Abstract
Aims: Carotid reocclusion (CRO) after mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to tandem lesion (TL) or isolated internal carotid occlusion (ICO) is associated with worse clinical outcomes. Our aim was to analyze the predictors and clinical impact of CRO.
Methods: A retrospective single-center analysis of all patients with anterior circulation strokes who underwent MT prospectively included in a registry between 2017 and 2020 was performed. ICO and TL as stroke causes were included. Stent deployment was left to the discretion of the interventionist. All patients received at least intravenous aspirin during MT. CRO was assessed using ultrasound within the first 24 h after MT. Efficacy and safety of stenting were assessed.
Results: Among 1304 AIS cases, 218 (16.7%) were related to TL or ICO. Of them, 5% (n=11) were associated with internal CRO 24 h after the endovascular procedure. After adjusting per confounders, multivariate analysis showed that the independent variables associated with CRO were the TICI recanalization grade [TICI 2b–3; OR 0.1, 95% confidence interval (CI) 0.01–0.89, p=0.040], pial collateral circulation presence (OR 0.09, 95% CI 0.02–0.45, p=0.03), stent deployment during MT (OR 0.17, 95% CI 0.03–0.84, p=0.030), and general anesthesia use (OR 2.92, 95% CI 1.13–7.90, p=0.034). CRO showed a trend toward worst outcomes (modified Rankin scale 3–6) at 3 months (OR 3.4, 95% CI 0.96–12, p=0.057). After multivariate analysis, variables independently associated with worse outcomes at 90 days were intrastent platelet aggregation phenomena during endovascular therapy, admission National Institute of Health Stroke Scale, and age. Conversely, intravenous thrombolysis and TICI 2b–3 recanalization grade were identified as independent predictors of good outcomes at 90 days.
Conclusions: CRO has a relevant clinical impact in our study, associating lower rates of good functional outcomes at 3 months. Independent factors of CRO were the recanalization degree, presence of pial collateral circulation, use of a stent as a protective factor, and use of general anesthesia during thrombectomy.
Introduction
Approximately 20% of patients with anterior circulation acute ischemic stroke (AIS) due to tandem lesions (TLs) undergo mechanical thrombectomy (MT). TL is defined as severe stenosis or occlusion of the internal carotid artery (ICA) associated with ipsilateral intracranial occlusion1). As shown in the HERMES meta-analysis2) and multicenter registry studies such as the collaborative group TITAN3-5) among others6-7), MT has demonstrated clinical benefit in TL, comparable to isolated intracranial occlusions. However, although intracranial recanalization in AIS is widely supported2), there is no general consensus about extracranial lesion management in TL8). Optimal antiplatelet treatment strategies to maximize recanalization success and minimize cervical complications is the goal of endovascular recanalization therapy for TLs. This antiplatelet strategy aims to control the appearance of distal cerebral thromboembolic events and stent reocclusion, without an increase in symptomatic intracranial hemorrhage (sICH). ICA patency within the first 24 h after MT has been more frequently observed in patients treated with balloon angioplasty or stenting in the acute phase than in those managed only with medical treatment and has been related to better clinical outcomes9-10). However, the antiplatelet protocol used in the acute phase probably has an impact in the development of carotid reocclusion (CRO) and sICH. The rates of reocclusion were reported to be up to 22%10), and reocclusion seems to be a relevant complication given its possible relation with higher rates of sICH, worse functional outcomes, and worse neurological recovery data10).
Aim
CRO rates in the acute management of TL and its clinical implications and risk predictors are yet to be defined. Our aim was to analyze the predictors and clinical impact of CRO.
Methods
A retrospective single-center analysis of all patients with anterior circulation strokes who underwent MT prospectively included in a registry between 2017 and 2020 was performed.
Patient Selection
Patients were eligible for study if they had anterior AIS within 6 h of symptom onset or within 6–24 h or a wake-up stroke with MT criteria based on advanced brain imaging (computed tomography (CT) perfusion)1). The inclusion criteria were as follows: 1) 18 years of age and older; 2) pre-stroke modified Rankin scale (mRS) 0–2; 3) National Institute of Health Stroke Scale (NIHSS) score of ≥ 6 or a disabling neurological deficit; 4) tandem occlusions with intracranial vascular occlusion in the terminal ICA, the M1 or M2 segments of the middle cerebral artery, or an isolated internal carotid occlusion (ICO); 5) Alberta Stroke Program Early CT Score (ASPECTS) of ≥ 6, with all evaluations carried out using an artificial intelligence and deep learning software package (e-ASPECTS, Brainomix®); and 6) fulfilling the DAWN11) or DEFUSE 3 12) eligibility criteria on wake-up stroke and the 6- to 24-h treatment window. Patients with intracranial occlusive atherosclerotic disease or stroke due to arterial dissection were excluded from the study. Likewise, patients with prior atrial fibrillation were excluded from this study, selecting only those whose carotid occlusion or TL derived from an atherosclerotic lesion.
Endovascular Treatment
In the TL cases, our hospital’s protocol lays out that the intracranial occlusion should always be treated first (Fig.1). Accordingly, the intracranial occlusion was treated as the first step unless the cervical carotid stenosis or occlusion prevented the passage of the distal aspiration catheter employed as an endovascular technique for intracranial reperfusion (Microvention SOFIA™ or SOFIA™ PLUS catheter as the first choice), forcing cervical angioplasty prior to intracranial navigation. Endovascular treatment (EVT) was performed with groin local anesthesia as the primary option, and if needed, subsequent general anesthesia or conscious sedation was used. Intravenous (iv) thrombolysis was administered to elective patients according to guidelines. In case of rtPA administration, 250 mg of iv aspirin was employed at the beginning of the endovascular procedure. In patients who did not receive rtPA, 500 mg of aspirin was administered. Further use of double antiplatelet therapy with orally administered clopidogrel or intraarterial glycoprotein platelet inhibitor (i.e., abciximab or tirofiban) was decided according to the individual discretion of the neurologist and neurorradiologist. Angiographic collateral grade was evaluated according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology Collateral Flow Grading System on baseline angiography13). When the score on this scale was ＞1 on the initial pre-MT angiography, we considered pial collateral circulation to be present. When initial angiography was performed, it was recommended that the anterior communicating artery and ipsilateral to occlusion site posterior communicating artery be evaluated. Once intracranial recanalization was achieved, treatment of the ICA lesion depended on residual cervical occlusion/severe stenosis or thrombus formation after waiting for 30 minutes after intracranial recanalization achievement. In case of platelet aggregation phenomena or plaque instability (Fig.1), stent was placed (Wallstent™ endoprosthesis Boston Scientific or RX Acculink™ carotid stent system from Abbot), waiting for another 30 minutes, to monitor new complications in the vascular endoprosthesis, in which case intraarterial abciximab or low-dose iv tirofiban regimen was administered to resolve stent-associated thrombus formation. Aggregation phenomena or plaque instability was defined as an intrastent filling defect due to the formation of a de novo thrombus or the presence of a residual atherosclerotic plaque with a protrusion greater than 2 mm over the lumen of a vessel that slows intracranial circulation. The procedure was terminated once stability in stent patency was achieved, as confirmed by the absence of an intrastent filling defect as indicative of platelet aggregation phenomena. Abciximab was administered from 2017 to 2019 (range of 2–8 mg). As of 2020, the administration of abciximab was replaced by a low-dose regimen of tirofiban. The low-dose tirofiban regimen started with a 500-µg bolus injection of tirofiban over 5 minutes. After 5 minutes, the dose was lowered to 200 µg/h for 24 h (total infused dose of 96 ml).
In the ICO cases, once the carotid occlusion was overcome, the placement of distal embolic protection was left to the discretion of the interventionist. Then, when necessary, cervical angioplasty was performed prior to the placement of a carotid stent (Wallstent™ endoprosthesis from Boston Scientific or the RX Acculink™ carotid stent system from Abbot). Antiplatelet management and completion of the procedure once carotid patency was obtained followed the same guidelines specified in the case of TLs.
Data Collection and Assessment
Demographic, radiologic, and clinical data were collected in the prospective ARTISTA registry (A Registry for Thrombectomy In Stroke Therapy from Andalusia), which was maintained jointly by interventional neuroradiologists and vascular neurologists.
To evaluate the presence of CRO, a Doppler ultrasound control of the stent was performed 24 h after the EVT. The following was determined:
- Presence of residual intrastent stenosis ≥ 70%: defined as a peak systolic velocity (PSV) ≥ 300 cm/s.
- Intrastent reocclusion: defined by the presence before the occlusion point by a characteristic biphasic, brief, and low-speed pattern both in the Doppler spectrum and in color mode (color image with both orthodromic and antidromic flow, just red-blue proximal to the occlusion). In addition, the image detected in mode B shows a hypoechoic or anechoic appearance, detecting the absence of flow in color and Doppler modes.
Successful recanalization was defined as modified Thrombolysis In Cerebral Ischemia (mTICI) grade 2b–3 on the final angiogram. Radiological appearance of brain hemorrhages and detection of symptomatic intracranial hemorrhage (any hemorrhagic transformation temporally combined with a neurological deterioration of ≥ 4 NIHSS points from baseline) were evaluated according to the traditional European Cooperative Acute Stroke Study (ECASS) classification14) in a follow-up brain CT scan performed in the first 24 h after MT. Clinical outcome was assessed by an independent neurologist with extensive experience in cerebrovascular diseases. The NIHSS before the procedure, after the procedure, and upon discharge was used, and functional evaluation using the mRS at discharge and 3 months after stroke was carried out. Ninety-day mRS was used to determine the neurological outcome of patients. Favorable outcome was defined by an mRS of ≤ 2.
Ethical Aspects and External Validity
The ARTISTA registry study protocol and the consent forms were approved by the institutional review board (ID 0992-N-17). All patients or relatives signed informed consent forms, including statements about the use of data for research.
Statistical Analysis
All categorical variables are presented as number and frequency (%), while continuous variables are presented as mean±SD or median±IQR. In bivariate analysis, the
χ
2 test, Fisher’s exact test, Student’s t-test, the Mann–Whitney U test, the Kruskal–Wallis test, or ANOVA, as appropriate, was used.
Univariate logistic regression analysis was used to test the association between predictors and the outcome variable (CRO dichotomized) and between CRO occurrence and clinical items. Variables significantly associated with a CRO appearance (p＜0.15) in the univariate analysis were included in multivariate models. The final model was selected using a backward selection strategy.
All statistical analyses were performed using IBM® SPSS Statistics V.23. A p level＜0.005 indicated a statistically significant difference.
Results
Baseline Characteristics
Among 1304 AIS cases, 218 (16.7%) were related to TL or ICO. Specifically, of these 218 patients, 88.1% had a TL (n=192) and 11.9% internal carotid lesions without intracranial occlusion (n=26). Fifty-two patients (23.8%) presented platelet aggregation phenomena during the procedure and 5% (n=11) had CRO 24 h after the endovascular procedure. Of the 52 patients who presented intrastent aggregation, 50 (96.1%) received rescue therapy. Stent was deployed in 85.3% (n=186). The main basal sample characteristics, MT parameters, and general outcomes are shown in Supplementary Table 1.
Supplementary Table 1.
Characteristics of the sample at baseline
| Basal characteristics
|
| Variable |
n = 218
|
% |
| Sex (Male) |
176 |
80.7 |
| Age [Me (IQR)] |
68 (60-75.5) |
|
| Smoke |
88 |
40.4 |
| Hypertension |
171 |
78.4 |
| Diabetes mellitus |
64 |
29.8 |
| Dyslipidemia |
106 |
48.8 |
| Ischemic heart disease |
24 |
11.1 |
| Peripheral artery disease |
15 |
7 |
| Previous ASA |
70 |
32.1 |
| Previous Clopidogrel |
21 |
9.6 |
| Previous ASA + Clopidogrel |
17 |
7.8 |
| Unknown stroke onset |
74 |
33.9 |
| Admission NIHSS [Me (IQR)] |
14 (9-19) |
|
| Admission blood glucose [Me (IQR)] mg/dL |
115.5 (99.5-137.5) |
|
| Admission platelets account [Me (IQR)]( x 103/μL) |
223.5 (193.5-264) |
|
| Intravenous thrombolysis |
81 |
37.2 |
| Mechanical thrombectomy parameters
|
| Variable |
n
|
% |
| ASPECTS [Me (IQR)] |
8 (7-10) |
|
| Groin-recanalization time [Me (IQR)] |
40 (23.5-69) |
|
| Conscious sedation |
12 |
5.6 |
| General anesthesia |
9 |
4.2 |
| Stent deployment |
186 |
85.3 |
| Closed cell stent |
163 |
74.8 |
| TICI 2b-3 |
209 |
96.8 |
| Pial collateral circulation presence |
168 |
78.9 |
| Anterior communicating artery |
124 |
56.8 |
| ASA |
168 |
77.1 |
| Clopidogrel |
22 |
10.1 |
| Tirofiban |
21 |
9.6 |
| Abciximab |
19 |
8.7 |
| Double antiplatelet therapy |
39 |
17.9 |
| Outcomes
|
| Variable |
n
|
% |
| mRS 0-2 (90 days) |
140 |
64.2 |
| sICH |
9 |
4.1 |
| Death (during admission) |
13 |
6.0 |
| Death (90 days) |
22 |
10.1 |
N: number. IQR: interquartile range. CI: confidence interval. Me: Median. NIHSS: National Institute of Health Stroke Scale. ASPECTS : Alberta Stroke Program Early CT scale. IVT: intravenous thrombolysis. TICI: Thrombolysis in Cerebral Infarction scale (TICI 2b-3 is considered a degree of successful recanalization). ACom: anterior communicating artery. PCom: posterior communicating artery. TIA: transient ischemic attack. ASA: acetylsalicylic acid. EVT: endovascular treatment CT: computed tomography. mRS: modified rankin scale. sICH: symptomatic intracranial hemorrhage.
As shown in Table 1, in the univariate analysis, ICA reocclusion was related to higher NIHSS admission score, general anesthesia use, and poorer recanalization grades (TICI 0–2a). The presence of pial collateral circulation and anterior communicating artery were associated with lower reocclusion rates. In addition, a trend toward lower reocclusion rates was found with stent deployment.
Table 1.
Variables associated with internal carotid artery re-occlusion: univariate analysis
| Past medical history
|
| Variable |
Carotid re-occlusion |
Non Carotid re-occlusion |
p
|
| N = 11 |
% |
N = 207 |
% |
| Male |
9 |
81.8 |
167 |
80.6 |
1 |
| Smoke |
3 |
27.3 |
85 |
41.1 |
0.121 |
| Hypertension |
9 |
81.8 |
162 |
78.2 |
0.780 |
| Diabetes mellitus |
4 |
36.3 |
60 |
28.9 |
0.736 |
| Dyslipidemia |
6 |
54.5 |
100 |
48.3 |
0.698 |
| Ischemic heart disease |
3 |
27.3 |
21 |
10.1 |
0.108 |
| Peripheral artery disease |
1 |
9.1 |
14 |
6.7 |
0.558 |
| Previous ASA |
4 |
36.3 |
66 |
31.8 |
0.748 |
| Previous Clopidogrel |
0 |
0 |
21 |
10.1 |
0.606 |
| Previous ASA + Clopidogrel |
0 |
0 |
17 |
8.2 |
0.503 |
| Current stroke episode characteristics
|
|
|
|
|
|
| Unknown stroke onset |
6 |
54.5 |
68 |
32.8 |
0.190 |
| Intravenous fibrinolysis |
2 |
18.1 |
79 |
38.1 |
0.218 |
| Mechanical thrombectomy
|
|
|
|
|
|
| Conscious sedation |
2 |
18.1 |
10 |
4.8 |
0.073 |
| General anesthesia |
1 |
9.1 |
8 |
3.8 |
|
| Stent deployment |
7 |
63.6 |
179 |
86.4 |
0.060 |
| Closed cell stent |
6 |
54.5 |
157 |
75.8 |
0.150 |
| TICI 0-2a |
2 |
18.1 |
5 |
2.4 |
＜0.001＊
|
| Pial collateral circulation presence |
5 |
45.4 |
163 |
78.7 |
0.013＊
|
| Anterior Communicating artery |
3 |
27.7 |
121 |
58.4 |
0.004 |
| ASA |
9 |
81.8 |
159 |
76.8 |
0.729 |
| Clopidogrel |
1 |
9.1 |
21 |
10.1 |
0.910 |
| Tirofiban |
0 |
0 |
21 |
10.1 |
0.606 |
| Abciximab |
1 |
9.1 |
18 |
8.6 |
0.964 |
| Double antiplatelet therapy |
1 |
9.1 |
38 |
18.3 |
0.640 |
| Platelet aggregation phenomena |
2 |
18.1 |
50 |
24.1 |
0.651 |
| Quantitative variables
|
| Variable |
Carotid re-occlusion |
Non Carotid re-occlusion |
p
|
| Me (IQR) |
CI 95 % |
Me (IQR) |
CI 95% |
| Age |
69 (62-77) |
(62.1-78.5) |
69 (61-77) |
(67.5-70.2) |
0.397 |
| Admission NIHSS |
18.5 (14-24) |
(12.6-22.5) |
14 (9-19) |
(13-14.8) |
0.044＊
|
| Admission blood glucose mg/dL |
144 (125-188) |
(123.1-17.4) |
119,5 (101-150) |
(127.2-141.3) |
0.084 |
| Admission platelets account ( x 103/μL)
|
226 (163-294) |
(185.2-285.9) |
235 (196-269) |
(231.3-251.4) |
0.782 |
| ASPECTS |
8 (8-9) |
(7.6-9.1) |
8 (7-10) |
(8-8.4) |
0.934 |
| Groin-recanalization time |
46 (39-105) |
(25.6-119.1) |
40.5 (39-76) |
(50.1-63.6) |
0.603 |
N: number, IQR: interquartile range, CI: confidence interval, Me: Median, HTN: arterial hypertension, DM: diabetes mellitus, NIHSS: National Institute of Health Stroke Scale, ASPECTS : Alberta Stroke Program Early CT scale, IVT: intravenous thrombolysis, TICI: Thrombolysis in Cerebral Infarction scale (TICI 2b-3 is considered a degree of successful recanalization), ACom: anterior communicating artery, PCom: posterior communicating artery. TIA: transient ischemic attack, ASA: acetylsalicylic acid, EVT: endovascular treatment CT: computed tomography, mRS: modified rankin scale, sICH: symptomatic intracranial hemorrhage.
After adjusting per confounders, multivariate analysis (Fig.2) showed that the variables remaining independently associated with CRO were the TICI 2b–3 recanalization grade, pial collateral circulation presence, stent deployment during MT, and general anesthesia use. The Hosmer–Lemeshow test showed that the final model had an adequate goodness of fit (
χ
2 =1.940, p=0.585). The model correctly classified a total of 95.7% of cases.
CRO and Clinical Outcomes
According to the reocclusion/no reocclusion state, there was a significant relation of CRO with lower rates of good functional outcomes at 90 days in bivariate analysis (Table 2).
Table 2.
Clinical outcomes regarding re-occlusion occurrence
| Variable |
Re-occlusion |
No re-occlusion |
p
|
| N = 11 |
% |
N = 207 |
% |
| mRS 0-2 (90 days) |
4 |
36.4 |
136 |
66 |
0.045＊
|
| sICH |
0 |
0 |
9 |
4.3 |
0.480 |
| Death (during admission) |
2 |
18.1 |
11 |
5.3 |
0.079 |
| Death (90 days) |
3 |
27.2 |
19 |
9.2 |
0.069 |
Variables associated with clinical outcome at day 90 in the univariate logistic regression analysis are shown in Supplementary Table 2. CRO showed a trend toward worst outcomes (mRS 3–6) at 3 months [OR 3.4, 95% confidence interval (CI) 0.96–12, p=0.057]. In addition, the presence of intrastent platelet aggregation phenomena showed a statistical significance relation with worst clinical outcomes at 90 days (OR 2.91, 95% CI 1.52–5.53, p＜0.001). Additional variables significantly associated with poor clinical outcome were ASA intake prior to ischemic stroke episode, older age, and higher NIHSS at admission. Conversely, variables significantly related to better outcomes at 3 months were male sex, smoking habit, iv thrombolysis, and higher ASPECTS score at admission.
Supplementary Table 2.
Variables related to clinical outcome at 90 days univariate analysis
| Past medical history
|
| Variable |
mRS 3-6 (90 days) |
| OR (CI 95%) |
p
|
| Male |
0.41 (0.21-0.82) |
0.012 |
| Smoke |
0.44 (0.23-0.84) |
0.013 |
| HTN |
0.85 (0.43-1.66) |
0.649 |
| DM |
0.76 (0.41-1.42) |
0.395 |
| Dyslipidemia |
0.75 (0.43-1.32) |
0.330 |
| Ischemic heart disease |
0.89 (0.36-2.18) |
0.802 |
| Peripheral artery disease |
2.25 (0.78-6.47) |
0.132 |
| ASA |
2.16 (1.20-3.91) |
0.010 |
| Clopidogrel |
0.53 (0.18-1.53) |
0.245 |
| ASA + Clopidogrel |
2.4 (0.74-7.71) |
0.142 |
| Current stroke episode characteristics
|
|
|
| Unknown stroke onset |
1.39 (0.77-2.48) |
0.264 |
| intravenous fibrinolysis |
0.45 (0.24-0.83) |
0.011 |
| Mechanical thrombectomy
|
|
|
| Conscious sedation |
2.50 (0.32-19.52) |
0.382 |
| General anesthesia |
2.91 (0.62-13.65) |
0.176 |
| Stent deployment |
0.77 (0.35-1.66) |
0.511 |
| Closed cell stent |
0.69 (0.37-1.30) |
0.257 |
| TICI 0-2a |
4.72 (0.89-24.94) |
0.068 |
| Pial collateral circulation |
0.71 (0.36-1.38) |
0.316 |
| ASA |
1.19 (0.81-1.73) |
0.365 |
| Clopidogrel |
0.37 (0.12-1.14) |
0.083 |
| Tirofiban |
0.97 (0.37-2.56) |
0.962 |
| Abciximab |
0.82 (0.30-2-26) |
0.710 |
| Double antiplatelet therapy |
1.47 (0.68-3.19) |
0.325 |
| Platelet aggregation phenomena |
2.91 (1.52-5.53) |
0.001 |
| Carotid reocclusion |
3.4 (0.96-12) |
0.057 |
| Quantitative variables
|
| Variable |
mRS 3-6 (90 days) |
| OR (CI 95%) |
p
|
| Age |
1.1 (1.04-1.11) |
＜0.001 |
| Admission NIHSS |
1.12 (1.11-1.18) |
＜0.001 |
| Admission blood glucose mg/dL |
1 (0.99-1) |
0.398 |
| Admission platelets account ( x 103/μL)
|
1 (1-1) |
0.112 |
| ASPECTS |
0.78 (0.64-0.95) |
0.014 |
| Groin-recanalization time |
1 (0.99-1.01) |
0.193 |
After adjusting per confounders, multivariate analysis (Fig.3) showed that the variables independently associated with worse outcomes (mRS 3–6) at 90 days were intrastent platelet aggregation phenomena during endovascular therapy, admission NIHSS (per point), and age (per year). Conversely, intravenous thrombolysis and TICI 2b–3 recanalization grade were identified as independent predictors of good outcomes at 90 days. The Hosmer–Lemeshow test showed that the final model had an adequate goodness of fit (
χ
2 =3.887, p=0.867). The model correctly classified a total of 77.1% of cases.
Finally, as shown in Table 2, death rates during hospitalization and cumulative death rate at 3 months showed a trend to be higher in the case of CRO. There were no significant differences in symptomatic intracranial hemorrhage, with no SICH in the reocclusion group.
Discussion
Our results, obtained from a study of EVT for 218 consecutive patients with TL or ICO, provide the largest single-center series reported in the literature. After performing systematic imaging follow-up of every patient assessed, our study provides various key findings. First, the CRO rate in our sample was 5%. Second, this complication was independently associated with TICI recanalization grade, pial collateral circulation, stent deployment, and general anesthesia use. Third, CRO seems to have a negative impact on functional outcomes. Finally, some factors are independently associated with worse outcomes at 90 days in patients with AIS due to TL or ICO, such as intrastent platelet aggregation phenomena during endovascular therapy, admission NIHSS, age, iv thrombolysis, and TICI recanalization grade.
The rates of CRO described in previous literature, show wide ranges6, 10, 15-17), given the heterogeneity of the studies themselves, with different antiplatelet protocols in the acute phase or the wide variability in the diagnostic methods for detecting CRO. However, the rate described in our study (5%) shows one of the lowest reported values, despite the changes in antiplatelet management during endovascular therapy over the years. It is possible that a key point to this rate is the uniform protocol used during EVT, carried out by a group of interventionists with extensive experience. Furthermore, in our study, the platelet aggregation phenomena rate was 23.8%; however, rescue therapy was performed in 96.1% of these patients, which could explain the low reported reocclusion rate as well as the absence of statistically significant association between platelet aggregation and CRO in the first 24 h. In addition, our results show a systematic assessment of all study participants, performed by the same experienced ultrasound team, which reduces imaging variability or misinterpretation of CRO.
This study found that CRO was independently related to different periprocedural variables. In case of stent placement, the debate seems to be served, given the need for the use of antiplatelet therapy that could increase the risk of bleeding in the context of an AIS18). However, there is increasing evidence on the safety of the use of the carotid stent in the acute phase, without an increase in symptomatic intracranial hemorrhage despite the combination of thrombolytic and antiplatelets in TLs3-5, 18). Beyond the demonstrated benefit of the carotid stent in TLs and its positive impact on the degree of intracranial recanalization and functional benefit3-7, 18), compared to balloon angioplasty alone, large artery stent deployment offers much improved radial strength preventing acute occlusion19-20). In line with previous reports, Wallocha and colleagues demonstrated in their study low rates of CRO in the stent group compared to those in the nonstent group of patients with AIS due to TL21).
Despite the stent’s proven ability to stabilize atheroma plaque19-20), minor nonocclusive adherent platelet/fibrin thrombi around stent struts are common in early implants of ＜3 days22). For this reason, in addition to using effective antiplatelet therapy, our protocol guarantees a waiting time during procedure to exclude acute intrastent aggregation phenomena that may progress to reocclusion in the next few hours.
The cerebral pial collateral circulation is the network of blood vessels recruited to perfuse the brain when large vessel occlusion occurs and primary cerebral arteries fail23-24). Our study reveals for the first time that the presence of pial collateral circulation on angiography is an independent and protective predictor of the development of CRO, with no prior scientific evidence linking both variables. The association between both factors could be related to the systemic compensation mechanisms once the occlusion of the great vessel occurs. Before successful recanalization, cerebral autoregulatory mechanisms are insufficient to maintain regional cerebral blood flow (CBF) owing to the depressed level of perfusion pressure25). At this point, blood pressure will rise in order to maintain pial collateral circulation and CBF consequently26). The mentioned blood pressure elevation could theoretically improve blood flow through carotid stent, favoring its patency. Unfortunately, in our study, we were unable to verify blood pressure values in patients with the presence of pial circulation.
However, it is not uncommon during general anesthesia to have hypotensive episodes due to anesthesia drugs27). Therefore, the blood pressure decrease associated with general anesthesia may worsen the arterial flow through the carotid, favoring greater blood stasis and reocclusion of the carotid artery.
Finally, another relevant finding of our study was the relationship between successful recanalization grade (TICI 2b–3) and stent patency. Recanalization grade and stent occlusion have been previously reported9-10), suggesting that a better distal flow was followed retrogradely by a faster flow that facilitated the proximal stent patency.
In relation to clinical outcomes, we found a significant association between CRO and worse functional outcomes at 90 days in the univariate analysis, with a trend toward statistical significance in the multivariate analysis (OR 3.4, 95% CI 1.52–5.53, p=0.057). These results are in agreement with previously reported studies9, 10, 16) demonstrating the negative impact of reocclusion on clinical outcomes. As a result of this link between CRO and poor functional prognosis, we should be improving antiplatelet therapy protocols in TL so that the artery is maintained without increasing bleeding risk.
Among independent predictors of poor functional outcomes, intrastent platelet aggregation phenomena during endovascular recanalization increased by 2.6 the risk of poor functional outcomes. It is striking that this variable per se has an impact on functional prognosis. It would be expected to be related with reocclusion, which in turn would be associated with worse clinical outcomes; however, in our results, such an association was not demonstrated. It is possible that microthrombi related to platelet aggregation phenomena would be released into the intracranial circulation, causing new embolisms that directly affect the improvement of the patient and his functional result despite a good degree of recanalization. Hence, the association between these platelet aggregation phenomena and the clinical result makes us consider the relevance of monitoring the behavior of the stent immediately after its placement, as we did in our study.
Unfortunately, we do not know the time that passed from the placement of the stent to the appearance of platelet aggregation. However, the plausible benefit of waiting time in these procedures requires future studies to validate our results.
Finally, we did not find a relation between CRO and sICH as described in other studies10, 16), possibly because of the low reocclusion rate in the sample and the scarce use of iv fibrinolysis in the group of patients with CRO.
This study has several limitations. It is a single-center retrospective analysis, and most of the procedures were performed using a retrograde strategy that limits the external validity of our results. According to our local protocol, most of the patients with acute carotid occlusions who received endovascular reperfusion treatment were treated with carotid stent placement, which implies that the application of our results is limited to centers with similar management. Changes have been made to the antiplatelet agents used during the procedure; in addition, except for the homogeneous use of aspirin, the antiplatelet therapy used during the procedure varied according to the criteria of the interventionist, which could impact the final results. Owing to the small subgroup of the patients in this cohort receiving glycoprotein IIb/IIIa inhibitors, we cannot provide information on stent thrombosis rates for this subgroup. The exact time of late stent thrombosis could not be established, as carotid stent occlusion was diagnosed at the time of sonographic examination and could have occurred at any time point between the end of the endovascular procedure and the diagnostic evaluation. Furthermore, we did not collect information on continuous blood pressure values before, during, and after thrombectomy, so its impact on CRO could not be analyzed. In addition, some variables that may have been associated with CRO or poor functional prognoses in the sample, such as anterior and posterior communicating arteries, were not correctly collected in the database despite our initial recommendation.
Conversely, among the strengths of the study include the prospectively collected clinical data, that all consecutive patients had a thorough assessment of vessel patency and platelet aggregation phenomena during EVT, and all received contemporary devices, homogenous care, and postinterventional antithrombotic regimens.
CRO in TL or ICO may have a negative impact on the patient’s functional prognosis. As key points of our study to prevent such reocclusion, we propose the following:
- Carotid stenting regardless of antiplatelet protocol during the acute phase of endoprosthesis placement.
- After simple carotid angioplasty or cervical stent placement, angiographic surveillance is recommended owing to the possibility of platelet aggregation phenomena. These phenomena are directly related to a poorer functional prognosis, as it is associated with CRO in our study. The standard angiographic surveillance time is difficult to establish. A management plan for these patients is given in Fig.1, where we describe an action protocol in patients with TLs.
- With the aim of knowing better management with mono-antiaggregant therapy in the acute phase of AIS due to TL in patients undergoing MT, we have started the recruitment in a national multicenter clinical trial in Spain (Eudrat-CT No: 2021-003874-30, clinical trials gov ID: NCT05225961).
Conclusions
In summary, our results show a relatively low rate of CRO, with relevance to the appearance of platelet aggregation phenomena and the rescue therapy used to resolve it as a possible cause. Despite this, CRO has a relevant clinical impact in our study, associating lower rates of good functional outcomes at 3 months. Independent factors of CRO were the degree of recanalization (TICI), presence of pial collateral circulation, use of a stent as a protective factor, and use of general anesthesia during thrombectomy. Among the factors associated with a worse functional prognosis, we highlight the presence of intrastent platelet aggregation phenomena, in addition to NIHSS at admission, age, the use of intravenous fibrinolysis, and the degree of intracranial recanalization. Overall, our findings support the implementation of systematic follow-up vascular studies within the first 24 h after stent placement to detect stent thrombosis. Further investigation is warranted for the evaluation of strategies aimed to prevent carotid stent occlusion.
Disclosures
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Sources of Funding
This project was funded by the Instituto de Salud Carlos III (ISCIII) through the project PI21/01322 and co-funded by the European Union. The ITRIBiS project (Improving Translational Research Potential at the Institute of Biomedicine of Seville) has the registration number REGPOT-2013-1. M. Medina was granted a Rio Hortega contract. The project was included in the Cooperative Cerebrovascular Disease Research Network (INVICTUS) (RD16/0019/0015).
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