{'fraction_non_alphanumeric': 0.043569573850618604, 'fraction_numerical': 0.02558423705513976, 'mean_word_length': 5.401613297482278, 'pattern_counts': {'":': 0, '<': 6, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Clinical Outcomes of Extracranial Carotid Artery-Related Stroke Eligible for Mechanical Reperfusion on Top of Per-Guidelines Thrombolytic Therapy: Analysis from a 6-Month Consecutive Patient Sample in 2 Centers

Background Systemic intravenous thrombolysis and mechanical thrombectomy (MT) are guideline-recommended reperfusion therapies in large-vessel-occlusion ischemic stroke. However, for acute ischemic stroke of extracranial carotid artery origin (AIS-CA) there have been no specific trials, resulting in a data gap. Material/Methods We evaluated referral/treatment pathways, serial imaging, and neurologic 90-day outcomes in consecutive patients, presenting in a real-life series in 2 stroke centers over a period of 6 months, with AIS-CA eligible for emergency mechanical reperfusion (EMR) on top of thrombolysis as per guideline criteria. Results Of 30 EMR-eligible patients (33.3% in-window for thrombolysis and thrombolysed, 73.3% male, age 39-87 years, median Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 10, pre-stroke mRS 0–1 in all, tandem lesions 26.7%), 20 (66.7%) were EMR-referred (60% – endovascular, 6.7% – surgery referrals). Only 40% received EMR, nearly exclusively in stroke centers with carotid artery stenting (CAS) expertise (100% eligible patient acceptance rate, 100% treatment delivery involving CAS±MT with culprit lesion sequestration using micronet-covered stents). The emergency surgery rate was 0%. Baseline clinical and imaging characteristics did not differ between EMR-treated and EMR-untreated patients. Ninety-day neurologic status was profoundly better in EMR-treated patients: mRS 0–2 (91.7% vs 0%; P<0.001); mRS 3–5 (8.3% vs 88.9%; P<0.001), mRS 6 (0% vs 11.1%; P<0.001). Conclusions In a real-life AIS-CA setting, the referral rate of EMR-eligible patients for EMR was low, and the treatment rate was even lower. AIS-CA revascularization was delivered predominantly in stroke thrombectomy-capable cardioangiology centers, resulting in overwhelmingly superior patient outcome. Large vessel occlusion stroke referral and management pathways should involve centers with proximal-protected CAS expertise. AIS-CA, irrespective of any thrombolysis administration, is a hyperacute cerebral emergency and EMR-eligible patients should be immediately referred for mechanical reperfusion.


Background
Carotid atherosclerotic disease is an important [1][2][3][4] yet underestimated [5] cause of ischemic stroke. Strokes of carotid bifurcation origin constitute at least 20% of ischemic strokes [1,6]; some of those present with a co-existing occlusion of the intracranial vessel(s) (tandem lesions) [7,8]. Acute ischemic stroke of extracranial carotid artery origin (AIS-CA) has an unfavorable clinical prognosis due to the large volume of affected brain tissue and the typically large thrombus load, with recanalization rates below 10% using systemic intravenous thrombolysis (IVT) [9][10][11]. IVT is an established part of stroke reperfusion therapy that, in the setting of large vessel occlusions (LVO), should be combined with mechanical reperfusion [10][11][12][13][14][15][16]. There is some evidence in intracranial LVO strokes that IVT administration prior to emergency mechanical reperfusion (EMR) may be associated with increased early recanalization rate [14][15][16]; but this may be less applicable to AIS-CA due to the typically large thrombus burden in AIS-CA [6,9,17]. Some authors suggest that the bleeding risk with mechanical recanalization may be increased if IVT precedes mechanical thrombectomy (MT) [13,18].
Pivotal trials of mechanical intervention in AIS have been focused on intracranial LVO; patients with AIS due to extracranial carotid artery (CA) occlusion were routinely excluded or severely underrepresented [17,19,20]. As a result of trials, MT of the intracranial CA occlusion causing AIS is today recommended in all eligible patients (class I, level of evidence A recommendation) [12,17]. This contrasts with the data gap regarding EMR of causative occlusions of the extracranial internal CA, including tandem lesions. Today, stroke guidelines from the American Heart Association/American Stroke Association [12] indicate that emergent interventional management of extracranial CA lesions causing stroke "may be considered" (class IIb recommendation), in the absence of clarification regarding which treatment method (ie, endovascular [7,14,21], or carotid surgery±intracranial thrombectomy [21,22]) should be used. Surprisingly, the current European Stroke Organization guideline on carotid stenosis management states that it does "not address carotid revascularization done as part of acute stroke therapy", leaving European stroke physicians without a guideline on AIS-CA patient management [23]. The relevance of those gaps for everyday clinical practice decision-making remains unknown.
Recent technological advances allow thrombus extraction using aspiration and/or stentrievers, with a high recanalization rate [11,17], from the extracranial internal CA (similarly to the intracranial segments of internal CA [24]), as well as a full reconstruction of the CA lumen with lesion sequestration [25]. However, data on the implementation of these new technologies in acute stroke are scarce [24].
In a sample of consecutive EMR-eligible patients in 2 centers, we performed an assessment of the real-life impact of randomized evidence gaps (resulting in class IIb guideline recommendation level) on contemporary referral and treatment pathways, as well as neurologic outcomes, in AIS-CA.

Ethics Approval
The study was approved by the Regional Ethics Committee (OIL/KBL/75/2021). Individual patient consents were waived due to retrospective analysis of anonymized data.

Study Centers
Prospective data collection involved all consecutive patients with AIS receiving cerebral and vascular imaging in 2 collaborating centers with acute stroke neurology. Study Center 1 is a high-volume major tertiary 24/7 cardiovascular center with carotid artery stenting (CAS) expertise with a case load of 350-400 CAS procedures per year [26][27][28] and MT service under World Federation for Stroke Treatment (WIST) certification and supervision (Level-2 stroke center -Thrombectomy-Capable Stroke Center, TCSC) [24,29]. In addition, vascular surgery treatments (including carotid endarterectomy of »200 cases per year) are performed [26][27][28]. A multispecialty local Stroke Endovascular Mechanical Reperfusion Team with interventional cardiology and angiology, stroke neurology, radiology, and anesthesia is operational within the Level-2 WIST stroke center framework [24,29].
Study Center 2 is a major district hospital (MDH) incorporating regional stroke neurology and on-site 24/7 interventional cardiovascular facilities with neuroradiology procedures performed on an elective basis. Center 2 has developed a CAS program and is presently en route to serve as a stroke MT (Level-2) center for patients in the region. Study Center 2 has a wellestablished cardiovascular collaboration with Study Center 1. However, its LVO stroke patients are typically referred to a regional Comprehensive Stroke Center (CSC, Level-1 stroke center). Travel time from Study Center 2 to the CSC is »90 min, resulting in a minimum transfer time of 120 min.
There are 5 Level-3 stroke centers in the region; these collaborate with both the CSC and TCSC. The CSC is the only Level 1 stroke center in an administrative area of about 3.5 million inhabitants.

Patient Eligibility
In a prospectively-run stroke imaging database in Center 1 and Center 2, 32 consecutive patients with AIS-CA were identified e938549-2 A clinical committee consisting of a neurologist, diagnostic radiologist, and stroke management-certified interventionist reviewed the clinical and imaging data in all consecutive AIS-CA stroke patients. Eligibility for EMR [12] was defined as: (1) NIHSS (National Institutes of Health Stroke Scale) ³6 or a significant neurologic deficit (eg, aphasia), (2) ASPECTS (Alberta Stroke Program Early Computed Tomography Score) ³6, (3) pre-stroke modified Rankin scale (mRS) £2, and (4) evidence of internal carotid artery occlusion/sub-occlusion on computed tomography angiography (CTA). For each study patient, their EMR eligibility was verified by a senior interventional neuroradiologist with over 15 years of experience in acute stroke interventions [30]. Administration of IV -thrombolysis, referral for EMR (surgical or endovascular), and the treatment received were evaluated.
Optimal (as per current criteria) medical therapy (OMT) prior to stroke onset was defined as pharmacological treatment involving at least 1 antiplatelet agent, statin dose titrated to achieve guideline-indicated LDL cholesterol level (or maximally tolerated dose), and angiotensin-converting enzyme inhibitor/receptor blocker [39].
At the index event, IVT was administered in eligible patients (ie, those without contraindications to thrombolysis and presenting within 4.5 h after stroke onset) [12]. In the group receiving endovascular treatment, peri-procedural pharmacotherapy included heparinization at a reduced or full dose (at operator's discretion) and a single periprocedural antiplatelet agent (IV acetylsalicylic acid), followed by a second antiplatelet agent after the intervention [12].
Care was taken to provide a tight periprocedural blood pressure control with: (1) systolic blood pressure of 160-180 mmHg prior to and during the intervention (to enhance flow through the stroke-related CA and enhance collateral supply), followed by (2) systolic blood pressure reduction to 100-120 mmHg after reperfusion of the intracranial vessels to reduce the risk of cerebral bleed [40].

Statistical Analysis
Continuous variables were reported as median (Q1-Q3) and categorical data were expressed as numbers and proportions. The Mann-Whitney U test or Wilcoxon matched pairs test was used for between-group and within-group comparisons. Bonferroni correction was applied for multiple comparisons. Statistical significance was defined as P<0.05. Statistica 10 (StatSoft GmBH, Hamburg, Germany) was used for computations. Table 1 shows clinical data in consecutive AIS-CA patients in the study (age 39-87 years, 26.7% women): 93.3% had ASPECTS ³9; NIHSS was 12-22 (median 17); 83.3% had pre-stroke mRS-0, 16.7% mRS-1; all eligible patients received thrombolysis (33.3%); and 20 (66.7%) were referred for EMR (18 for emergency endovascular management, 2 for emergency carotid endarterectomy). Figures 1 and 2 present typical examples of the disease course in EMR-untreated and EMR-treated patients on top of IVT as per guidelines.

Imaging and Clinical Pathways
Seventy five percent EMR-treatment-eligible referrals were rejected by the CSC. Out of the 2 patients referred for emergency surgery (carotid endarterectomy, CEA), none were treated (1 rejected on referral, 1 initially accepted for CEA but surgery was not performed). Once rejected, an alternative center was not contacted or alternative reperfusion method referral was not attempted in any of the EMR-eligible patients rejected by CSC or vascular surgery.
Only 40% of all study participants (60% of all EMR referrals, n=12 patients) received EMR. The EMR-untreated group included EMR-eligible patients who were either not referred or were referred but rejected (n=18; 60% of the study cohort). There were no significant clinical, demographic, or lesion-related differences between the EMR-untreated group and EMRtreated group, including NIHSS and functional status prior to stroke onset ( Table 1). Prior to stroke onset, 13 patients (43.3%) were on documented OMT.
Eighty percent of patients who (subsequently) did not receive EMR presented within 6 h of symptom onset and had a favorable ASPECTS ³6. A further 20% of the EMR-untreated group were wake-up strokes with favorable DWI/FLAIR mismatch and an ASPECTS ³6, consistent with EMR eligibility. Similarly, 75% of EMRtreated patients presented within the 6-h window. Cerebral perfusion imaging confirmed EMR eligibility in a further 12.5% who presented with stuttering symptoms. Another 12.5% of EMR-treated patients initially presented with a "low" NIHSS (NIHSS of 3 and 4) in peripheral hospitals, without an initial referral. These patients were referred for EMR when their NIHSS exceeded 6; imaging repeated within 1 h of EMR still showed ASPECTS ³6.
In the patients who did not receive EMR despite eligibility, the reasons were (1) lack of referral (56%), (2) being referred but not accepted for EMR treatment by CSC (40.7%), or carotid endarterectomy treatment not being performed (3.3%, no patient referred for CEA or referred and accepted for CEA received CEA).

Reperfusion Strategy
IVT was administered in all eligible patients (10, 33.3%), of which only 2 were immediately transferred for EMR ( Table 1).
Proximal cerebral protection with transient flow reversal was applied if feasible (91.7%; distal filter use in 8.3% of interventions). In patients with particularly large thrombus burden at the carotid bifurcation, thrombectomy was performed using a dedicated large-diameter (9-mm) stentriever on top of aspiration ( Figure 2B) [24]. Tandem lesion presence mandated intracranial thrombectomy performed with aspiration as the technique of 1 st choice (followed, if needed, by stentriever). Micronet-covered stents were routinely used for culprit lesion

Discussion
Our principal findings with regard to referral and treatment pathways and outcomes in AIS-CA patients in a contemporary clinical setting were as follows: (1) real-life patient access to reperfusion therapy remains severely limited (majority of eligible patients did not receive EMR); (2) AIS-CA patient acceptance for EMR occurred predominantly in CAS-experienced stroke thrombectomy-capable cardioangiology centers; and (3) endovascular EMR with proximal neuroprotection use and micronet-covered stents for culprit lesion sequestration and lumen reconstruction was safe and highly effective, with    treated patients achieving overwhelmingly better functional outcomes at 90 days.
The striking difference in favorable functional outcome (mRS 0-2) at 90 days (91.7% vs 0%; P<0.001; Figure 3B) is consistent with emergency mechanical reperfusion as the fundamental predictor of functional independence in patients after acute ischemic stroke of carotid artery origin.
EMR with (when indicated) intra/extracranial MT is the most commonly used method to achieve effective reperfusion in patients with AIS-CA, but reported series are small. A recent review of 4 studies with a total of 38 AIS-CA patients found that recanalization and favorable clinical outcome were significantly higher for stent-assisted endovascular management than with IVT (87% vs 48%, P=0.001; and 68% vs 15%, P<0.001) [41], with lower mortality (18% vs 41%, P=0.048) and no difference in symptomatic intracranial hemorrhage (0% vs 4%, P=0.23).
In our series, emergency carotid artery stenting in AIS-CA was safe in all patients, including those with high NIHSS (median 14, Table 1). Our work contrasts with prior studies that reported outcomes mainly in patients with TIA or low NIHSS stroke (such as 3-6), usually treated within several days after the neurologic event. The SWEDVASC study [42] reported safe carotid stent treatment (CAS) of 13 TIA or minor stroke selected patients within 2 days. However, the proportion of emergency treatments was not given, which is a crucial aspect of stroke reperfusion [12,43]. Similarly, 2 other studies [44,45] included only selected patients with TIA or minor neurologic deficit treated in the post-acute stroke phase. Not surprisingly, outcomes in these highly selected patients were similar to those treated with elective CAS [44,45]. It is important to note that the patient populations in these studies [42,44,45] were fundamentally different from our real-world, unselected, hyperacute stroke patients with large neurologic deficit (median NIHSS 17, Table 1) and hyperacute emergency (rather than delayed) management, first demonstrated by Papanagiotou et al [46]. In another small study of carotid artery revascularization in atherosclerosis-related AIS-CA that included 14 patients prior to the era of mechanical thrombectomy and had a very limited use of proximal neuroprotection, successful revascularization was achieved in 83.3% of patients [47]. More recently, Mizowaki et al [7] reported outcomes of emergency balloon angioplasty in a cohort smaller than ours, including 8 patients with atherosclerotic AIS-CA among a total of 19 with carotid artery involvement (median NIHSS 20). Despite a significant carotid reopening rate with balloon angioplasty alone (84%), the 90-day mRS £2 was only 39%. This is in contrast to the 91.7% in our treatment cohort (Figure 3), where sealing of the culprit lesion and lumen reconstruction was routinely performed novel micronet-covered stents to sequestrate the plaque and prevent further plaque-related events [4,25,28,37,38], suggesting that culprit lesion effective exclusion and optimal lumen reconstruction may be clinically fundamental in AIS-CA.
In our cohort, all eligible patients (33.3%) received thrombolysis. This, however, was largely ineffective (note the lack of IVT clinical efficacy, major cerebral tissue loss on control CT scans in EMR-eligible patients who received IVT but no EMR; Figure 1), consistent with prior reports of very poor efficacy of IVT in recanalizing CA [9][10][11]. Data from the present study reinforce the guidelines' position that any "waiting" for a clinical effect of IVT (which is typically achieved in less than 10% of AIS-CAs) must no longer be a part of any contemporary clinical practice [12].
All AIS-CA patients, whether receiving IVT or not, should be immediately referred for EMR, if eligible. According to our study results (16.7% EMR-treated cases had initial IVT) and data in the literature, EMR (CAS or CEA) can be safely performed after initial IVT [13][14][15][16]. CAS, in contrast to CEA, is immediately feasible after initial IVT. Another clinically relevant caveat is the present routine of "observing" the progress of accumulating cerebral tissue loss until NIHSS exceeds 6, making the patient eligible for EMR. The position of the authors is that any preventable tissue loss should be, if feasible, prevented.
Emergency CEA to treat AIS-CA, although reported by some centers [21,22,44], remained of theoretical feasibility in our setting (2 patients referred for emergency CEA, 1 accepted but treatment was not performed). Studies comparing CAS and CEA in semi-acute (rather than hyperacute) stroke indicate delayed availability of CEA as compared to CAS [44], consistent with the notion of poor emergency CEA availability. An important limitation of CEA in AIS-CA is its inability to resolve, in tandem lesions, the distal or intracranial occlusion. Thus, in tandem lesions CEA needs to be combined with intracranial thrombectomy performed before or after surgery makes this strategy cumbersome.
Our primary strategy in AIS-CA intervention was to use proximal cerebral protection (flow reversal). This was applied in 91.7% procedures in the present series (vs »50% in elective CAS [28]), with filter use only if use of the proximal device was unfeasible. Data from high-risk lesions in elective CAS show that proximal balloon occlusion, compared with distal filter protection, significantly reduces intraprocedural cerebral microembolism by transcranial Doppler and DWI MRI [31][32][33][34]. There is also recent evidence that proximal neuroprotection in acute intracranial interventions in ischemic stroke can reduce periprocedural embolism (higher mTICI score) and improve clinical outcome (better functional status at 90 day and lower mortality) [35,36].
While larger scale data would be desired, our work indicates that recent technological advances including micronet-covered e938549-10 stents for culprit lesion sequestration and lumen optimization [24,25,28,48] and routine use of proximal protection (transient flow reversal) can improve emergency mechanical reperfusion rates and clinical outcomes in AIS-CA patients (Figure 3).
AIS-CA patients are considered high-risk for intervention [7,45], a feature that may reduce the likelihood of patient acceptance of intervention. However, we showed that the health benefit gain for these patients can be very high (Figure 3). Establishing of center-specific standard operating procedures and a multispecialty team approach can play an important role in creating a delay-free process [29]. Stroke mechanical reperfusion should be offered within high-volume cardiovascular centers (Level 2 stroke centers -TCSCs) and performed by operators trained in both carotid interventions and MT [49,50]. Cardioangiologyrun (in collaboration with local stroke neurology physicians) [24,29] Level 2 stroke centers (TCSCs, providing 100% AIS-CA acceptance rate in our cohort) can play an important role in improving patient access to stroke mechanical reperfusion [49,51,52]. These centers may be able to not only accept and effectively treat AIS-CA patients (Figures 2, 3), but also manage the excess volume of conventional intracranial LVO patients [29,52]. Our regional CSC (the only center formally part of the national stroke MT reimbursement system [52]) is theoretically supposed to serve a population of about 3.5 million, but this far exceeds its practical capacities (guidelines indicate 1 interventional stroke center per 0.5-1 million population, which in our study cohort might have been a potential reason for rejection of EMR-eligible patients) [51]. In our reallife experience, the CSC rejection rate of AIS-CA patients eligible for intervention was high (75%).
Our data support that CAS experience [53] with knowledge of proximal cerebral protection (flow reversal) can play an important role in the evolution of cardioangiology operators to manage acute LVO stroke [50]. This will increase the proportion of stroke patients who can benefit from receiving mechanical reperfusion treatment [24,29,54]. Our findings reinforce that the "watch and wait" strategy (patient "observation" or waiting for the effect of thrombolysis, if given) has no place in contemporary management of AIS-CA patients; a message that is critically important to reach the stroke neurology community.

Limitations
Limitations include our retrospective analysis of prospectively collected data and the sample size. In the era of MT, obtaining further randomized evidence with regard to AIS-CA management in patients who qualify for EMR on top of thrombolysis is unlikely, as this would be unethical today. While the sample size may be considered moderate, it is similar to other AIS-CA cohort studies published [7,41,46,47]. An important element of our present work is the comparison of contemporary outcomes in the treated and untreated AIS-CA patients (Figure 3). With the moderate study size, however, the present comparison needs to be regarded as a pilot study with respect to the size of the treatment effect. As it would be unethical today to randomize AIS-CA patients to emergency intervention vs no intervention (or delayed intervention) [12], it is crucial to expand the body of knowledge by analysis of real-life datasets such as ours. Next, larger datasets, such as data from multiple centers and/or regional or national databases, are needed. However, it must be noted that detailed patient-level verification of criteria for emergency mechanical recanalization (which we achieved through detailed analysis using access to full imaging and clinical data) would be difficult for large patient cohorts with limited access to source data.
Regrettably, we could not obtain any specific information regarding reasons for non-referral/non-acceptance for EMR. Likely contributing factors include: (1) "symptomatic" carotid disease being historically considered a primarily surgical disease, to be addressed within 14 days from symptom onset [23]; (2) CSCs primary focus on intracranial LVO management [8,19,20]; (3) unfamiliarity with the treatment of carotid origin disease under flow reversal [7,21,45]; (4) shortage of stroke MT centers [50,51]; and (5) lack of established pathways for emergency AIS-CA stroke referrals that would involve centers with expertise in endovascular carotid revascularization [49]. Furthermore, clinical practice suggests that rejection of a particular patient type will impact further referrals of similar patients. Thus, "symptomatic" (elective) CA stenosis guidelines should not be applied blindly to AIS-CA, but should rather be used together with the acute stroke guidelines that demand emergency reperfusion not only in intracranial LVO but also in carotid LVO [12].
Finally, it is important to note that in many patients with large carotid-related strokes, once they reach the post-acute stroke stage, any potential intervention "within 14 days" [39] (whether surgical or endovascular) becomes futile due to the large irreversible loss of brain tissue and an unacceptable risk of intracranial hemorrhage. Such patients are not included in most statistics on symptomatic carotid stenosis and its revascularization.

Conclusions
An acute stroke due to an underlying carotid lesion represents a cerebral emergency, irrespective of the presence/absence of co-existing intracranial LVO and irrespective of any thrombolysis administration. Our analysis suggests that patients receiving emergency mechanical reperfusion have overwhelmingly better clinical outcomes. To increase the proportion of AIS-CA patients who receive mechanical reperfusion in acute stroke,

e938549-11
cardioangiology centers with expertise in endovascular carotid revascularization and with knowledge of proximal cerebral protection and stenting should actively participate in delivering mechanical reperfusion for patients with acute stroke [55].

Declaration of Figures' Authenticity
All figures submitted have been created by the authors, who confirm that the images are original with no duplication and have not been previously published in whole or in part.