Keywords combined technique - intravenous thrombolysis - anterior circulation stroke - Solitaire
stent - outcome
Introduction
Acute ischemic stroke (AIS) caused by large vessels occlusion (LVO) is also one of
the major causes of death and disabilities.[1 ] Therefore, re-establishment of blood flow is necessary as early as possible to prevent
morbidity and mortality. Revascularization following intravenous thrombolysis (IVT)
or mechanical thrombectomy (MT) in AIS patients with LVOs is a significant predictive
factor for functional outcome.[2 ] IVT with recombinant tissue plasminogen activator (rt-PA) has become standard therapy
with better clinical results for 20 years;[3 ] however, effectiveness of IVT is confined due to time frame where it should be given
within 4.5 hours of onset of symptoms having no history of recent surgery/active bleeding/blood
coagulation disorder as well as lower rate of recanalization in AIS with LVO.[4 ] The effectiveness in clinical outcome by using the newest generation thrombectomy
device, called as stent retriever, in AIS because of LVO is superior compared with
systemic thrombolysis alone, and has been described in a series of large-scale randomized
trials.[5 ] However, the application of IVT by rt-PA within 4.5 hours after symptom onset in
AIS caused by LVO and (MT has become a standard of care with significant reduction
in mortality and disabilities.[5 ]
[6 ] Furthermore, longer stent retriever MT may cause higher friction and shearing forces,
leading to damage to the vessel's wall or tearing of perforators, and postprocedural
complications have been reported in literature.[7 ]
[8 ] However, it has been described that age was independent for MT, age directly affected
the clinical outcome.[9 ] Older people tend to have more significant comorbidities such as atherosclerosis,
hypertension (HTN), diabetes mellitus (DM), which alter brain plasticity, arterial
collateral network, and self-recovering system.[10 ]
[11 ] These predictive factors may lead to vascular remodeling, which can cause technical
difficulties, and procedure time has been reported.[12 ] The purpose of this study was to assess the safety and efficacy of the combined
technique with Solitaire (Medtronic, Irvine, California, United States) stent in anterior
circulation stroke in two different age groups as well as to analyze predictive factors
for outcome.
Materials and Methods
Patient Selection
We retrospectively studied all patients (n = 500) who had ≥ modified thrombolysis in cerebral infarction (mTICI)2b following
Solitaire stent retriever MT after IVT with AIS caused by LVO of anterior circulation
between January 2015 and January 2024 ([Fig. 1 ]). Among consecutive patients, those who have been initiated IVT within 4.5 hours
after onset were included. Additionally, we limited this study to LVO of intracranial
internal carotid artery, proximal middle cerebral artery (M1/M2), and proximal anterior
cerebral artery (A1/A2) established using cerebral DSA. Patient with age younger than
18 years, posterior circulation stroke, as well as postthrombectomy < mTICI2b grade
were excluded from this study. Patient's data included age, sex, medical history,
history of antithrombotic medications, National Institute of Health Stroke Scale (NIHSS)
score assessed by neurologist at emergency department, and etiology of AIS, which
was classified based on the Trial of Org 10172 in Acute Stroke Treatment.[13 ] Procedural variables included Alberta Stroke Program Early CT Score (ASPECTS) on
admission based on brain computed tomography scan, site of vascular occlusion, and
onset to puncture (OTP) defined as the time from stroke onset to puncture time. Two
age groups were dichotomized, young age group (age ≤50 years) and old age group (age
>50 years) and compared with variables. Postprocedural variables included puncture
to recanalization (PTR) time defined as the time from puncture time to recanalization,
and score of mTICI after thrombectomy. Outcome measures included postprocedural hemorrhage
within 7 days, decompressive hemicraniectomy within 7 days, favorable outcome (modified
Rankin scale [mRS] 0–2) at 3 months, and mortality at 3 months. Favorable outcome
was defined as mRS ≤2 and unfavorable outcome as mRS >2 at 3 months. This is a retrospective
study, so informed consent was taken from the institute as well as from all participants
included in this study. This study was approved by local Institutional Review Board.
Fig. 1 Flow chart of included patients. AIS, acute ischemic stroke; IVT, intravenous thrombolysis;
MT, mechanical thrombectomy; LVO, large vessels occlusion; mTICI, modified thrombolysis
in cerebral infarction.
Procedure
All procedures were performed by single neurointerventionalist under general anesthesia.
Prior to MT, all patients were administered rt-PA intravenously within 4.5 hours of
stroke onset at a maximum dose of 0.9 mg/kg by a neurologist according to the conventional
guidelines.[14 ] MT was performed using second-generation stent retriever (4 × 40 mm—Solitaire, Medtronic).
A 6-Fr, 90-cm Shuttle sheath (Cook Medical, Bloomington, Indiana, United States) was
used as the guiding catheter. A distal access catheter, Navien 5F, 0.058Inch (EV3,
Medtronic) was used. Microcatheter, Phenom 21 (Medtronic) was advanced to the target
location with the support of microwire, Synchro select, 0.0014 Inch (Stryker Neurovascular,
United States). Microwire was removed, and the Solitaire stent was advanced and placed
at the occlusion site for 5 minutes. The stent was retrieved with simultaneous aspiration
from the distal access catheter (by a 50-mL syringe).[15 ] After each pass of device recanalization, status was assessed based on the mTICI
score and noted as per inclusion criteria.
Statistical Analysis
Patients were dichotomized by age based on whether they were younger or older than
50 years at the time of intervention. All data are expressed as mean and standard
deviation or median and range for continuous variables and number of patients with
percentage for categorical variables, where appropriate. Comparative analyses between
patients who achieved favorable and unfavorable outcomes as well as baseline characteristics,
clinical variables, and clinical outcomes between the two age groups were performed
using the Student's t -test, chi-square test, and Fisher's exact test, as appropriate. Statistical analyses
were performed using SPSS 26.0 for Windows (SPSS Inc.; Chicago, Illinois, United States).
A p -value of less than 0.05 was considered statistically significant.
Results
There were 500 patients who had ≥mTICI2b following IVT and Solitaire stent retriever
(size 4 × 40 mm) MT between January 2015 and January 2024. There were 59.03% male
and 40.97% female in the young age group, and 56.18% male and 43.82% female in the
old age group. Major vascular risk factors were: HTN (59.02%), DM (50.69%), dyslipidemia
(47.22%), coronary artery diseases (36.80%), and smoking (31.25%) in young age group;
and dyslipidemia (79.21%), DM (76.40%), HTN (74.43%), coronary artery diseases (51.68%),
and smoking (46.91%) in old age group in which there was significant association between
the two groups (p = 0.0004). There was a significant association of stroke etiologies with these two
age groups (p = 0.0090), where large vessels atherosclerosis/cardioembolic origin were 42.36%/23.62%
and 40.45%/28.09% in the young and old age groups, respectively. PTR time was significantly
different between these two age groups (p < 0.0001), where mean time was 24.45 and 32.81 minutes in the young and old age groups,
respectively ([Table 1 ]).
Table 1
Baseline characteristics of two age grouped patients with acute ischemic stroke of
anterior circulation
Variables
Young age group (≤50 y)
Old age group (>50 y)
p -Value
Age,(mean ± SD), y
37.10 ± 10.56 (22–50)
63.55 ± 7.81 (52–84)
<0.0001
Sex
Male
85 (59.03%)
200 (56.18%)
0.5602
Female
59 (40.97%)
156 (43.82%)
Medical history
Hypertension
85 (59.02%)
265 (74.43%)
0.0007
Smoking history
73 (50.69%)
167 (46.35%)
Atrial fibrillation
27 (18.75%)
65 (18.26%)
Coronary artery disease
53 (36.80%)
184 (51.68%)
Dyslipidemia
68 (47.22%)
282 (79.21%)
Previous stroke history
24 (16.66%)
95 (26.68%)
Use of antithrombotic drugs
38 (26.38%)
124 (34.83%)
Diabetes mellitus
45 (31.25%)
272 (76.40%)
Alcoholic history
24 (16.22%)
90 (25.28%)
NIHSS score at admission, median (IQR)
12 (9–18)
14 (9–19)
0.3493
ASPECTS, median (IQR)
8 (7–8)
8 (7–8)
0.5811
Stroke etiology
Large artery atherosclerosis
52 (36.11%)
153 (42.98%)
0.0431
Cardio embolic
58 (40.28%)
113 (31.74%)
Others or unknown
34 (23.61%)
90 (25.28%)
Vascular occlusion site
MCA (M1/M2)
84 (58.33%)
190 (53.37%)
0.0694
ACA (A1/A2)
15 (10.41%)
45 (12.64%)
T-occlusion
18 (12.5%)
34 (9.55%)
ICA and M1/M2
13 (9.02%)
62 (17.41%)
ICA and A1/A2
14 (9.72%)
25 (7.02%)
Time of onset to recanalization, min
Onset to puncture, min
173.8 (120–240)
176.5 (120–240)
0.6512
Puncture to recanalization, min
25.45 (7–60)
32.81 (5–75)
<0.0001
Modified TICI grade(postthrombectomy)
mTICI2b/2c
78 (54.16%)
206 (57.86%)
0.4496
mTICI3
66 (45.84%)
150 (42.14%)
Abbreviations: ACA, anterior cerebral artery; ASPECTS, Alberta Stroke Program Early
CT Score; ICA, internal carotid artery; IQR, interquartile range; MCA, middle cerebral
artery; mTICI, modified thrombolysis in cerebral infarction; NIHSS, National Institute
of Health Stroke Scale; SD, standard deviation; TICI, thrombolysis in cerebral infarction.
There was a significant association of age between functional and nonfunctional outcomes
(p < 0.0292). Younger age had 69.44% of favorable outcome and 30.56% of unfavorable
outcome, and older age had 58.98% of favorable outcome and 41.02% of unfavorable outcome.
The NIHSS score at admission was significantly associated with functional outcome.
The NIHSS score less than 15 at admission had 57.20% of favorable outcome compared
with NIHSS score more than 15 (38.60%). The ASPECTS having less than 5 had 59.85%
of favorable outcome and 40.115% of unfavorable outcome, and ASPECTS more than 5 had
41.50% of favorable outcome and 58.50% of unfavorable outcome. Onset to recanalization
time was significantly associated with outcome (p <0.0001) ([Table 2 ]).
Table 2
Factors for outcomes of patients with acute ischemic stroke of anterior circulation
after IVT and MT
Variables
Favorable outcome (mRS < 2)
Unfavorable outcome (mRS > 2)
p -Value
Age, y
≤50
100 (69.44%)
44 (30.56%)
0.0292
> 50
210 (58.98%)
146 (41.02%)
Medical history
Hypertension
250 (71.42%)
100 (28.57%)
0.4222
Smoking history
180 (52.17%)
165 (47.82%)
Atrial fibrillation
50 (54.34%)
42 (45.65%)
Coronary artery disease
128 (54.01%)
109 (45.99%)
Dyslipidemia
150 (42.86%)
200 (57.14%)
Use of antithrombotic drugs
116 (71.60%)
46 (28.40%)
Previous stroke history
44 (36.97%)
75 (63.03%)
Diabetes mellitus
86 (40.56%)
126 (59.44%)
Alcoholic history
65 (57.02%)
49 (42.98%)
NIHSS score at admission
< 15
123 (57.20%)
92 (42.79%)
<0.0001
> 15
110 (38.60%)
175 (61.40%)
ASPECTS
< 5
100 (41.50%)
141 (58.50%)
<0.0001
> 5
155 (59.85%)
104 (40.15%)
Stroke etiology
Large artery atherosclerosis
127 (61.96%)
78 (38.04%)
0.3038
Cardio embolic
97 (56.73%)
74 (43.27%)
Vascular occlusion site
MCA (M1/M2)
170 (62.04%)
104 (37.96%)
0.0768
ACA (A1/A2)
48 (80%)
12 (20%)
T-occlusion
32 (61.54%)
20 (38.46%)
ICA and M1/M2
41 (54.67%)
34 (45.34%)
ICA and A1/A2
25 (64.10%)
14 (35.90%)
Episodes of stent pass to reperfusion
First pass
108 (55.67%)
86 (44.33%)
0.7476
Second pass
111 (58.42%)
79 (41.58%)
Multiple pass
42 (36.20%)
74 (63.80%)
Modified TICI grade (postthrombectomy)
mTICI2b/2c
135 (47.54%)
149 (52.46%)
0.0013
mTICI3
134 (62.03%)
82 (27.97%)
Onset to recanalization, min
< 4 h
212 (68.38%)
98 (31.62%)
<0.0001
> 4 h
67 (35.26%)
123 (64.745)
Abbreviations: ACA, anterior cerebral artery; ASPECTS, Alberta Stroke Program Early
CT Score; ICA, internal carotid artery; IVT, intravenous thrombolysis; CA, middle
cerebral artery; MT, mechanical thrombectomy; mTICI, modified thrombolysis in cerebral
infarction; NIHSS, National Institute of Health Stroke Scale; TICI, thrombolysis in
cerebral infarction.
We did not find device-related problem in all cases. The procedural and clinical outcomes
were not significantly associated with age groups (p = 0.0806). Symptomatic intracerebral hemorrhage (ICH) within 7 days of procedure
was found 15.97 and 25.56% in the young and old age groups, respectively, where 10.42%
in the young age group and 11.52% in the old age group underwent decompressive surgery
within 7 days after the procedure. Functional outcome at 90 days was noted as 79.86
and 69.10% in the young age group and the old age group, respectively. Similarly,
mortality at 90 days was 6.9 and 10.95% in the young and the old age groups, respectively
([Table 3 ]).
Table 3
Procedural and clinical outcomes following treatment in the two age groups of acute
ischemic stroke of anterior circulation
Variables
Young age group (≤50 y)
Old age group (>50 y)
p -Value
Procedural and clinical outcome
Symptomatic ICH within 7 d
23 (15.97%)
91 (25.56%)
0.0497
Second surgery (DHC) within 7 d
15 (10.42%)
47 (13.20%)
Favorable outcome (mRS 0–2) at 90 d
115 (79.86%)
246 (69.10%)
Mortality (mRS 6) at 90 d
11 (6.9%)
57 (16.01%)
Abbreviations: DHC, decompressive hemicraniectomy; ICH, intracerebral hemorrhage;
mRS, modified Rankin scale.
Discussion
In this present study, we found that AIS of LVO in anterior circulation treated with
combined technique following IVT by rt-PA was safe and effective. Eight randomized
trials have demonstrated the value of MT in addition to IVT for AIS patients harboring
an LVO in anterior circulation,[16 ] where majority of patient enrolled in these trials had received IV rt-PA before
MT in which IVT is not contradicted. However, the matter of whether MT without prior
IVT is better or worse than combined treatment is now matter of strong debate.[16 ] Many arguments have been advanced in favor of pretreatment with IVT, including the
opportunity of an early reperfusion or even in case of failure of MT, and possible
reopening of distal occluded vessels after MT.[17 ] Solitaire 4 × 40 had better recanalization rate, and similarly, 58.7 to 88.0% of
rate of recanalization were reported in the literature using stent retriever MT.[5 ]
[7 ] Furthermore, longer or oversized Solitaire stent may cause more friction and result
in trauma to vessels' wall as well as straighten the vessels during device retrieval.[18 ] However, we did not notice more friction and traumatic injuries while using Solitaire
4 × 40 in our study. Solitaire 2 Fr 4 × 40 is laser-cut, closed-cell, nitinol stent
specifically designed to retrieve larger clots and negotiate tortuous anatomies where
it can be difficult to achieve an exact stent placement to cover the clot in large
vessels AIS.[7 ]
In the MR CLEAN Registry, a prospective survey from the Netherlands, ∼10% of patients
treated with endovascular therapy were young patients with LVO, where 9.61% of patients
were young, 18 to 49 years old, and 90.39% of older patients, >50 years,[10 ] which is lower than our data of 22.8% of young patients (144/500). AIS caused by
cardioembolic causes (40.28%) was found to be significantly higher in young age than
older age (31.74%), and large artery atherosclerosis (42.98%) was found to be significantly
higher in older age than younger age (36.11%) (p = 0.0431), which is consistent with other study where cardioembolic causes was most
common causes of stroke caused by embolic stroke of undermined source in young age
followed by carotid dissection.[10 ] Dyslipidemia (79.21%) was more common risk factor for AIS followed by DM (76.40%)
and HTN (74.43%) in older age group, while HTN (59.02%) was more common in younger
age group followed by smoking history (50.69%) and dyslipidemia (47.22%) (p = 0.0007) in our study. Likewise, HTN was found to be more common followed by hypercholesterolemia
in both young and older age groups (p < 0.001),[10 ] which is inconsistent with a study where AF ischemic heart diseases were more common
in the older age and where smoking was more common in the younger age group and where
smoking was more common in the younger age group.[19 ] The median NIHSS score at admission was 12 in the younger age group and 14 in the
older age group, but no significant differences (p = 0.3493) were noted. Our finding was almost similar to the report of the previous
studies where the median NIHHS score 13 to 14 in the younger age group and 15 to 16
in the older age group have been described.[10 ]
[20 ]
Our study showed that mortality rate was significantly higher in older patients (16.01%,
57/356) compared with younger patients (6.9%, 11/144), and favorable outcome, mRS
0 to 2 was 69.10% (246/356) in older patients and 79.86% (115/144) in younger patients
at 90 days. Symptomatic ICH was found to be lower (15.97% [23/144]) in young age group
as compared with older age group (25.56% [91/356]) (p = 0.0497). Shi et al described no significant association between younger patients
and older patients (>50 years) with AIS with regard to good clinical outcome, successful
reperfusion, mortality and symptomatic ICH,[21 ]
[22 ] which is contrast with another study where mortality and symptomatic ICH were significantly
lower in younger age group with similar reperfusion rate.[10 ] Similarly, we observed that there was no significant association between these two
age groups with reperfusion grading (mTICI2b/2c and mTICI3) after MT (p = 0.1121). Furthermore, our younger age group with AIS had more favorable outcome
and lower mortality rate compared with older age group, which is consistent to other
studies where 61 to 87%[11 ]
[14 ]
[23 ]
[24 ] of favorable outcomes and 7 to 12%[10 ]
[25 ] of mortality in younger patients have been reported. Our mortality rate was lower
than a study done by Li et al where mortality rate was 32.3% (21/113) in young patients
(<50 years) with AIS with LVO following MT.[19 ] Elder people tend to have more comorbidities such as HTN, DM, atherosclerosis, as
well as natural aging process with decreasing immunity which may hamper in elasticity
of brain or arterial collateral circulation and ability to recover.[10 ] These explanations are consistent with our findings, such as arterial HTN, DM, coronary
artery diseases, dyslipidemia; previous stroke history and use of antithrombotic drugs
were significantly higher in older patients compared with younger patients in this
present study, which may be major reasons for poor functional outcome and more mortality
in older age patients.
Combined technique after IVT for AIS with LVO is also safe and effective in older
patients; however, age is significant predictor of functional outcome following MT.[26 ] The HERMES study described better outcomes of patients treated with MT versus medical
therapy at 3 months follow-up and revealed that older patients populations get benefit
even more from MT than younger patients.[9 ] But, younger age was significantly associated with higher rate (69.44%, 11/144)
of favorable outcome compared with older patients (58.98%, 210/356) (p = 0.0292) in our study. The rates of recanalization are higher in young patients
and may lead to high favorable outcome, which may be due to less tortuosity of arterial
anatomy and atherosclerosis in younger populations.[27 ] Furthermore, risk factors for stroke, etiologies, frequency of stent pass, and vascular
occlusion site were not found to be significant predictive factor for outcome. The
NIHSS score less than 15 at admission was found to be significantly associated with
57.20% (123/215) of favorable outcome and 42.79% (92/215) of unfavorable outcome as
compared with NIHSS score more than 15 at admission; and NIHSS score more than 15
at admission was found to be directly related with higher unfavorable outcome (61.40%,
174/285) and low favorable outcome (38.60%, 110/285) (p < 0.0001). Similarly, ASPECTS were also significantly differences with favorable
and unfavorable outcomes (p < 0.0001), where ASPECTS more than 5 were found to be significant predictor for high
favorable outcome (59.85%, 155/259) as compared with ASPECTS less than 5. Our findings
are deferent with other study, where NIHSS and ASPECTS were independent predictors
of favorable outcome.[28 ] Campbell et al described that great benefit and good outcome can be obtained from
patients with AIS having NIHSS score ≤15 as compared with stroke patients with NIHSS
score >20.[29 ] We also noted that onset to recanalization time was directly associated with outcome.
Onset to recanalization time (ORT) < 4 hours or > 4 hours were found to be significant
differences with more favorable outcome and unfavorable outcome (p < 0.0001). There was higher favorable outcome when ORT less than 4 hours (68.38%,
212/310) compared with ORT > 4 hours (35.26%, 67/190). Similar to our results, symptoms
onset to recanalization or reperfusion were strongly associated with more favorable
outcome with loss of significant treatment by 6 hours have been described in the MR
CLEAN trail.[30 ] Earlier recanalization after MT following IVT may lead to earlier reperfusion of
ischemic/penumbra brain which may positively impact on favorable outcome in patients
with AIS caused by LVO. A higher mTICI grade, mTICI3, was found to be significantly
associated with more favorable outcome as compared with mTICI2b/c (p = 0.0013) in our study.
To our knowledge, this is first study to examine the predictive factors for favorable
and unfavorable outcomes as well as adverse results including mortality rate at 3
months in young (≤50 years) and old (>50 years) age patients with AIS caused by LVO
in anterior circulation treated by combined technique after IVT. However, there are
some limitations of our study: its retrospective design and relatively numbers of
patients are not large enough. And also, sample sizes of the younger age groups were
rather small as compared with older age groups. In addition to, this is a single-center
study of observational character. Only inclusion of patients with mTICI >2b is also
another limitation. We also could not describe the different score of mTICI after
MT as well as analyze to evaluate its effect on functional outcome. This study should
include onset to door, door to puncture along with PTR time to correlate with functional
outcome. We also did not explain different local and systemic complications such as
puncture site hematoma, deep vein thrombosis, pneumonia, pulmonary embolism, status
of secondary vasospasm, and brain edema, which might also be causes of mortality in
patients with AIS due to LVO after MT following IVT. Moreover, collateral circulation
plays a pivotal role in maintaining viable brain tissue for a longer period and allowing
a secondary path for reperfusion therapies, and has evolved as a prognostic factor
to consider when selecting patients for acute ischemic treatments.[31 ] Collateral circulation status in patients who had a functional outcome needs to
be studied, which was not described in our study.
Conclusion
In conclusion, combined technique after IVT for patients with AIS caused by LVO in
anterior circulation is safe and effective. However, mortality rate is lower, and
functional outcome is higher in younger age groups as compared with old age groups
at 3 months following thrombectomy. Patient age ≤50 years, NIHSS score at admission<
15, ASPECTS >5, mTICI3, and onset to recanalization time < 4 hours were found to be
significant predictive factors for functional outcome in our study.
