Original Contribution

Impact of Antiplatelet Therapy During Endovascular

Therapy for Tandem Occlusions
A Collaborative Pooled Analysis
François Zhu , MD, MSc; Mohammad Anadani, MD;
Julien Labreuche, BST; Alejandro Spiotta, MD; Francis Turjman, MD, PhD;
Michel Piotin, MD, PhD; Henrik Steglich-Arnholm, MD; Markus Holtmannspötter, MD;
Christian Taschner, MD, PhD; Sebastian Eiden, MD; Diogo C. Haussen, MD;
Raul G. Nogueira, MD; Panagiotis Papanagiotou, MD, PhD; Maria Boutchakova, MD;
Adnan H. Siddiqui, MD, PhD; Bertrand Lapergue, MD, PhD; Franziska Dorn, MD;
Christophe Cognard, MD, PhD; Monika Killer-Oberpfalzer, MD; Salvatore Mangiafico, MD;
Marc Ribo, MD, PhD; Marios N. Psychogios, MD, PhD; Marc-Antoine Labeyrie, MD;
Mikael Mazighi, MD, PhD; Alessandra Biondi, MD, PhD; René Anxionnat, MD, PhD;
Serge Bracard, MD; Sébastien Richard, MD, PhD; Benjamin Gory, MD, PhD;
and the TITAN Investigators*

Background and Purpose—Antiplatelet agents could be used in the setting of endovascular therapy for tandem occlusions
to reduce the risk of de novo intracranial embolic migration, reocclusion of the extracranial internal carotid artery lesion,
or in-stent thrombosis in case of carotid stent placement but have to be balanced with the intracerebral hemorrhagic
transformation risk. In this study, we aim to investigate the impact of acute antiplatelet therapy administration on outcomes
during endovascular therapy for anterior circulation tandem occlusions.
Methods—This is a retrospective analysis of a collaborative pooled analysis of 11 prospective databases from the multicenter
observational TITAN registry (Thrombectomy in Tandem Lesions). Patients were divided into groups based on the
number of antiplatelet administered during endovascular therapy. The primary outcome was favorable outcome, defined
Downloaded from http://ahajournals.org by on March 19, 2020

as a modified Rankin Scale score of 0 to 2 at 90 days.

Results—This study included a total of 369 patients; 145 (39.3%) did not receive any antiplatelet agent and 224 (60.7%)
received at least 1 antiplatelet agent during the procedure. Rate of favorable outcome was nonsignificantly higher in
patients treated with antiplatelet therapy (58.3%) compared with those treated without antiplatelet (46.0%; adjusted
odds ratio, 1.38 [95% CI, 0.78–2.43]; P=0.26). Rate of 90-day mortality was significantly lower in patients treated with
antiplatelet therapy (11.2% versus 18.7%; adjusted odds ratio, 0.47 [95% CI, 0.22–0.98]; P=0.042), without increasing
the risk of any intracerebral hemorrhage. Successful reperfusion (modified Thrombolysis in Cerebral Ischemia score 2b-
3) rate was significantly better in the antiplatelet therapy group (83.9% versus 71.0%; adjusted odds ratio, 1.89 [95% CI,
1.01–3.64]; P=0.045).

Received October 30, 2019; final revision received January 30, 2020; accepted February 24, 2020.
From the Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nancy, France (F.Z., R.A., S.B., B.G.), INSERM U1254,
IADI, F-5400, Université de Lorraine, Nancy, France (R.A., S.B., B.G.), Department of Neurology, Washington University School of Medicine, St. Louis,
MO (M.A.); Department of Biostatistics, EA 2694–Santé Publique: Epidémiologie et Qualité des Soins, University of Lille, CHU Lille, France (J.L.);
Department of Neurosurgery, Medical University of South Carolina, Charleston (A.S., M.A.); Department of Interventional Neuroradiology, Hospices
Civils de Lyon, France (F.T.); Department of Interventional Neuroradiology, Rothschild Foundation, Paris, France (M.P., M.M.); Department of Neurology
(H.S.-A.) and Department of Neuroradiology (M.H.), Rigshospitalet, Copenhagen, Denmark; Department of Neuroradiology, Medical Center-University
of Freiburg, Germany (C.T., S.E.); Department of Neurology, Emory University/Grady Memorial Hospital, Atlanta, GA (D.C.H, R.G.N.); Diagnostic and
Interventional Neuroradiology, Hospital Bremen-Mitte/Bremen-Ost, Deutschland (P.P., M.B.); Department of Neurosurgery, State University of New
York, Buffalo (A.H.S.); Department of Neurology Stroke Center, Foch Hospital, Suresnes, France (B.L.); Department of Neuroradiology, University
Hospital of Munich, Germany (F.D.); Department of Neuroradiology, University Hospital of Toulouse, France (C.C.); Department of Neuroradiology,
Paracelsus Medical University, Salzburg, Austria (M.K.-O.); Department of Interventional Neuroradiology, Careggi University Hospital, Florence, Italy
(S.M.); Department of Neurology, Hospital Vall D’Hebron, Barcelona, Spain (M.R.); Department of Neuroradiology, University Medical Center Göttingen,
Germany (M.N.P.); Department of Interventional Neuroradiology, Lariboisière Hospital, Paris, France (M.-A.L.); Department of Neuroradiology,
University Hospital of Besançon, France (A.B.); and Department of Neurology, Stroke Unit, Unversity Hospital of Nancy, Centre d’Investigation Clinique
Plurithématique, CIC-P 1433, INSERM U1116, Université de Lorraine, Nancy, France (S.R.).
*A list of TITAN Investigators is given in the Appendix.
Guest Editor for this article was Kazunori Toyoda, MD, PhD.
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.119.028231.
Correspondence to François Zhu, MD, MSc, Department of Diagnostic and Therapeutic Neuroradiology, CHRU Nancy, Hôpital Central, 29 Ave du
Maréchal de Lattre de Tassigny, 54035 Nancy, France. Email f.zhu@chru-nancy.fr
© 2020 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str DOI: 10.1161/STROKEAHA.119.028231

1
 2  Stroke  May 2020
Conclusions—Administration of antiplatelet therapy during endovascular therapy for anterior circulation tandem occlusions
was safe and was associated with a lower 90-day mortality. Optimal antiplatelet therapy remains to be assessed, especially
when emergent carotid artery stenting is performed. Further randomized controlled trials are needed.   (Stroke. 2020;51:-
00. DOI: 10.1161/STROKEAHA.119.028231.)
Key Words: antiplatelet ◼ cerebral hemorrhage ◼ infarction ◼ prognosis
T reatment of extracranial internal carotid artery (ICA)
lesion in the setting of acute ischemic stroke due to an-
terior circulation tandem occlusion is controversial due to the
lack of randomized trials.1 Observational studies demonstrated
a higher rate of successful reperfusion2,3 and favorable out-
come4 with acute extracranial ICA stenting when compared
with conservative management. Antiplatelet therapy is gener-
ally delayed after reperfusion therapy due to concern of intra-
cerebral hemorrhage (ICH)—a practice that was supported by
a randomized trial showing increased risk of ICH with early
administration of aspirin after intravenous thrombolysis.5 In
the setting of endovascular therapy (EVT) for tandem occlu-
sion, antiplatelet therapy can reduce intraprocedural embolic
events and reocclusion of the cervical ICA lesion.6,7 Moreover,
it can reduce the risk of in-stent thrombosis, as evident in the
cardiac literature.8,9 Therefore, antiplatelet administration dur-
ing or soon after EVT may be beneficial. Studies assessing the
safety and efficacy of antiplatelet therapy given during EVT
for tandem occlusions are lacking.
In this study, we aimed to investigate the safety, angio-
graphic, and functional outcomes according to the antiplate-
let regimen administered during EVT for anterior circulation
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tandem large vessel occlusions in a large multicenter cohort.
Methods
Data Availability Statement
Any data not published within the article are available in a public
repository and anonymized data can be shared upon reasonable re-
quest to B.G.
Patients Selection
TITAN (Thrombectomy in Tandem Lesions) international registry
pooled individual data from prospectively collected EVT databases
across 11 institutions for all consecutive acute ischemic stroke
patients who underwent EVT for anterior circulation tandem occlu-
sions. Patient eligibility and methods of TITAN collaboration have
been reported previously.2,3,10,11 Briefly, tandem occlusion was defined
as a proximal intracranial occlusion (distal intracranial carotid artery
or M1-M2 segment of the middle cerebral artery) and an extracranial
ICA lesion (complete occlusion or stenosis ≥90% North American
Symptomatic Carotid Endarterectomy Trial). Patients were eligible
if they were treated with modern mechanical devices (stent retrievers
or large bore distal aspiration catheters). Intravenous thrombolysis
with tissue plasminogen activator was administered according to the
guidelines. The management of the extracranial ICA lesions included
stenting, balloon angioplasty, and no treatment. The choice of the
extracranial ICA lesion treatment approach was left to the operator’s
discretion. Antiplatelet therapy was administered during the EVT at
operator discretion and included aspirin, clopidogrel, or glycopro-
tein 2b/3a receptor antagonist (anti-Gp2b/3a). For the purpose of
this study, patients were divided into 2 groups according to the ad-
ministration of procedural antiplatelet therapy (yes versus no). Then,
antiplatelet group was divided into 2 subgroups based on the number
of procedural antiplatelet agents (single, dual, or triple antiplatelet
agents). All patients underwent a computed tomography or magnetic
resonance imaging at 24 hours after treatment onset to assess ICH
complications. TITAN investigators at each institution independently
evaluated images and outcomes. The local institutional review boards
approved the study. Informed consent was not required as this was a
retrospective analysis.
Outcomes
The primary study outcome was favorable outcome, defined by a
modified Rankin Scale score of 0 to 2 at 90 days. Secondary outcomes
included angiographic and safety outcomes. Angiographic outcomes
were assessed using modified Thrombolysis in Cerebral Ischemia
at the end of EVT. Successful reperfusion was defined as modified
Thrombolysis in Cerebral Ischemia score 2b-3 and complete reper-
fusion as modified Thrombolysis in Cerebral Ischemia score of 3.
Safety outcomes included all-cause 90-day mortality, any procedural-
related complications (dissection, perforation, and embolus in a new
territory), any ICH, parenchymal hematoma, and symptomatic ICH.
Symptomatic ICH was defined as any parenchymal hematoma, suba-
rachnoid hemorrhage, or intraventricular hemorrhage associated with
worsening of the National Institutes of Health Stroke Scale score by
≥4 points according to the European Cooperative Acute Stroke Study
II criteria. In-stent thrombosis was monitored during EVT or within
24 hours using computed tomography angiography or magnetic res-
onance angiography.
Statistical Analysis
Quantitative variables are expressed as mean±SD or median (inter-
quartile range), and categorical variables are expressed as numbers
(percentage). Normality of distributions was assessed using histo-
grams and Shapiro-Wilk test. Data analysis was conducted among
the 369 patients with extracranial ICA atherosclerosis or dissection
lesions. Main analysis was conducted by dividing the patients into
2 groups according to the use or not of antiplatelet agents during
endovascular procedure. As secondary analyses, analyses were
done according to the number of antiplatelet agents used. Main
baseline characteristics and outcomes were compared between
patients with and without antiplatelet therapy during endovascular
procedure using χ2 test (or Fisher exact test when the expected cell
frequency was <5) for categorical variables and Student t test (or
Mann-Whitney U test for nongaussian distribution) for quantitative
variables. Comparisons between the number of antiplatelet agents
used (none versus single versus dual or triple antiplatelet agents)
were done using χ2 test (or Fisher exact test when the expected cell
frequency was <5) for categorical variables and 1-way ANOVA (or
Kruskall-Wallis test for nongaussian distribution) for quantitative
variables, as appropriate. Association of antiplatelet therapy use
with outcomes was further adjusted for prespecified confounding
factors (center, age, admission National Institutes of Health Stroke
Scale, admission Alberta Stroke Program Early CT Score, and prior
intravenous thrombolysis) by using mixed binary logistic regres-
sion models for binary outcomes, mixed ordinal logistic regression
model for overall 90-day modified Rankin Scale distribution (after
5 and 6 pooled together),12 and linear mixed model for time from
puncture to successful reperfusion; center was included as random
effect and other factors as fixed effects. To handle missing data, mul-
tivariate analyses were done by treating missing value in outcomes
and covariates by multiple imputation using regression switching
approach (chained equations with m=10 obtained). Imputation pro-
cedure was performed under the missing-at-random assumption
using all baseline characteristics and the study outcomes with a
 Zhu et al   Antiplatelet Therapy in Tandem Occlusions   3
predictive mean matching method for continuous variables and lo-
gistic regression models (binary, ordinal, or multinomial) for cate-
gorical variables.13 Estimates obtained in the different imputed data
sets were combined using the Rubin rules.14 Primary analyses cov-
ered the overall study population and were repeated after excluding
patients without extracranial stenting. Finally, we investigated the
association of main clinical outcomes (90-day favorable outcome,
90-day all-cause mortality, any ICH, and parenchymal hematoma)
with antiplatelet therapy in key subgroups defined according to the
use of intravenous thrombolysis and heparin by including corre-
sponding interaction term into logistic regression models. Statistical
testing was done at the 2-tailed α-level of 0.05. Data were analyzed
using the SAS software, version 9.4 (SAS Institute, Cary, NC).
Results
Among 405 patients with acute tandem occlusions in-
cluded from January 2012 to February 2016, 36 patients
were excluded (Figure 1). Of the 369 included patients,
145 (39.3%) patients did not receive any antiplatelet
therapy, 128 (34.7%) received single antiplatelet therapy,
and 96 patients (26.0%) received dual or triple antiplate-
let agents (62 dual and 34 triple therapy) during EVT.
Patients and treatment baseline characteristics are reported
according to the use or not of antiplatelet therapy in the
Table and according to the number of antiplatelet agents
(none versus single versus ≥2 agents) in Table I in the
Data Supplement. As expected, antiplatelet therapy was
mainly used in the case of acute extracranial ICA stenting
(n=188/229 [82.1%] versus 11/114 [9.6%]). In addition,
patients treated by antiplatelet therapy during EVT have
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significantly less pretreatment Alberta Stroke Program
Early CT Score <7 (16.0%) than patients without anti-
platelet therapy (32.0%).
Clinical Outcomes
In bivariate analysis, favorable outcome was associated with
antiplatelet therapy with unadjusted odds ratio (aOR) of 1.64
(95% CI, 1.05–2.52) per at least 1 agent (Figure 2) and 1.26
(95% CI, 1.01–1.56) per number increase (Table II in the
Data Supplement). However, this association became non-
significant in multivariate analysis even in sensitivity anal-
ysis restricted to patients treated by extracranial ICA stenting
(Figure 3; Table III in the Data Supplement). When the overall
distribution of 90-day modified Rankin Scale was analyzed,
the adjusted common OR for 1 point improvement was 1.43
(95% CI, 0.93–2.20) per at least 1 agent and 1.20 (95% CI,
0.96–1.49) per number increase in the main analysis and 1.47
(95% CI, 0.94–2.29) and 1.20 (95% CI, 0.96–1.51) in sensi-
tivity analysis, respectively.
Regarding all-cause mortality, patients with antiplatelet
therapy have lower risk of 90-day mortality, with aOR of 0.47
(95% CI, 0.22–0.98) in the main analysis and 0.37 (95% CI,
0.13–1.04) in the sensitivity analysis. As shown in Tables II
and III in the Data Supplement, there was no decreased mor-
tality risk with increased in the number of agents used. We
found no association between antiplatelet therapy and the risk
of in-stent thrombosis, or the risk of ICH complications, with
an aOR per at least 1 agent of 1.27 (95% CI, 0.71–2.27) for
any ICH, 1.27 (95% CI, 0.41–3.85) for the parenchymal he-
matoma, and 1.14 (95% CI, 0.54–2.41) for symptomatic ICH
in the overall study sample.
As shown in Figure 4 and Figure I in the Data Supplement,
we found no evidence of heterogeneity in associations be-
tween the antiplatelet therapy and clinical outcomes according
to the use of intravenous thrombolysis prior EVT, as well as
according to the procedural heparin use.
Figure 1. Study flowchart. GP2b3a indicates
glycoprotein 2b/3a inhibitor.
 4  Stroke  May 2020

Table.  Patient and Treatment Characteristics (95% CI, 1.28–3.54). Similar results were found with com-
Antiplatelet Agent Administration plete reperfusion (Figure 2). When a number of antiplatelet
During Therapy agents were analyzed, a significant increased reperfusion rate
with increasing number of antiplatelet agents was observed,
None ≥1 Agent
(n=145) (n=224) P Value with an unadjusted OR per number increase for successful re-
perfusion of 1.50 ([95% CI, 1.11–2.01]; Table II in the Data
Age, y; mean±SD 62.8 (12.1) 64.0 (12.6) 0.35
Supplement). In multivariate analysis adjusted for prespeci-
Sex (women) 47/143 (32.9) 81/224 (36.2) 0.52 fied confounding factors (center, age, intravenous thrombol-
Medical history ysis, admission National Institutes of Health Stroke Scale,
and Alberta Stroke Program Early CT Score), the associa-
 Hypertension 62/121 (51.2) 132/217 (60.8) 0.087
tion between successful reperfusion and antiplatelet therapy
 Diabetes mellitus 23/122 (18.9) 26/218 (11.9) 0.081 remained significant for use of at least 1 agent (aOR, 1.89
 Hypercholesterolemia 39/122 (32.0) 86/217 (39.6) 0.16 [95% CI, 1.01–3.54]) but not with the number of agents (OR
per number increase, 1.41 [95% CI, 0.99–2.01]). The asso-
 Current smoking 29/121 (24.0) 71/209 (34.0) 0.057
ciation of antiplatelet therapy with complete reperfusion
 Admission NIHSS 16.3 (5.2) 15.3 (6.3) 0.088 remained not significant in multivariate analysis (Figure 2;
score,* mean (SD)
Table II in the Data Supplement). When analyses were re-
ASPECTS score 8 (6–9) 8 (7–9) <0.001 stricted to patients treated by extracranial ICA stenting, no
 <7 39/122 (32.0) 34/212 (16.0) <0.001 differences were observed between groups except a signifi-
cant higher rate of complete reperfusion in antiplatelet group
Extracranial carotid lesion
compared with no antiplatelet group (aOR, 2.71 [95% CI,
 Stenosis ≥90% 65/145 (44.8) 120/224 (53.6) 0.11 1.09–6.71]; Figure 3; Table III in the Data Supplement).
 Complete occlusion 80/145 (55.2) 104/224 (46.4) Among patients with successful reperfusion, the time
Extracranial carotid pathogenesis
from groin puncture to reperfusion was longer in patients
with antiplatelet therapy, with an adjusted mean difference be-
 Atherosclerosis 111/145 (76.6) 177/224 (79.0) 0.58 tween antiplatelet users versus nonusers: 15.0 minutes (95%
 Dissection 34/145 (23.5) 47/224 (21.0) CI, 1.9–27.9). Regarding the number of antiplatelet agents,
Intracranial occlusion location the increase in reperfusion time from groin puncture with
increasing number of agents was no longer significant in mul-
 Middle cerebral artery 102/145 (70.3) 147/224 (65.6) 0.34
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tivariate analysis (Table II in the Data Supplement). In anal-

 ICA 43/145 (29.7) 77/224 (34.4) ysis restricted to patients treated by extracranial ICA stenting,
Treatment characteristics reperfusion time from groin puncture was not associated with
antiplatelet therapy in both univariate and multivariate anal-
 Prior use of IV tPA 93/145 (64.1) 138/224 (61.6) 0.62
yses, with an adjusted mean difference between antiplatelet
 General anesthesia 73/145 (50.3) 132/224 (58.9) 0.11 users versus nonusers of 8.8 minutes (95% CI, −18.3 to 35.8).
 Onset to groin 260 (185–333) 228 (180–322) 0.38 Procedural complications occurred less frequently in
puncture,† min patients with antiplatelet therapy (9.7%) compared with
 Intracranial thrombectomy devices patients without antiplatelet therapy (21.3%; aOR, 0.61 [95%
CI, 0.28–1.32]; P=0.21). However, this difference was not
  Stent retriever 126/145 (86.9) 200/224 (89.3) 0.48
observed in multivariate analysis or when analyses were re-
  ADAPT alone 19/145 (13.1) 24/224 (10.7) stricted to patients treated by extracranial carotid stenting
Extracranial carotid procedure (Figure 3). Similar results were found with number of anti-
 None 66/144 (46.8) 5/199 (2.5) <0.001
platelet agents (Tables II and III in the Data Supplement).

 Angioplasty alone 37/144 (25.7) 6/199 (3.0)

Discussion
 Stenting 41/144 (28.5) 188/199 (94.5) In this large multicenter study, administration of antiplatelet
Use of heparin 23/145 (15.9) 45/224 (20.1) 0.31 therapy during EVT for anterior circulation tandem occlu-
Values expressed as n/total n (%) or median (IQR) unless otherwise as sions was associated with better angiographic results and
indicated. ADAPT indicates a direct aspiration first pass technique; ASPECTS, lower mortality risk, without increasing the risk of procedural
Alberta Stroke Program Early CT Score; ICA, internal carotid artery; IQR, or hemorrhagic complications. When patients were divided
interquartile range; IV tPA, intravenous tissue-type plasminogen activator; and according to the number of antiplatelets, we did not observe
NIHSS, National Institutes of Health Stroke Scale. differences in angiographic, hemorrhagic, and functional out-
*One missing value.
comes between the 3 groups (none versus 1 versus ≥2 agents).
†One hundred twenty-five missing values.
The effect of periprocedural antiplatelet treatment on
outcome of EVT for ischemic stroke is not well known, and
Angiographic Outcomes previous studies reported conflicting results. In a retrospec-
As shown in Figure 2, a significant difference in successful tive study of 217 patients treated with EVT, pretreatment
reperfusion rate was found between patients with and without antiplatelet therapy was not associated with functional or
antiplatelet therapy during EVT, with unadjusted OR of 2.13 safety outcomes.15 Similar results were reported by a study
 Zhu et al   Antiplatelet Therapy in Tandem Occlusions   5

Figure 2. Efficacy and safety outcomes in patients with tandem occlusions in the overall population. ICH indicates intracranial hemorrhage; mRS, modified
Rankin Scale; mTICI, modified Thrombolysis in Cerebral Infarction; and OR, odds ratio. aAdjusted for center (including as random effect) and prespecified
confounders (age, admission National Institutes of Health Stroke Scale, admission Alberta Stroke Program Early CT Score, and prior thrombolysis) and calcu-
lated after handling missing data by multiple imputation (m=10).

looking specifically at pre-EVT aspirin treatment. On the con-
trary, a post hoc analysis of the MR CLEAN trial (Multicenter
Randomized Clinical Trial of Endovascular Treatment for
Acute Ischemic Stroke in the Netherlands) demonstrated an
association between pretreatment antiplatelet therapy and
increased risk of ICH.16 Likewise, analysis of the RESCUE
registry (Recovery by Endovascular Salvage for Cerebral
Ultra-Acute Embolism) identified prior antiplatelet therapy as
a predictor of symptomatic ICH.17 Collating the above stud-
ies, a systematic review reported a neutral effect of peripro-
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supporting this practice are lacking. In this study, we explored
the effect of antiplatelet therapy on outcome during EVT for
acute tandem occlusions. We did not find a significant associa-
tion between procedural antiplatelet therapy and hemorrhagic
or procedural complications. Prior intravenous thrombolysis
did not alter our results.
On the other hand, we found a negative association be-
tween 90-day mortality and procedural antiplatelet adminis-
tration. There is a sound evidence from the cardiac literature
that supports the use of periprocedural antiplatelet therapy

cedural use of antiplatelet on the functional outcome with an
increased risk of symptomatic ICH,18 as well as a recent meta-
analysis of early antiplatelet therapy administration, without
impact on safety outcomes.19 However, tandem occlusions
are underrepresented or excluded from the above studies. In
this particular clinical situation, antiplatelet therapy could be
considered to prevent intracranial embolic events, reocclusion
of the cervical disease, or in-stent thrombosis,6 but the data
to prevent in-stent thrombosis.8,9 However, data on the effect
of procedural antiplatelet therapy on outcomes after acute
ICA stenting are scarce. Pop et al20 investigated the predic-
tors of delayed stent thrombosis among 81 patients with
tandem occlusion treated with carotid stenting and found
that the rate of stent occlusion was significantly lower among
patients treated with aspirin and clopidogrel than those
with aspirin alone. In our study, we observed no significant

Figure 3. Efficacy and safety outcomes in patients with tandem occlusions treated with thrombectomy plus acute carotid stenting. ICH indicates intracranial
hemorrhage; mRS, modified Rankin Scale; mTICI, modified Thrombolysis in Cerebral Infarction; and OR, odds ratio. aAdjusted for center (including as random
effect) and prespecified confounders (age, admission National Institutes of Health Stroke Scale, admission Alberta Stroke Program Early CT Score, and prior
thrombolysis) and calculated after handling missing data by multiple imputation (m=10). bAssessed during endovascular procedure and within 24-h imaging
follow-up.
 6  Stroke  May 2020
Figure 4. Association of main clinical outcomes and antiplatelet agent use in patients with tandem occlusions according to key subgroups. P for heteroge-
neity (P het) across subgroups calculated in logistic regression models by including the corresponding interaction term. ICH indicates intracranial hemor-
rhage; IV tPA, intravenous tissue-type plasminogen activator; mRS, modified Rankin Scale; OR, odds ratio; and PH, parenchymal hematoma.
Downloaded from http://ahajournals.org by on March 19, 2020
difference in the rate of in-stent thrombosis according to the
number of antiplatelet agents given during EVT. However,
there was a higher rate of complete reperfusion with an
increasing number of antiplatelet agents. It is conceivable
that patients who achieved successful recanalization after
EVT were more likely to receive antiplatelets than those
who did not; therefore, the significant association between
the angiographic results and antiplatelet use could represent
a noncasual association.
Our study, along with other studies,15,16,21 provides fur-
ther evidence regarding the safety and potential benefit of
acute antiplatelet therapy, especially when carotid stent-
ing is pursued in the setting of EVT for tandem occlusions.
The ongoing TITAN randomized trial evaluates the effect
of acute carotid stenting-EVT approach plus aspirin com-
pared with EVT alone in the setting of tandem occlusions
(NCT03978988).
Limitations are mainly related to its retrospective anal-
ysis, nonrandomized design, and heterogeneous antithrom-
botic protocols. Most of the patients in the antiplatelet group
were treated with ICA stenting; therefore, the observed ben-
efit from antiplatelet therapy could potentially be secondary,
at least in part, to improved intracranial recanalization with
ICA stenting.3 In addition, there are missing data regarding
in-stent thrombosis/occlusion and recurrent stroke. Moreover,
the exact timing of administration and the type and the dose
of antiplatelet therapy after the acute phase were unknown.
Finally, despite the multicenter design, it is possible that our
study was underpowered to detect the difference in outcomes
between the groups.
Conclusions
In acute ischemic stroke patients due to anterior circulation
tandem occlusion, antiplatelet therapy administered during
EVT was associated with lower mortality and better angio-
graphic results without increased risk of hemorrhagic com-
plications. Our results support that procedural antiplatelet
therapy is safe and may be beneficial in the setting of EVT for
tandem occlusion.
Appendix
TITAN (Thrombectomy in Tandem Lesions)
Investigators
Jonathan Andrew Grossberg, Adrien Guenego, Julien Darcourt,
Isabelle Vukasinovic, Elisa Pomero, Jason Davies, Leonardo
Renieri, Corentin Hecker, Maria Muchada Muchada, Arturo Consoli,
Georges Rodesch, Emmanuel Houdart, Johanna Lockau, Andreas
Kastrup, Raphaël Blanc, Hocine Redjem, Daniel Behme, Hussain
Shallwani, Maurer Christopher, Gioia Mione, Lisa Humbertjean,
Jean-Christophe Lacour, Nolwenn Riou-Comte, François Zhu,
Anne-Laure Derelle, Romain Tonnelet, Liang Liao.
Sources of Funding
This study was supported by Stryker. The funder of the study had no
role in study design, data collection, data analysis, data interpretation,
or writing of the report.
Disclosures
Dr Spiotta reports nonfinancial support from Penumbra, Pulsa
Vascular, MicroVention, Cerenovus, and Stryker, outside the submit-
ted work. Dr Turjman reports grants from Stryker, during the con-
duct of the study, and nonfinancial support from Stryker, Medtronic,
 Zhu et al   Antiplatelet Therapy in Tandem Occlusions   7
Johnson & Johnson, Phenox, Cerenovus, and from Balt, outside the
submitted work. Dr Piotin reports grants from Penumbra; personal
fees from Medtronic; other from Stryker, Microvention, and Balt,
outside the submitted work. Dr Holtmannspötter reports personal
fees for proctor and consultant services from Covidien and Sequent
Medical and personal fees for consultant services from Microvention,
Medtronic, and Stryker, outside of the submitted work. Dr Taschner
reports grants and nonfinancial support from Microvention, personal
fees and nonfinancial support from Stryker and Neuravi, and nonfi-
nancial support from Acandis and Medtronic, outside the submitted
work. Dr Haussen reports financial support from Viz-Ai and nonfi-
nancial support from Stryker and Vesalio outside the submitted work.
Dr Nogueira reports potential conflicts with Stryker Neurovascular
(DAWN trial [DWI or CTP Assessment With Clinical Mismatch
in the Triage of Wake-Up and Late Presenting Strokes Undergoing
Neurointervention With Trevo] principal investigator, no compensa-
tion; TREVO Registry [Thrombectomy Revascularization of Large
Vessel Occlusions in Acute Ischemic Stroke] Steering Committee,
no compensation; TREVO-2 trial principal investigator, modest;
consultant, modest), Medtronic (SWIFT Trial Steering Committee,
modest; SWIFT PRIME Trial [Solitaire With the Intention for
Thrombectomy as Primary Endovascular Treatment] Steering
Committee, no compensation; STAR trial [Solitaire FR
Thrombectomy for Acute Revascularisation] Angiographic Core Lab,
significant), Penumbra (3D Separator Trial Executive Committee, no
compensation), Cerenovus/Neuravi (ENDOLOW trial [Endovascular
Therapy for Low NIHSS Ischemic Strokes] principal investigator,
EXCELLENT registry [EmboTrap Revascularization Device Post
Market Registry] principal investigator, ARISE II Trial [Analysis
of Revascularization in Ischemic Stroke With EmboTrap] Steering
Committee, no compensation; Physician Advisory Board, modest),
Phenox (Physician Advisory Board, modest), Anaconda (Physician
Advisory Board, modest), Genentech (Physician Advisory Board,
modest), Biogen (Physician Advisory Board, modest), Prolong
Pharmaceuticals (Physician Advisory Board, modest), Allm, Inc
Downloaded from http://ahajournals.org by on March 19, 2020
(Physician Advisory Board, no compensation), IschemaView
(Speaker, modest), Brainomix (Research Software Use, no com-
pensation), Sensome (Research Device Use, no compensation),
Viz-AI (Physician Advisory Board, stock options), Philips (Research
Software Use, no compensation; Speaker, modest), and Corindus
Vascular Robotics (Physician Advisory Board, stock options), out-
side the submitted work. Dr Papanagiotou reports grants from
Medtronic and nonfinancial support from Penumbra, Inc, and
Johnson & Johnson, outside the submitted work. Dr Siddiqui reports
grants from the National Institutes of Health/National Institute of
Neurological Disorders and Stroke/National Institute of Biomedical
Imaging and Bioengineering, University at Buffalo; financial interest/
investor/stock options/ownership at Amnis Therapeutics, Apama
Medical, Blink TBI, Inc, Buffalo Technology Partners, Inc, Cardinal
Consultants, Cerebrotech Medical Systems, Inc, Cognition Medical,
Endostream Medical, Ltd, Imperative Care, International Medical
Distribution Partners, Neurovascular Diagnostics, Inc, Q’Apel
Medical, Inc, Rebound Therapeutics Corp, Rist Neurovascular, Inc,
Serenity Medical, Inc, Silk Road Medical, StimMed, Synchron,
Three Rivers Medical, Inc, and Viseon Spine, Inc; is a consultant/
advisory board member at Amnis Therapeutics, Boston Scientific,
Canon Medical Systems USA, Inc, Cerebrotech Medical Systems,
Inc, Cerenovus, Corindus, Inc, Endostream Medical, Ltd, Guidepoint
Global Consulting, Imperative Care, Integra LifeSciences Corp,
Medtronic, MicroVention, Northwest University–Data Safety
Monitoring Board Chair for HEAT Trial (Hydrogel Endovascular
Aneurysm Treatment), Penumbra, Q’Apel Medical, Inc, Rapid
Medical, Rebound Therapeutics Corp, Serenity Medical, Inc, Silk
Road Medical, StimMed, Stryker, Three Rivers Medical, Inc, VasSol,
W.L. Gore and Associates; is a principal investigator/steering com-
ment of the trials NAPA (Treatment Study of Wide-Neck Bifurcation
Intracranial Aneurysm) and ARISE II (Cerenovus), SWIFT PRIME
and SWIFT DIRECT (Medtronic), FRED (Flow Re-Direction
Endoluminal Device) and CONFIDENCE (MicroVention),
POSITIVE (Perfusion Imaging Selection of Ischemic Stroke Patients
for Endovascular Therapy) (Medical University of South Carolina),
and 3D Separator, COMPASS (Aspiration Thrombectomy Versus
Stent Retriever Thrombectomy as First-Line Approach for Large
Vessel Occlusion), and INVEST (Minimally Invasive Endoscopic
Surgical Treatment With Apollo/Artemis in Patients With Brain
Hemorrhage) (Penumbra) outside the submitted work. Dr Lapergue
reports research grants from Microvention, Stryker, and Penumbra.
Dr Dorn is a consultant for Acandis, Phenox, Balt, and Cerenovus
outside the submitted work. Dr Cognard is a member of the medical
advisory board of Sensome Medical, Merlin Medical, and Serenity
Medical and reports personal fees from Medtronic, Microvention,
Stryker, Cerenovus, and Mivi outside the submitted work. Dr Mazighi
reports nonfinancial support from Medtronic, Bayer, and Servier
and personal fees from Acticor Biotech, Amgen, and Boehringer
Ingelheim outside the submitted work. Dr Biondi reports nonfinancial
support from Balt, Medtronic, Microvention, Stryker, and Phenox,
outside the submitted work. Dr Gory reports grants from Stryker,
personal fees from Medtronic, and nonfinancial support from Balt,
during the conduct of the study. The other authors report no conflicts.
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