and Chamorro
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Concept and design: San Román, Blasco,
Martí-Fàbregas, Urra, Barranco, López-Rueda,
Torres, Chamorro.
Acquisition, analysis, or interpretation of data:
Renú, Millán, San Román, Blasco, Martí-Fàbregas,
Terceño,Amaro, Serena, Urra, Laredo,
Camps-Renom, Zarco, Oleaga, Cardona, Castaño,
Macho, Cuadrado-Godía, Vivas, López-Rueda,
Guimaraens, Ramos-Pachón, Roquer, Muchada,
Tomasello,Dávalos, Torres, Chamorro.
Drafting of the manuscript: Renú, San Román,
Torres, Chamorro.
Critical revision of the manuscript for important
intellectual content: Renú, Millán, San Román,
Blasco, Martí-Fàbregas, Terceño, Amaro, Serena,
Urra, Laredo, Barranco, Camps-Renom, Zarco,
Oleaga, Cardona, Castaño, Macho, Cuadrado-Godía,
Vivas, López-Rueda, Guimaraens, Ramos-Pachón,
Roquer, Muchada, Tomasello, Dávalos,Torres.
Statistical analysis: Torres.
Obtained funding: Chamorro.
Administrative, technical, or material support: Renú,
San Román, Martí-Fàbregas, Terceño, Amaro,
Serena, Urra, Laredo, Zarco, Castaño, Vivas,
López-Rueda, Muchada, Chamorro.
Supervision: San Román, Blasco, Terceño, Serena,
Barranco, Oleaga, Cardona, Macho, López-Rueda,
Ramos-Pachón, Roquer,Dávalos, Torres, Chamorro.
Conflict of Interest Disclosures: Dr Blasco
reported receiving personal fees from Stryker
Neurovascular,MicroVention, and Medtronic. Dr
Chamorro reported a patent pending (Ox-02:
2021/14997) with FreeOxBiotech. No other
disclosures were reported.
Funding/Support: This work was supported by
Fundació La Marató de TV3 (140/C/2017) and by
the Spanish Ministry of Health cofinanced by the
European Regional Development Fund(Instituto de
Salud Carlos III, Red Temáticade Investigación
Cooperativa Invictus+; RD16/0019/0014) grant
PI20/00901 to Dr Renú and grant PI18/00444 to
Dr Chamorro. The study medication and placebo
were provided by Boehringer Ingelheim. This work
was partially developed at the Centre de Recerca
Biomèdica Cellex, Centre Esther Koplowitz,
IDIBAPS Barcelona, CERCA Programme/Generalitat
de Catalunya.
Role of the Funder/Sponsor:The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; or decision to submit
the manuscript for publication.
Group Information: The CHOICE Investigators are
listed in Supplement 4.
Meeting Presentation: This paper was presented
at the International Stroke Conference; February
10, 2022; New Orleans, Louisiana.
Data Sharing Statement: See Supplement 5.
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