ARTICLE IN PRESS

Safety and Efficacy of Mechanical Thrombectomy in Acute

Ischemic Stroke of Anticoagulated PatientsA Prospective
Observational Study
Lorena Benavente, MD, PhD,* Davinia Larrosa, MD,* Carmen Garca-Cabo,
ngel I. Prez, MD,* Mara Rico, MD, Pedro Vega, MD,
Eduardo Murias, MD, PhD, and Sergio Calleja, MD, PhD*

MD,*

Background: Anticoagulated patients (APs) are excluded from the acute stroke management with alteplase in Europe, not in the United States. They could benefit
from mechanical thrombectomy (MT), which was not undoubtedly proven. There
are scarce data about its results in such patients. The authors aim is to analyze
the efficacy and safety of MT in APs presenting with an acute stroke in our institution.
Methods: Prospective observational study comparing 30 APs and 109 nonanticoagulated patients (N-APs) underwent direct MT without alteplase. Demographic
data, clinical severity (National Institutes of Health Stroke Scale [NIHSS]), efficacy (recanalization thrombolysis in cerebral infarction [TICI] 2b and modified
Rankin Scale score 2 at 3 months), and security (symptomatic intracranial hemorrhage [SICH], mortality at 3 months) were compared between both groups. Results:
In both groups men were more frequent (63.3% of APs were men and 61.5% of
N-APs were men). Mean age was 73 in APs and 67.2 in N-APs. Median NIHSS
was similar (17 APs; 16 N-APs), also TICI greater than or equal to 2b (93.3% APs;
89.9% N-APs). The 3-month modified Rankin Scale score less than or equal to 2
was 46.7% in APs and 55.2% in N-APs (P = .40). SICH was present in 16.7% of
APs and 8.3% of N-APs (P = .15). Mortality at 3 months was 6.7% in APs and
19% in N-APs (P = .08). Conclusions: MT is a valid treatment option in APs. It
achieves an efficacy as in N-APs with a tendency to suffer more from SICH, but
lower mortality. We hypothesize that cardioembolic clots may be easier to be removed
than atherotrombotics, and that embolic stroke in APs might be less severe than
that in N-APs or might suffer less of other complications than atherotrombotics.
Key Words: Anticoagulantscerebrovascular disordersrevascularization
strokethrombolysis.
2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Introduction
From the *Neurology Department, Hospital Universitario Central
de Asturias, Oviedo, Spain; Neurology Department, Hospital de
Cabuees, Gijn, Spain; and Radiology Department, Hospital
Universitario Central de Asturias, Spain.
Received February 11, 2016; revision received May 25, 2016; accepted
June 3, 2016.
Address correspondence to Lorena Benavente, MD, PhD, Neurology
Department, Hospital Universitario Central de Asturias, Avda. Coln,
22 5H 33012, Oviedo 33006, Spain. E-mail: lbf.benfer@gmail.com.
1052-3057/$ - see front matter
2016 National Stroke Association. Published by Elsevier Inc. All
rights reserved.
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.06.006

Until very recently, intravenous alteplase (recombinant tissue plasminogen activator [rtPA]) administered
within 4.5 hours after symptom onset has been the only
reperfusion therapy with proven efficacy in patients with
acute ischemic stroke.1 However, this treatment has a lot
of well-known absolute and other relative contraindications,
such as anticoagulation therapy. Alteplase is approved
in anticoagulated patients (APs) with International Normalized Ratio (INR) less than 1.7 in the United States,
but not in Europe, where current use of anticoagulation
is still a limitation for intravenous thrombolysis regardless of the INR.2,3

Journal of Stroke and Cerebrovascular Diseases, Vol. , No. (), 2016: pp

ARTICLE IN PRESS
L. BENAVENTE ET AL.

Moreover, proximal arterial occlusions are more likely

to fail treatment with intravenous rtPA, as it only achieves
early recanalization in about one third of patients with
terminal internal carotid occlusion,4 the prognosis generally being poor in these cases.5 Taking into account the
numerous limitations of intravenous alteplase, different
intra-arterial recanalization approaches have been developed during the last 20 years.6-11 Some of them achieve
higher rates of recanalization in proximal occlusions, but
they have not been able to demonstrate better functional prognosis until now.12-16 As a consequence, there are
scarce data about the results of mechanical thrombectomy (MT) in certain subgroups of patients such as APs
compared with non-anticoagulated patients (N-APs).
Our aim is to analyze the efficacy and safety of MT
with stent retriever in APs, comparing the results with
N-APs and nonreceivers of intravenous alteplase.

Methods
This is a prospective observational study comparing
30 APs with current use of dicumarins and 87 N-APs
treated with direct MT with a stent retriever. All patients who had received any dose of alteplase were
excluded. Patients with INR greater than 3.5 or activated thromboplastin time ratio (ATPTr) greater than 2
were also excluded. Upon arrival at the hospital, patients suffering acute stroke underwent the clinical practice
established protocol, according to the ethical committee
from our hospital. The time window for beginning the
intervention is 4.5 hours for anterior circulation and 12
hours for basilar territory, and multimodal cranial tomography (CT) is practiced in every patient under
consideration for MT, according to the previous mentioned protocol. Sometimes, when time of onset and
multimodal CT were unclear, a magnetic resonance (MR)
was carried out. In all cases, the infarct core according
to the cerebral blood volume (CBV) was less than a third
of the affected tissue, measured by mean transit time (MTT)
and time to peak (TTP) in multimodal CT. A clinical
radiological mismatch was also demonstrated.
Demographic data and cardiovascular risk factors were
compared between both groups. Clinical severity of stroke
was compared at admission according to the National
Institutes of Health Stroke Scale (NIHSS).17
Efficacy of MT was analyzed in terms of arterial recanalization according to the thrombolysis in cerebral
infarction (TICI) scale,18 assuming recanalization when TICI
greater than or equal to 2b was achieved, and functional outcome by modified Rankin Scale (mRS), considering
the prognosis to be good when mRS score is less than
or equal to 2 at 90 days.19
Safety was evaluated according to symptomatic intracranial hemorrhage (SICH), defined as any intracranial,
intraventricular, or subarachnoid hemorrhage associated with a 4-point or greater worsening on the NIHSS

within the admission period, and mortality rates at 3

months. Other neurologic and systemic complications were
also recorded. Causes of death and time of death were
also described.
Statistical analysis was performed with the free distribution software R.2.10 (www.r-project.org). Quantitative
variables were characterized by either the mean and standard deviation or the median, minimum and maximum
values, depending on whether or not they were normally distributed. For categorical variables, absolute and
relative frequencies were employed.
For comparison between groups, either parametric
(Students t-test, analysis of variance) or nonparametric
tests (MannWhitney U-test, KruskalWallis test) were employed on quantitative variables, depending on the
KolmogorovSmirnov test for normality with Lilliefors
correction. For categorical variables, the 2 test with exact
significance was used. The cutoff point for statistical significance was P < .05 in all cases.

Results
Epidemiological and Demographic Characteristics
Between June 2012 and December 2014, a total of 117
patients fulfilled the inclusion criteria for this study. Eightyseven of the patients were N-APs and the remaining 30
were APs. APs were older (N-APs 67.07 10.60; APs
72.8 7.85; P = .007) and had a more frequent history of
hypertension (N-APs 55.9%; APs 80%; P = .039) and
cardioembolic sources, such as atrial fibrillation and prosthetic valves (N-APs 11.11%; APs 87.49%; P < .001). There
is also a nonsignificant tendency to use more antiplatelets
in N-APs (N-APs 39.13%; APs 7.69%; P = .095). The rest
of the epidemiological and demographic characteristics
were similar between both groups as Table 1 details.
The reasons for avoiding alteplase in N-APs were as
follows: recent major surgery (2.28%); stroke on awakening (7.6%); previous intracranial hemorrhage (ICH)
(3.42%); recent stroke (4.56%); out-of-time window (36%);
hypovolemic shock (1.14%); and large-vessel occlusion
(45%).

Stroke Characteristics and Management

When analyzing the stroke etiology according to the
TOAST (Trial of Org 10172 in Acute Stroke Treatment)
scale,20 cardioembolic stroke was significantly related to
the AP group (N-APs 39.75%; APs 80%). However,
the mean INR was 1.78 .71. In the N-AP group,
atherothrombotic etiology was predominant (N-APs 26.50%;
APs 3.33%). Details about etiologies are shown in Table 2.
Patients locations after the procedure (stroke unit versus
intensive care unit) were similar in both groups, as approximately two thirds of the patients were admitted to
the stroke unit in both groups. There were no differences in the type of anesthesia, either being mainly sedation

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MECHANICAL THROMBECTOMY IN ANTICOAGULATED PATIENTS

Table 1. Epidemiological and demographic characteristics

Age (mean SD)

Sex (male, %)
Cigarettes (%)
OH 40 g/day (%)
HTA (%)
DM (%)
DL (%)
Chronic lower limb ischemia (%)
Cardioembolic sources (%)
Ischemic cardiopathy (%)
Previous stroke/TIA (%)
Previous antiplatelets (%)
Basal MR 2 (%)

N-APs (n = 87)

APs (n = 30)

P value

67.07 10.60
63.21
25.61
15.87
55.29
22.35
45.88
6.25
17.44
20.73
20
39.13
90.58

72.8 7.85
60
24.14
16.66
80
33.33
36.66
13.63
87.49
24.13
30.43
7.69
86.66

.007
.780
.957
.591
.039
.344
.478
.551
<.001
.812
.573
.095
.346

Abbreviations: AP, anticoagulated patient; DL, dyslipidemia; DM, diabetes mellitus; HTA, hypertension; MR, magnetic resonance; N-AP,
non-anticoagulated patient; OH, alcohol intake; SD, standard deviation; TIA, transient ischemic attack.
Bold numbers: Statistically significative differences between both groups: APs were older, HTA and cardioembolic sources were more frequent between APs.

in both groups. Neither did the point of occlusion differ,

although there was a tendency for terminal internal carotid
artery occlusion to be more frequent in APs, whereas
extracranialintracranial tandem occlusions were more
frequent in the N-AP group (N-APs 19.35%; APs 0%;
P = .012). NIHSS were similar in both groups (N-APs 16
[2-24]; APs 17 [7-28]; P = .459). Time from stroke onset
to groin puncture, time from door to groin puncture, and
time from groin puncture to arterial recanalization were
also similar in both groups. All of these data are explained in Table 2.

Efficacy and Security Parameters

The rate of recanalization was 89.66% in N-APs and
93.33% in APs (P = .421), and mRS score less than or equal
to 2 was also similar in both groups (N-APs 54.21%; APs
46.67%; P = .426).
ICH, both symptomatic and asymptomatic, was related
to the AP group (13 cases in N-APs; 10 cases in APs;
P = .031), but SICH was not significantly related to any
group (N-APs 8.23%; APs 16.66%; P = .169). There was
a nonsignificant trend to higher mortality in the N-AP
group (N-APs 21.68%; APs 6.67%; P = .062). On the other
hand, we did not find any relationship between INR at
admission and mRS score greater than 2 at 3 months or
SICH (P = .101 and P = .933, respectively). All the other
characteristics were also similar between both groups, as
shown in Table 2, although very severe potential complications such as reperfusion syndrome or early stent
reocclusion were only present in N-APs.
Table 3 shows the behavior in safety parameters taking
into account the dosage of anticoagulants and treatment with antiplatelets. Antiplatelets were more frequent

in N-APs, although without a statistical association. There

were no substantial differences between groups, except
for mRS score at 90 days, with less independency in wellanticoagulated patients.

Discussion
The outlook of acute stroke treatment has recently taken
a giant step forward, thanks to the long-awaited positive results that have just been revealed in the last
published trials.12-16,21 Published reports have demonstrated22
that intravenous alteplase is less effective at opening proximal occlusions of the major intracranial arteries than
endovascular procedures. However, because of methodological mistakes in the studies and the scarce use of
modern stent retrievers, these good results have long been
delayed.
APs have traditionally been excluded from recanalization therapies in Europe, but not so strictly in United
States,2,3 so there are no data about their response to treatment compared with N-APs. Moreover, these patients are
considered a higher risk group with poorer functional
outcome because of a higher expected rate of hemorrhages. According to the local protocol, following
recommendations, patients with INR greater than 3.5 or
ATPTr greater than 2 were excluded from MT.
Despite the limitation of the small sample, our study
demonstrated that MT in APs is effective, as the rate of
arterial recanalization and good functional outcome at 90
days are similar in APs and N-APs. It also proves that
endovascular treatment is safe, as APs suffer from higher
ICH complications, but no more SICH than the control
group, and they even showed a tendency toward less mortality at 3 months than N-APs.

ARTICLE IN PRESS
L. BENAVENTE ET AL.

Table 2. Stroke characteristics and management. Efficacy and security parameters

N-APs (n = 87)
TOAST (%)

Occlusion (%)

Cardioembolic
Atherothrombotic
Infrequent
Undetermined
M1
M2
TICA
Tandem ICAIC
AB P1
Cervical ICA
Tandem ECIC + cervical
ICA occlusion

NIHSS median (range)

Onset to groin puncture (mean SD) (min)
Door to groin puncture (mean SD) (min)
Groin puncture to recanalization (mean SD) (min)
Recanalization (TICI 2b) (%)
NRL complications (n)
ICH
Reperfusion syndrome
Extracranial dissection
Stent retriever hung up
Early reocclusion
Contralateral stroke
Systemic complications (%)
SICH (%)
MR 2 at 90 days (%)
Mortality at 90 days (%)
Moment of death (days) (mean SD)

39.75
26.50
7.22
26.48
45.16
9.68
16.13
17.74
6.44
4.84
19.35
16 (2-24)
194.95 67.77
80.38 27.91
64.96 33.17
89.66
13
1
1
1
3
1
7.59
8.23
54.22
21.68
19.27 28.07

APs (n = 30)
80
3.33
3.33
13.33
60
4.17
29.17
4.17
12.51
0
0
17 (7-28)
199.71 71.22
88.67 42.66
55.57 21.51
93.33
10
0
0
0
0
0
7.14
16.66
46.67
6.66
19.50 24.74

P value
.004

.431

.012
.459
.753
.318
.309
.423
.031
.351

.642
.169
.452
.064
.108

Abbreviations: AB P1, basilar artery and/or P1 portion from the posterior cerbral artery; AP, anticoagulated patient; ICA, internal carotid
artery; ICH, intracranial hemorrhage; MR, magnetic resonance; N-AP, non-anticoagulated patient; NIHSS, National Institutes of Health Stroke
Scale; NRL, neurological; SD, standard deviation; SICH, symptomatic intracranial hemorrhage; tandem ECIC, tandem extracranial
intracranial; Tandem ICA-IC, tandem internal carotid artery-intracranial occlusion; TICA, terminal internal carotid artery; TICI, thrombolysis
in cerebral infarction; TOAST, Trial of Org 10172 in Acute Stroke Treatment.
Bold numbers: Statistically significative differences between both groups: APs were older, HTA and cardioembolic sources were more frequent between APs.

We hypothesized that N-APs may have other characteristics that interfere with good progress. They more
frequently had atherothrombotic stroke and they presented other potentially severe complications, such as

reperfusion syndrome or vessel reocclusion. It should be

noted that in atherothrombotic stroke, cerebral tissue is
chronically hypoperfused, leading to impaired vasoreactivity
and greater vulnerability.

Table 3. Comparison between antithrombotic treatments/range of anticoagulation and security and functional outcomes

Antiplatelets (%)
ICH (%)
SICH (%)
Mortality at 90 days (%)
MR 2 at 90 days (%)

N-APs (n = 87)

APs (INR < 1.7) (n = 17)

APs (INR 1.7) (n = 12)

P value

39.13
14.11
8.23
21.69
54.21

14.36
37.61
17.64
0
64.71

0
33.33
17
17
16.67

.076
.264
.572
.381
.042

Abbreviations: AP, anticoagulated patient; ICH, intracranial hemorrhage; INR, International Normalized Ratio; MR, magnetic resonance;
N-AP, non-anticoagulated patient; SICH, symptomatic intracranial hemorrhage.
Bold numbers: Statistically significative differences between both groups: APs were older, HTA and cardioembolic sources were more frequent between APs.

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MECHANICAL THROMBECTOMY IN ANTICOAGULATED PATIENTS

We took into consideration some possible confounding factors as the time window for intervention or
differences in mismatch between both groups of patients. It may be expected that carotid lesions have
considerably reduced the time window because of the
significantly affected cerebrovascular reserve, but there
were no differences in terms of onset to groin puncture,
door to groin puncture, or groin puncture to recanalization comparing groups. Perhaps this fact would be more
relevant in case of a longer time window, but in our protocol it is 4.5 hours for anterior circulation strokes. All
patients underwent multimodal CT and sometimes, when
time of onset and multimodal CT were unclear, an MR
was carried out. In all cases, the infarct core according
to the CBV was less than a third of the affected tissue,
measured by MTT and TTP in multimodal CT. A clinical
radiological mismatch was also demonstrated and there
were no differences between both groups of the sample.
We also found interesting the verification that AP suffered mainly from cardioembolic stroke, despite being
under the correct prophylaxis with anticoagulants.
However, we also observed that 65.51% of the APs had
INR less than 2, which can in part explain this fact.
Antiplatelets were more frequent in N-APs, although
without a statistically significant association. This fact is
consistent in comparison between APs and N-APs, and
also when we compared N-APs and sufficiently APs
(INR 1.7). Furthermore, ICH was more frequent in APs,
regardless of range of anticoagulation, and without a statistical difference. Moreover, symptomatic ICH was not
related to APs regardless of the dosage. Other studies
tried to explore these aspects with higher SICH rates in
case of APs under heparin, and also with a lower rate
of patient independency at 3 months, perhaps because
of a lower rate of recanalization.23
Mortality was similar when we compared N-APs and
APs with correct anticoagulation dosage. Perhaps this was
influenced by the more complicated tandem lesions and
more systemic complications in case of N-APs and the
higher risk of hemorrhage in the adequate INR range of
APs. APs under dicumarins trended toward lower mortality, perhaps with a lower risk of ICH and clots that
were easier to be removed, most of them cardioembolic,
compared to atherotrombotic and tandem lesions. So, this
fact may explain the big difference in terms of mortality
between underdose APs and INR greater than or equal
to 1.7. APs with INR less than 1.7 are in a lower risk to
hemorrhage and an easy clot to be removed, whereas APs
with INR greater than or equal to 1.7 were perhaps in a
higher hemorrhagic risk and N-APs in a higher risk of
systemic complications. Anyway, we are not accurate in
this explanation. However, dependency at 90 days was
higher in APs with the correct dosage of dicumarins, without
more systemic complications, and without higher significant hemorrhage rates as Tables 2 and 3 show. We consider
that this is a limit of the study, perhaps for a small sample,

as even though without an absence of significant association, both ranges of dosage APs suffer from more
hemorrhages. Furthermore, it could be possible that in
case of INR greater than or equal to 1.7, the SICHs were
more severe. Anyway, MT seems to be a valid treatment
option in APs, mostly in those with INR less than 1.7.
Acknowledgments: We acknowledge the previous and present
colleagues who make possible the stroke code in our region.

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