Journal of Neuroradiology (2015) 42, 169—175
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ORIGINAL ARTICLE
Early versus late carotid artery stenting for symptomatic carotid stenosis Luis Henrique de Castro-Afonso a, Guilherme S. Nakiri a, Lucas M. Monsignore a, Antônio C. Dos Santos b, João Pereira Leite c, Soraia R.C. Fábio c, Pedro Telles Cougo-Pinto c, Millene Rodrigues Camilo c, Octávio M. Pontes-Neto c, Daniel G. Abud a,∗ a
Division of Interventional Neuroradiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil b Division of Neuroradiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil c Division of Neurology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Available online 1st April 2015
KEYWORDS Carotid artery angioplasty stenting; Symptomatic carotid artery stenosis; Urgent carotid stenting
Summary Introduction: Early carotid revascularization (≤ 14 days) is recommended for symptomatic carotid stenosis. Carotid artery stenting (CAS) has become an alternative to carotid endarterectomy (CEA); however, safety data on early CAS is controversial. The study aims to compare early versus late CAS, when CAS is performed as a first intention revascularization strategy. Methods: A retrospective analysis of all symptomatic patients admitted to our stroke unit who underwent CAS was conducted. Patients were divided between two groups: patients who had undergone CAS within 14 days after symptoms and those who had undergone CAS later. Primary endpoints were ipsilateral ischemic stroke or ipsilateral parenchymal hemorrhage (iPH) at 30 days. The secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) at the 30-day and at the 12-month follow-up. Results: One hundred twenty-seven consecutive patients were evaluated. Primary endpoints obtained in the early and late CAS groups were, respectively, ipsilateral stroke (2.0% vs. 2.6%, P = 1.00) and iPH (2.0% vs. 0.0%, P = 0.40). The rates of MACCE between the early and the late CAS groups were, respectively, (7.8% vs. 2.6%, P = 0.21) at the 30-day follow-up, and (12.2% vs. 10.5%, P = 0.77) at the 12-month follow-up.
∗ Corresponding author. Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, SP 14048-090, Brazil. Tel.: +55 16 360 226 40; fax: +55 16 360 226 48. E-mail address: [email protected] (D.G. Abud).
http://dx.doi.org/10.1016/j.neurad.2015.03.002 0150-9861/© 2015 Elsevier Masson SAS. All rights reserved.
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L.H.d. Castro-Afonso et al. Conclusions: In this study, CAS seems to be safe when used as first intention revascularization treatment within 2 weeks of symptoms, if infarcted area is less than one third of the middle cerebral artery territory. Our results need to be confirmed by larger studies. © 2015 Elsevier Masson SAS. All rights reserved.
Introduction Carotid artery stenting (CAS) is an emerging revascularization alternative to the standard carotid endarterectomy (CEA) [1—3]. The current guidelines recommend carotid revascularization for symptomatic carotid stenosis within the first 2 weeks after a non-disabling ischemic symptom [1,2]. It is noteworthy that that statement was based on an analysis of pooled data from CEA trials [4,5]. Although CAS has been indicated as an alternative to CEA [1—3], safety outcome data regarding CAS within the first 2 weeks of ischemic symptom onset remains controversial [6—10]. The present study aims to compare early versus late CAS as a first intention revascularization strategy for symptomatic patients admitted at our institutional stroke unit.
Materials and methods Study design and patient population This is a single-center retrospective study. The study protocol conformed to generally accepted scientific principles and the research ethics standards of our institution and was approved by the ethics committee (number: 20977113.0.0000.5440). Our institutional review board waived the need for written informed consent from the participants. We retrospectively assessed radiological and clinical data on patients presenting symptomatic carotid artery atherosclerotic stenosis who underwent CAS from July 2010 to December 2012. All patients evaluated by our institutional stroke team presenting internal carotid artery stenosis ≥ 50% in a carotid ultrasound (US) underwent a computed tomography angiography (CTA) or a 3 T magnetic resonance angiography (MRA). Patients were evaluated for CAS as a first intention revascularization treatment if the inclusion and exclusion criteria were fulfilled (Table 1) [11]. Patients were divided between two groups: the first group consisted of patients who had undergone CAS within 14-days after ischemic symptoms (early CAS group), and the second group of patients who had undergone CAS later than 14 days after ischemic symptoms (late CAS group). Data on patients who had not undergone CAS was not collected. The primary endpoints were incidence of ipsilateral ischemic stroke or ipsilateral parenchymal hemorrhage (iPH) at the 30-day follow-up. Secondary endpoints consisted of major adverse cardiac and cerebrovascular events (MACCE) at the 30-day and at the 12-month follow-ups. MACCE are defined as any stroke, symptomatic myocardial infarction, vascular complications or death. Other secondary endpoints included ipsilateral TIA, ipsilateral
stroke, and iPH between 1-month and 12-month followups.
CAS procedure All procedures were performed by the interventional neuroradiology team of our institutional stroke team, which is formed by training fellows and staff. The CAS procedure protocol was the same that had already been published [12]. We used cerebral embolic protection devices, whenever possible. The antiplatelet regimen recommended was aspirin (300 mg daily) and clopidogrel (75 mg daily) at least five days before treatment or aspirin (300 mg attack) and clopidogrel (300 mg attack) at least four hours before the procedure and continuing for three months afterward. Aspirin 300 mg daily was maintained indefinitely. When an anticoagulant was indicated for secondary stroke prevention only aspirin 300 mg daily was recommended in combination with the anticoagulant drug, and clopidogrel was not indicated. After femoral punctures, 7500 IU of heparin bolus was administered intravenously for all patients. The procedures were performed with patients under local anesthesia with conscious sedation or under general anesthesia at the discretion of anesthesiology team. The hemodynamic monitoring followed recommendations of a previous published protocol on CAS [13]. All patients were discharged 24 h after treatment if no contra-indication occurred.
Clinical and radiological assessment All patients were examined by independent certified vascular neurologists in-hospital, at the 1-month and at the 12-month follow-ups. The neurologists measured the neurological deficit and outcomes using validated Portuguese versions of the NIHSS and the modified Rankin Scale (mRS) [14]. The mRS scores were obtained at hospital admission, 1 month after treatment, and at the 12-month follow-up. A stroke was defined as an ischemic neurologic deficit (NIHSS’ score ≥ 4) or aphasia that persisted for more than 24 h, and TIA was defined as an ischemic neurologic deficit (NIHSS’ score ≥ 4) or aphasia that persisted for less than 24 h. The patients, who were not at the follow-up, were contacted by means of phone calls. A carotid ultrasound (US) was obtained at admission, at the 3-month, at the 6-month, and at the 12-month follow-ups.
Statistical analysis Categorical variables were presented as numbers and percentages and compared among groups using Chi2 or Fisher
Early versus late carotid artery stenting for symptomatic carotid stenosis Table 1
171
Eligible criteria.
Inclusion criteria Patient age ≥ 18 years Life expectancy ≥ 1 year Symptomatic ICA stenosis ≥ 50%a Symptoms were defined as ischemic stroke, transient ischemic attack, hypoperfusion symptoms or retinal ischemia Early CAS (≤ 14 days) was indicated for patients admitted before 14 days from symptoms onset, if the infarcted brain tissue was not larger than one third of territory supplied by the middle cerebral artery Late CAS (> 14 days) was indicated for all patients who were admitted after 14 days of symptoms or for patients who were admitted before 14 days of symptoms but presented an infarcted brain tissue larger than one third of the territory supplied by the middle cerebral artery, any parenchymal hemorrhage or any acute severe clinical condition, defined as an evolving infection, myocardial infarction, acute heart failure, acute renal failure, acute respiratory failure Exclusion criteria Total occlusion of the target carotid artery Patients who undergone CAS and mechanical thrombectomy for acute ischemic stroke Carotid related severe disabling ischemic stroke (mRS > 4) Severe chronic renal insufficiency under non-dialytic management (creatinine clearance ≤ 40 mL/min) Untreatable bleeding diathesis or hypercoagulable state or refusal of blood transfusion Contra-indication for antiplatelet therapy Impending major surgery a
Based on the criteria defined by the American Heart Association Stroke Council, NASCET criteria [1,2,11].
exact tests, as appropriate. Continuous variables were presented as mean (range ± SD) or median, and the Student t or Mann—Whitney test was used, as appropriate. Patients treated with early CAS (< 15 days), and late CAS (> 14 days), were compared. One independent blinded investigator received all data collected for statistical analysis. The IBM SPSS Statistics software version 20.0 (Chicago, IL, USA) was used for statistical analysis.
Results Patient population and procedures A total of 233 patients who had undergone CAS were screened, 106 were excluded and 127 were included. Among all patients excluded: 73 were treated for asymptomatic carotid stenosis, 28 had undergone CAS during mechanical thrombectomy for acute ischemic strokes, 2 were treated for carotid stenosis related to radiotherapy, 1 had undergone staged CAS-open-heart surgery, and 2 patients were lost at follow-up and could not be contacted. Among the 127 patients included, 51 were treated within 2 weeks of symptoms (early CAS), whereas 76 were treated between 2 weeks and 6 months later (late CAS). Among the 76 patients of the late CAS group, 61 patients (81.3%) were referred to our center from other institutions after 2 weeks of symptoms onset, while the other 15 patients (19.7%) were admitted within 2 weeks of symptoms onset. Because all of these 15 patients presented an unstable severe clinical condition or a large ischemic stroke at admission (Table 1), they were treated only after stabilization of their clinical conditions. Therefore, theses 15 patients were treated later than 2 weeks and included in the later CAS group. The baseline characteristics of patients divided between groups are summarized in the Table 2. All the CAS procedures
were successfully accomplished. Only one patient presented an asymptomatic carotid restenosis (> 70%) at the 6-month follow-up and required retreatment. Despite the retrospective design of the study, most of the baseline characteristics of the patients were equipoised between the two groups. The baseline variables that were significantly unbalanced were the timing for CAS, carotid stenosis grade, and prevalence of TIA. Compared to the late CAS group, the early CAS group had a mean time from symptom to treatment of 5.5 days versus 4 months (P < 0.001). In the early CAS group, the mean carotid stenosis grade was 79.7%, versus 72.6% (P = 0.01) in the late CAS group, while TIA was present among 23.5% and 10.5% (P = 0.02) of the patients of the early and late CAS groups, respectively. In addition, carotid related stroke had a greater tendency toward increased frequency in the late CAS group versus the early CAS group (85.5% vs. 72.5%, P = 0.06). Despite having strokes with small infarcted brain tissue, 16 patients, among all 127 patients had a significant functional disability (mRS = 4) before the procedures, of which 8 patients belonged to each group (P = 0.42). Among the 8 patients (mRS = 4) of the early CAS group, no patient died at 30 days after CAS; however, 3 patients (37.5%) died between the 1- and 12-month follow-ups. While in the late CAS group, no patients died at 30 days and only 1 patient of 8 (12.5%) died between the 1- and 12-month follow-ups (P = 0.56).
Primary endpoints All 127 patients were included in the primary analysis and, at the 30-day follow-up, the overall incidence of ipsilateral stroke was 3.2% (4/127) and the overall rate of MACCE was 4.7% (6/127), which were in accordance with recommended safety statements [1,2]. The incidence of primary endpoints did not significantly differ between the two groups (Table 3). When comparing the early and late CAS groups, the incidence of ipsilateral ischemic
172 Table 2
L.H.d. Castro-Afonso et al. Patient’s baseline clinical data per group.
Male (n, %) Age (mean) 70 years and older (n, %) 80 years and older (n, %) Carotid related stroke (n, %) Transient ischemic attack (n, %) Retinal infarct (n, %) Previous non-related stroke (n, %) Coronary heart disease (n, %) Congestive heart failure (n, %) Atrial fibrillation (n, %) Peripheral artery disease (n, %) Chronic renal insufficiency (creatinine clearance ≤ 60 mL/min) Chronic obstructive pulmonary disease (n, %) Tobacco smokers (n, %) High blood pressure (n, %) Hypercholesterolemia (n, %) Diabetes melitus (n, %) Baseline mRS (mean, SD) Baseline mRS = 4 (n, %) Time from symptoms onset to CAS (days, mean) Left carotid stenosis (n, %) Carotid stenosis grade (mean, NASCET %) Contralateral carotid occlusion (n, %) Cerebral embolic protection (n, %) Pre-dilatation Successful CAS procedure (n, %)
Table 3
Total (n = 127)
Early CAS (n = 51)
Late CAS (n = 76)
P value
84 (66.1) 68.1 (35—88, SD ± 9.42) 53 (41.7) 17 (13.4) 102 (80.3) 20 (15.7) 5 (3.9) 31 (24.4) 21 (16.5) 15 (11.8) 7 (4.7) 15 (11.8) 24 (18.9)
35 (68.6) 67.4 (43—88, SD ± 9.98) 20 (39.2) 7 (13.7) 37 (72.5) 12 (23.5) 1 (2.0) 13 (25.5) 6 (11.8) 3 (5.9) 5 (9.8) 5 (9.8) 9 (17.6)
49 (64.5) 68.5 (35—87, SD ± 9.07) 33 (43.4) 10 (13.2) 65 (85.5) 8 (10.5) 4 (5.3) 18 (23.7) 15 (19.7) 12 (15.8) 2 (2.6) 10 (13.2) 15 (19.7)
0.70 0.49 0.71 1.00 0.06 0.02 0.64 0.83 0.33 0.10 0.11 0.78 0.82
9 (7.1)
4 (7.8)
5 (6.6)
1.00
78 (61.4) 117 (92.1) 94 (74) 47 (37) 1.9 (0—4, SD ± 1.25) 16 (12.6) —
29 (56.9) 46 (90.2) 39 (76.5) 20 (39.2) 2.0 (0—4, SD ± 1.29) 8 (15.6) 5.56 (1—14, SD ± 3.85)
49 (64.5) 71 (93.4) 55 (72.4) 27 (35.5) 1.8 (0—4, SD ± 1.22) 8 (10.5) 127.21 (17—180, SD ± 48.77)
0.45 0.52 0.68 0.71 0.46 0.42 < 0.01
61 (48) 75.5 (50—95, SD ± 16.3)
24 (47.1) 79.7 (50—95, SD ± 15.67)
37 (48.7) 72.6 (50—95, SD ± 16.19)
1.00 0.01
10 (7.9)
4 (7.8)
6 (7.9)
1.00
122 (96.1)
50 (98.0)
72 (94.7)
0.64
59 (46.5) 127 (100)
27 (52.9) 51 (100)
32 (42.1) 76 (100)
0.27 —
Clinical outcomes per group during the first 30 days after CAS. Total (n = 127)
Ipsilateral ischemic stroke (n, %) Ipsilateral parenchymal hemorrhage (n, %) Any stroke (n, %) Ipsilateral transient ischemic attack (n, %) Symptomatic myocardial infarction (mean, %) Deaths (n, %) MACCE (n, %) mRS (mean, SD)
Early CAS (n = 51)
Late CAS (n = 76)
One-tailed P value
Two-tailed P value
3 (2.4)
1 (2.0)
2 (2.6)
0.64
1.00
1 (0.8)
1 (2.0)
0 (0.0)
0.40
0.40
4 (3.1) 3 (2.4)
2 (3.9) 2 (3.9)
2 (2.6) 1 (1.3)
0.53 0.64
1.00 1.00
0 (0.0)
0 (0.0)
0 (0.0)
—
—
0.16 0.17 —
0.16 0.21 0.32
2 (1.6) 2 (3.9) 0 (0.0) 6 (4.7) 4 (7.8) 2 (2.6) 2.03 (0—6, SD ± 1.51) 2.27 (0—6, SD ± 1.72) 1.86 (0—6, SD ± 1.34)
Clinical outcomes per group during the first 30 days after CAS; mRS: modified Rankin Scale; MACCE: major adverse cardiac and cerebrovascular events, defined as any stroke, symptomatic myocardial infarction, vascular complications or death.
Early versus late carotid artery stenting for symptomatic carotid stenosis Table 4
173
Clinical outcomes per group between 1 and 12-months follow-up. Total (n = 125)
Ipsilateral ischemic stroke (n, %) Ipsilateral parenchymal hemorrhage (n, %) Any stroke (n, %) Ipsilateral transient ischemic attack (n, %) Symptomatic myocardial infarction (mean, %) Deaths (n, %) MACCE (n, %) mRS (mean, SD)
Early CAS (n = 49)
Late CAS (n= 76)
One-tailed P value
Two-tailed P value
0 (0.0)
0 (0.0)
0 (0.0)
—
—
0 (0.0)
0 (0.0)
0 (0.0)
—
—
1 (0.8) 0 (0.0)
0 (0.0) 0 (0.0)
1 (1.3) 0 (0.0)
0.60 —
1.00 —
2 (1.6)
0 (0.0)
2 (2.6)
0.36
0.51
0.39 0.49 —
0.76 0.77 0.48
13 (10.4) 6 (12.2) 7 (7.9) 14 (11.2) 6 (12.2) 8 (10.5) 2.29 (0—6, SD ± 1.73) 2.49 (0—6, SD ± 1.90) 2.15 (0—6, SD ± 1.61)
Clinical outcomes per group between 1- and 12-months follow-up; MACCE: major adverse cardiac and cerebrovascular events, which is defined as any stroke, symptomatic myocardial infarction, vascular complications or death.
stroke and iPH were 2.0% vs. 2.6% (P = 1.00) and 2.0% vs. 0.0% (P = 0.40), respectively. In the early CAS group, 2 strokes were observed, which were 1 ipsilateral ischemic stroke and 1 iPH. The ipsilateral ischemic stroke occurred right after the procedure resulting in a significant functional disability (mRS = 4) at the 12-month follow-up, while the iPH occurred 2 days after the procedure and the patient died 10 months later from a hospital-acquired pneumonia. This patient had no history of arterial hypertension or bleeding diathesis and no contralateral carotid artery occlusion. Therefore, the iPH may be explained by a revascularization of a critical stenosis of the right internal carotid artery (95%), and a CAS performed after 4 days of a relatively large brain infarct. Despite of infarcted area measured less than one third of the middle cerebral artery territory, the patient had a pre-procedure mRS score of 4. In the late CAS group, 2 ipsilateral ischemic strokes were observed. The first stroke occurred 6 h after the procedure, resulting in a moderate patient disability at the 12-month follow-up (mRS = 3). The second stroke occurred after carotid angioplasty and the patient presented a moderate neurological deficit (mRS = 3) at the 12-month follow-up.
Secondary endpoints The incidence of clinical secondary outcomes did not significantly differ between the two groups (Tables 3 and 4). Compared to late CAS, early CAS resulted in non-significant higher rates of MACCE at the 30-day and between 1 and 12 follow-ups, respectively (7.8% vs. 2.6%, P = 0.21) and (12.2% vs. 10.5%, P = 0.77). At the 30-day follow-up, two deaths occurred in the early CAS group, while no death occurred in the late CAS group (3.9% vs. 0.0%, P = 0.16). One patient died from a hospital-acquired pneumonia and the other patient died from an acute myelodyspastic syndrome; both deaths were not related to cardiovascular complications or to CAS procedures. Moreover, 2 patients of the early CAS group presented ipsilateral TIA versus 1 patient of the late CAS group;
however, these 3 patients did not presented any recurrence of TIA or stroke during the 12-month follow-up. During the follow-up period between 1 to 12 months, 6 patients (12.2%) of the early CAS group died and no patient presented stroke, TIA, or cardiovascular events. One patient that had iPH at the 30-day follow-up died from pneumonia 10 months later, and the other 5 patients died for causes unrelated to cerebrovascular or cardiovascular events. In the late CAS group, there were 7 deaths; 2 died from acute myocardial infarction and 5 died from other causes unrelated to cerebrovascular or cardiovascular events. In addition, 1 patient of the late CAS group presented a cerebellar hemorrhage requiring surgical intervention 7 months after CAS, and the patient presented a moderate neurological deficit (mRS = 3) at the 12-month follow-up.
Discussion Carotid artery atherosclerosis is associated with around 15% of all ischemic strokes [1,2]. Considering all common causes of stroke, carotid artery stenosis has been reported to be the first cause of early recurrent ischemic events [15,16]. The recurrence rates of ischemic events associated with symptomatic carotid stenosis have been reported to be higher than 30% during the first weeks of symptoms [15,16]. Currently, CEA is indicated for patients presenting a symptomatic carotid stenosis ≥ 50%, aiming at stroke prevention, if the rate of peri-procedural stroke or death is < 6% [1,2]. Based on a pooled analysis of randomized trials assessing CEA, the timing of carotid revascularization recommended is ≤ 14 days of the last ischemic symptom, if there is no contra-indication [1,2,4,5]. However, evidence suggests the earlier the CEA is performed after symptoms, the higher the risks of mortality or stroke, which may be higher than 10% [17—20]. In spite of that, according to Naylor based on data from The Carotid Endarterectomy Trialists Collaboration, performing a carotid revascularization procedure with a 10% risk within 2 weeks could prevent approximately 150 strokes per 1000 CEA, versus only 100 strokes if the procedure is performed after 4 weeks with a 3% risk [17,18].
174 Although CAS has become an acceptable alternative treatment to CEA, carotid revascularization within 2 weeks of symptoms is advocated mainly based on data extracted from CEA trials. Few studies have assessed safety data on CAS performed earlier after symptoms and those that did showed conflicting results [6—10]. In the present study, we reported clinical data of patients presenting carotid symptomatic stenosis who underwent CAS as a first intention treatment in a high-volume university hospital, outside randomized trials. Known limitations of observational studies that evaluate CAS are selection biases, because most patients treated with CAS usually are at a high risk or had a CEA contra-indicated [21,22]. The new insight of this study was to assess the clinical outcome data of patients who undergone CAS as a first intention revascularization treatment in a real clinical practice. In this study, an overall major complication rate (MACCE) of 4.7% (6/127) at 30 days was in accordance with the safe rates recommended after CAS for symptomatic patients (< 6%) [1,2]. The overall results reported showed a lower rate of poor outcomes, considering that 16 patients (12.6%) presenting severe neurological disability (mRS = 4) were included in the analysis. Moreover, compared to the late CAS, early CAS was associated with a non-significant higher frequency of any ipsilateral stroke (3.9% and 2.6%, P = 1.00) and MACCE (7.8% vs. 2.6%, P = 0.21) at 30 days. An analysis of these results in the perspective of the unbalanced baseline variables may explain the differences obtained. The baseline carotid stenosis grade was significantly higher in the early CAS group compared to the late CAS group (79.7 vs. 72.6, P = 0.01). In addition, the mean timing of CAS after the qualifying symptom had a huge discrepancy between the two groups. The mean timing for CAS in the early and late CAS groups was, respectively, 5.5 days vs. 127 days (P < 0.001). In the late CAS group, the mean time from symptoms to CAS was 4.2 months, relatively longer than the early CAS group, which could explain why the complication rates observed in that group were very similar with that obtained even among asymptomatic patients treated with CAS (< 3%). Another important issue was the occurrence of 2 deaths non-related to CAS procedures among patients of the early CAS group, which elevated the rate of MACCE to 7.8% (4/51). An analysis of the baseline variables TIA and stroke revealed that the higher prevalence of TIA in the early CAS group, and the tendency toward a high prevalence of stroke in the late CAS group, might reflect our institutional revascularization protocol. Accordingly to our protocol (Table 1), patients presenting TIA are usually treated as soon as possible, while patients presenting large strokes usually preclude an early carotid intervention, because of the potential risks of a symptomatic bleeding in the recent infracted tissue after an early carotid revascularization, or because patients presenting large strokes more frequently present acute clinical conditions, like infections. The aim of this study was to assess safety data on CAS within the first 14 days of the qualifying event using a comparator group of symptomatic patients who underwent CAS in a very late period after symptoms. Both primary and secondary outcomes did not significantly differ between the two groups, even in the setting of significant unbalance between the two groups regarding some clinically relevant baseline variables. However, because of the small sample size and the
L.H.d. Castro-Afonso et al. low rates of clinical events observed, we cannot make definitive conclusions regarding differences in clinical outcomes between the two groups. Despite of that, it is noteworthy that, in a setting which all patients were symptomatic, we included 15.6% patients presenting baseline mRS = 4, and patients were treated in a mean time of 5.5 days of symptoms, the outcomes obtained in the early CAS group may be considered encouraging. The major limitations of the study are the small sample size, which come from a single institution, the nonrandomized retrospective design, and the lack of a clinical and a surgical control groups. As CAS requires anticoagulation and antiplatelet therapies, on contrary to CEA, a surgical comparator group would be necessary to compare the incidence of iPH among patients treated within 2 weeks after ischemic strokes. The lack of a clinical comparator group is explained because we did not assess clinical outcomes, nor the incidence of recurrent ischemic events among patients who had not undergone CAS. Indeed, all patients who were not treated had a severe functional disability (mRS ≥ 5), an unstable and refractory clinical condition, or died in-hospital. Although CAS was performed as a first intention treatment modality to a broad range of patients, the external validity of the present study is limited by the single-center, the small sample size and by the low rates of clinical events observed. The small sample size and the lower rates of major clinical events found prevent us to make definitive conclusions regarding differences in clinical outcomes between the two groups.
Conclusion In this study, CAS seems to be safe when used as first intention revascularization treatment within 2 weeks of symptoms, if infarcted area is less than one third of the middle cerebral artery territory. Our results need to be confirmed by larger studies.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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ORIGINAL ARTICLE
Early versus late carotid artery stenting for symptomatic carotid stenosis Luis Henrique de Castro-Afonso a, Guilherme S. Nakiri a, Lucas M. Monsignore a, Antônio C. Dos Santos b, João Pereira Leite c, Soraia R.C. Fábio c, Pedro Telles Cougo-Pinto c, Millene Rodrigues Camilo c, Octávio M. Pontes-Neto c, Daniel G. Abud a,∗ a
Division of Interventional Neuroradiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil b Division of Neuroradiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil c Division of Neurology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Available online 1st April 2015
KEYWORDS Carotid artery angioplasty stenting; Symptomatic carotid artery stenosis; Urgent carotid stenting
Summary Introduction: Early carotid revascularization (≤ 14 days) is recommended for symptomatic carotid stenosis. Carotid artery stenting (CAS) has become an alternative to carotid endarterectomy (CEA); however, safety data on early CAS is controversial. The study aims to compare early versus late CAS, when CAS is performed as a first intention revascularization strategy. Methods: A retrospective analysis of all symptomatic patients admitted to our stroke unit who underwent CAS was conducted. Patients were divided between two groups: patients who had undergone CAS within 14 days after symptoms and those who had undergone CAS later. Primary endpoints were ipsilateral ischemic stroke or ipsilateral parenchymal hemorrhage (iPH) at 30 days. The secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) at the 30-day and at the 12-month follow-up. Results: One hundred twenty-seven consecutive patients were evaluated. Primary endpoints obtained in the early and late CAS groups were, respectively, ipsilateral stroke (2.0% vs. 2.6%, P = 1.00) and iPH (2.0% vs. 0.0%, P = 0.40). The rates of MACCE between the early and the late CAS groups were, respectively, (7.8% vs. 2.6%, P = 0.21) at the 30-day follow-up, and (12.2% vs. 10.5%, P = 0.77) at the 12-month follow-up.
∗ Corresponding author. Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, SP 14048-090, Brazil. Tel.: +55 16 360 226 40; fax: +55 16 360 226 48. E-mail address: [email protected] (D.G. Abud).
http://dx.doi.org/10.1016/j.neurad.2015.03.002 0150-9861/© 2015 Elsevier Masson SAS. All rights reserved.
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L.H.d. Castro-Afonso et al. Conclusions: In this study, CAS seems to be safe when used as first intention revascularization treatment within 2 weeks of symptoms, if infarcted area is less than one third of the middle cerebral artery territory. Our results need to be confirmed by larger studies. © 2015 Elsevier Masson SAS. All rights reserved.
Introduction Carotid artery stenting (CAS) is an emerging revascularization alternative to the standard carotid endarterectomy (CEA) [1—3]. The current guidelines recommend carotid revascularization for symptomatic carotid stenosis within the first 2 weeks after a non-disabling ischemic symptom [1,2]. It is noteworthy that that statement was based on an analysis of pooled data from CEA trials [4,5]. Although CAS has been indicated as an alternative to CEA [1—3], safety outcome data regarding CAS within the first 2 weeks of ischemic symptom onset remains controversial [6—10]. The present study aims to compare early versus late CAS as a first intention revascularization strategy for symptomatic patients admitted at our institutional stroke unit.
Materials and methods Study design and patient population This is a single-center retrospective study. The study protocol conformed to generally accepted scientific principles and the research ethics standards of our institution and was approved by the ethics committee (number: 20977113.0.0000.5440). Our institutional review board waived the need for written informed consent from the participants. We retrospectively assessed radiological and clinical data on patients presenting symptomatic carotid artery atherosclerotic stenosis who underwent CAS from July 2010 to December 2012. All patients evaluated by our institutional stroke team presenting internal carotid artery stenosis ≥ 50% in a carotid ultrasound (US) underwent a computed tomography angiography (CTA) or a 3 T magnetic resonance angiography (MRA). Patients were evaluated for CAS as a first intention revascularization treatment if the inclusion and exclusion criteria were fulfilled (Table 1) [11]. Patients were divided between two groups: the first group consisted of patients who had undergone CAS within 14-days after ischemic symptoms (early CAS group), and the second group of patients who had undergone CAS later than 14 days after ischemic symptoms (late CAS group). Data on patients who had not undergone CAS was not collected. The primary endpoints were incidence of ipsilateral ischemic stroke or ipsilateral parenchymal hemorrhage (iPH) at the 30-day follow-up. Secondary endpoints consisted of major adverse cardiac and cerebrovascular events (MACCE) at the 30-day and at the 12-month follow-ups. MACCE are defined as any stroke, symptomatic myocardial infarction, vascular complications or death. Other secondary endpoints included ipsilateral TIA, ipsilateral
stroke, and iPH between 1-month and 12-month followups.
CAS procedure All procedures were performed by the interventional neuroradiology team of our institutional stroke team, which is formed by training fellows and staff. The CAS procedure protocol was the same that had already been published [12]. We used cerebral embolic protection devices, whenever possible. The antiplatelet regimen recommended was aspirin (300 mg daily) and clopidogrel (75 mg daily) at least five days before treatment or aspirin (300 mg attack) and clopidogrel (300 mg attack) at least four hours before the procedure and continuing for three months afterward. Aspirin 300 mg daily was maintained indefinitely. When an anticoagulant was indicated for secondary stroke prevention only aspirin 300 mg daily was recommended in combination with the anticoagulant drug, and clopidogrel was not indicated. After femoral punctures, 7500 IU of heparin bolus was administered intravenously for all patients. The procedures were performed with patients under local anesthesia with conscious sedation or under general anesthesia at the discretion of anesthesiology team. The hemodynamic monitoring followed recommendations of a previous published protocol on CAS [13]. All patients were discharged 24 h after treatment if no contra-indication occurred.
Clinical and radiological assessment All patients were examined by independent certified vascular neurologists in-hospital, at the 1-month and at the 12-month follow-ups. The neurologists measured the neurological deficit and outcomes using validated Portuguese versions of the NIHSS and the modified Rankin Scale (mRS) [14]. The mRS scores were obtained at hospital admission, 1 month after treatment, and at the 12-month follow-up. A stroke was defined as an ischemic neurologic deficit (NIHSS’ score ≥ 4) or aphasia that persisted for more than 24 h, and TIA was defined as an ischemic neurologic deficit (NIHSS’ score ≥ 4) or aphasia that persisted for less than 24 h. The patients, who were not at the follow-up, were contacted by means of phone calls. A carotid ultrasound (US) was obtained at admission, at the 3-month, at the 6-month, and at the 12-month follow-ups.
Statistical analysis Categorical variables were presented as numbers and percentages and compared among groups using Chi2 or Fisher
Early versus late carotid artery stenting for symptomatic carotid stenosis Table 1
171
Eligible criteria.
Inclusion criteria Patient age ≥ 18 years Life expectancy ≥ 1 year Symptomatic ICA stenosis ≥ 50%a Symptoms were defined as ischemic stroke, transient ischemic attack, hypoperfusion symptoms or retinal ischemia Early CAS (≤ 14 days) was indicated for patients admitted before 14 days from symptoms onset, if the infarcted brain tissue was not larger than one third of territory supplied by the middle cerebral artery Late CAS (> 14 days) was indicated for all patients who were admitted after 14 days of symptoms or for patients who were admitted before 14 days of symptoms but presented an infarcted brain tissue larger than one third of the territory supplied by the middle cerebral artery, any parenchymal hemorrhage or any acute severe clinical condition, defined as an evolving infection, myocardial infarction, acute heart failure, acute renal failure, acute respiratory failure Exclusion criteria Total occlusion of the target carotid artery Patients who undergone CAS and mechanical thrombectomy for acute ischemic stroke Carotid related severe disabling ischemic stroke (mRS > 4) Severe chronic renal insufficiency under non-dialytic management (creatinine clearance ≤ 40 mL/min) Untreatable bleeding diathesis or hypercoagulable state or refusal of blood transfusion Contra-indication for antiplatelet therapy Impending major surgery a
Based on the criteria defined by the American Heart Association Stroke Council, NASCET criteria [1,2,11].
exact tests, as appropriate. Continuous variables were presented as mean (range ± SD) or median, and the Student t or Mann—Whitney test was used, as appropriate. Patients treated with early CAS (< 15 days), and late CAS (> 14 days), were compared. One independent blinded investigator received all data collected for statistical analysis. The IBM SPSS Statistics software version 20.0 (Chicago, IL, USA) was used for statistical analysis.
Results Patient population and procedures A total of 233 patients who had undergone CAS were screened, 106 were excluded and 127 were included. Among all patients excluded: 73 were treated for asymptomatic carotid stenosis, 28 had undergone CAS during mechanical thrombectomy for acute ischemic strokes, 2 were treated for carotid stenosis related to radiotherapy, 1 had undergone staged CAS-open-heart surgery, and 2 patients were lost at follow-up and could not be contacted. Among the 127 patients included, 51 were treated within 2 weeks of symptoms (early CAS), whereas 76 were treated between 2 weeks and 6 months later (late CAS). Among the 76 patients of the late CAS group, 61 patients (81.3%) were referred to our center from other institutions after 2 weeks of symptoms onset, while the other 15 patients (19.7%) were admitted within 2 weeks of symptoms onset. Because all of these 15 patients presented an unstable severe clinical condition or a large ischemic stroke at admission (Table 1), they were treated only after stabilization of their clinical conditions. Therefore, theses 15 patients were treated later than 2 weeks and included in the later CAS group. The baseline characteristics of patients divided between groups are summarized in the Table 2. All the CAS procedures
were successfully accomplished. Only one patient presented an asymptomatic carotid restenosis (> 70%) at the 6-month follow-up and required retreatment. Despite the retrospective design of the study, most of the baseline characteristics of the patients were equipoised between the two groups. The baseline variables that were significantly unbalanced were the timing for CAS, carotid stenosis grade, and prevalence of TIA. Compared to the late CAS group, the early CAS group had a mean time from symptom to treatment of 5.5 days versus 4 months (P < 0.001). In the early CAS group, the mean carotid stenosis grade was 79.7%, versus 72.6% (P = 0.01) in the late CAS group, while TIA was present among 23.5% and 10.5% (P = 0.02) of the patients of the early and late CAS groups, respectively. In addition, carotid related stroke had a greater tendency toward increased frequency in the late CAS group versus the early CAS group (85.5% vs. 72.5%, P = 0.06). Despite having strokes with small infarcted brain tissue, 16 patients, among all 127 patients had a significant functional disability (mRS = 4) before the procedures, of which 8 patients belonged to each group (P = 0.42). Among the 8 patients (mRS = 4) of the early CAS group, no patient died at 30 days after CAS; however, 3 patients (37.5%) died between the 1- and 12-month follow-ups. While in the late CAS group, no patients died at 30 days and only 1 patient of 8 (12.5%) died between the 1- and 12-month follow-ups (P = 0.56).
Primary endpoints All 127 patients were included in the primary analysis and, at the 30-day follow-up, the overall incidence of ipsilateral stroke was 3.2% (4/127) and the overall rate of MACCE was 4.7% (6/127), which were in accordance with recommended safety statements [1,2]. The incidence of primary endpoints did not significantly differ between the two groups (Table 3). When comparing the early and late CAS groups, the incidence of ipsilateral ischemic
172 Table 2
L.H.d. Castro-Afonso et al. Patient’s baseline clinical data per group.
Male (n, %) Age (mean) 70 years and older (n, %) 80 years and older (n, %) Carotid related stroke (n, %) Transient ischemic attack (n, %) Retinal infarct (n, %) Previous non-related stroke (n, %) Coronary heart disease (n, %) Congestive heart failure (n, %) Atrial fibrillation (n, %) Peripheral artery disease (n, %) Chronic renal insufficiency (creatinine clearance ≤ 60 mL/min) Chronic obstructive pulmonary disease (n, %) Tobacco smokers (n, %) High blood pressure (n, %) Hypercholesterolemia (n, %) Diabetes melitus (n, %) Baseline mRS (mean, SD) Baseline mRS = 4 (n, %) Time from symptoms onset to CAS (days, mean) Left carotid stenosis (n, %) Carotid stenosis grade (mean, NASCET %) Contralateral carotid occlusion (n, %) Cerebral embolic protection (n, %) Pre-dilatation Successful CAS procedure (n, %)
Table 3
Total (n = 127)
Early CAS (n = 51)
Late CAS (n = 76)
P value
84 (66.1) 68.1 (35—88, SD ± 9.42) 53 (41.7) 17 (13.4) 102 (80.3) 20 (15.7) 5 (3.9) 31 (24.4) 21 (16.5) 15 (11.8) 7 (4.7) 15 (11.8) 24 (18.9)
35 (68.6) 67.4 (43—88, SD ± 9.98) 20 (39.2) 7 (13.7) 37 (72.5) 12 (23.5) 1 (2.0) 13 (25.5) 6 (11.8) 3 (5.9) 5 (9.8) 5 (9.8) 9 (17.6)
49 (64.5) 68.5 (35—87, SD ± 9.07) 33 (43.4) 10 (13.2) 65 (85.5) 8 (10.5) 4 (5.3) 18 (23.7) 15 (19.7) 12 (15.8) 2 (2.6) 10 (13.2) 15 (19.7)
0.70 0.49 0.71 1.00 0.06 0.02 0.64 0.83 0.33 0.10 0.11 0.78 0.82
9 (7.1)
4 (7.8)
5 (6.6)
1.00
78 (61.4) 117 (92.1) 94 (74) 47 (37) 1.9 (0—4, SD ± 1.25) 16 (12.6) —
29 (56.9) 46 (90.2) 39 (76.5) 20 (39.2) 2.0 (0—4, SD ± 1.29) 8 (15.6) 5.56 (1—14, SD ± 3.85)
49 (64.5) 71 (93.4) 55 (72.4) 27 (35.5) 1.8 (0—4, SD ± 1.22) 8 (10.5) 127.21 (17—180, SD ± 48.77)
0.45 0.52 0.68 0.71 0.46 0.42 < 0.01
61 (48) 75.5 (50—95, SD ± 16.3)
24 (47.1) 79.7 (50—95, SD ± 15.67)
37 (48.7) 72.6 (50—95, SD ± 16.19)
1.00 0.01
10 (7.9)
4 (7.8)
6 (7.9)
1.00
122 (96.1)
50 (98.0)
72 (94.7)
0.64
59 (46.5) 127 (100)
27 (52.9) 51 (100)
32 (42.1) 76 (100)
0.27 —
Clinical outcomes per group during the first 30 days after CAS. Total (n = 127)
Ipsilateral ischemic stroke (n, %) Ipsilateral parenchymal hemorrhage (n, %) Any stroke (n, %) Ipsilateral transient ischemic attack (n, %) Symptomatic myocardial infarction (mean, %) Deaths (n, %) MACCE (n, %) mRS (mean, SD)
Early CAS (n = 51)
Late CAS (n = 76)
One-tailed P value
Two-tailed P value
3 (2.4)
1 (2.0)
2 (2.6)
0.64
1.00
1 (0.8)
1 (2.0)
0 (0.0)
0.40
0.40
4 (3.1) 3 (2.4)
2 (3.9) 2 (3.9)
2 (2.6) 1 (1.3)
0.53 0.64
1.00 1.00
0 (0.0)
0 (0.0)
0 (0.0)
—
—
0.16 0.17 —
0.16 0.21 0.32
2 (1.6) 2 (3.9) 0 (0.0) 6 (4.7) 4 (7.8) 2 (2.6) 2.03 (0—6, SD ± 1.51) 2.27 (0—6, SD ± 1.72) 1.86 (0—6, SD ± 1.34)
Clinical outcomes per group during the first 30 days after CAS; mRS: modified Rankin Scale; MACCE: major adverse cardiac and cerebrovascular events, defined as any stroke, symptomatic myocardial infarction, vascular complications or death.
Early versus late carotid artery stenting for symptomatic carotid stenosis Table 4
173
Clinical outcomes per group between 1 and 12-months follow-up. Total (n = 125)
Ipsilateral ischemic stroke (n, %) Ipsilateral parenchymal hemorrhage (n, %) Any stroke (n, %) Ipsilateral transient ischemic attack (n, %) Symptomatic myocardial infarction (mean, %) Deaths (n, %) MACCE (n, %) mRS (mean, SD)
Early CAS (n = 49)
Late CAS (n= 76)
One-tailed P value
Two-tailed P value
0 (0.0)
0 (0.0)
0 (0.0)
—
—
0 (0.0)
0 (0.0)
0 (0.0)
—
—
1 (0.8) 0 (0.0)
0 (0.0) 0 (0.0)
1 (1.3) 0 (0.0)
0.60 —
1.00 —
2 (1.6)
0 (0.0)
2 (2.6)
0.36
0.51
0.39 0.49 —
0.76 0.77 0.48
13 (10.4) 6 (12.2) 7 (7.9) 14 (11.2) 6 (12.2) 8 (10.5) 2.29 (0—6, SD ± 1.73) 2.49 (0—6, SD ± 1.90) 2.15 (0—6, SD ± 1.61)
Clinical outcomes per group between 1- and 12-months follow-up; MACCE: major adverse cardiac and cerebrovascular events, which is defined as any stroke, symptomatic myocardial infarction, vascular complications or death.
stroke and iPH were 2.0% vs. 2.6% (P = 1.00) and 2.0% vs. 0.0% (P = 0.40), respectively. In the early CAS group, 2 strokes were observed, which were 1 ipsilateral ischemic stroke and 1 iPH. The ipsilateral ischemic stroke occurred right after the procedure resulting in a significant functional disability (mRS = 4) at the 12-month follow-up, while the iPH occurred 2 days after the procedure and the patient died 10 months later from a hospital-acquired pneumonia. This patient had no history of arterial hypertension or bleeding diathesis and no contralateral carotid artery occlusion. Therefore, the iPH may be explained by a revascularization of a critical stenosis of the right internal carotid artery (95%), and a CAS performed after 4 days of a relatively large brain infarct. Despite of infarcted area measured less than one third of the middle cerebral artery territory, the patient had a pre-procedure mRS score of 4. In the late CAS group, 2 ipsilateral ischemic strokes were observed. The first stroke occurred 6 h after the procedure, resulting in a moderate patient disability at the 12-month follow-up (mRS = 3). The second stroke occurred after carotid angioplasty and the patient presented a moderate neurological deficit (mRS = 3) at the 12-month follow-up.
Secondary endpoints The incidence of clinical secondary outcomes did not significantly differ between the two groups (Tables 3 and 4). Compared to late CAS, early CAS resulted in non-significant higher rates of MACCE at the 30-day and between 1 and 12 follow-ups, respectively (7.8% vs. 2.6%, P = 0.21) and (12.2% vs. 10.5%, P = 0.77). At the 30-day follow-up, two deaths occurred in the early CAS group, while no death occurred in the late CAS group (3.9% vs. 0.0%, P = 0.16). One patient died from a hospital-acquired pneumonia and the other patient died from an acute myelodyspastic syndrome; both deaths were not related to cardiovascular complications or to CAS procedures. Moreover, 2 patients of the early CAS group presented ipsilateral TIA versus 1 patient of the late CAS group;
however, these 3 patients did not presented any recurrence of TIA or stroke during the 12-month follow-up. During the follow-up period between 1 to 12 months, 6 patients (12.2%) of the early CAS group died and no patient presented stroke, TIA, or cardiovascular events. One patient that had iPH at the 30-day follow-up died from pneumonia 10 months later, and the other 5 patients died for causes unrelated to cerebrovascular or cardiovascular events. In the late CAS group, there were 7 deaths; 2 died from acute myocardial infarction and 5 died from other causes unrelated to cerebrovascular or cardiovascular events. In addition, 1 patient of the late CAS group presented a cerebellar hemorrhage requiring surgical intervention 7 months after CAS, and the patient presented a moderate neurological deficit (mRS = 3) at the 12-month follow-up.
Discussion Carotid artery atherosclerosis is associated with around 15% of all ischemic strokes [1,2]. Considering all common causes of stroke, carotid artery stenosis has been reported to be the first cause of early recurrent ischemic events [15,16]. The recurrence rates of ischemic events associated with symptomatic carotid stenosis have been reported to be higher than 30% during the first weeks of symptoms [15,16]. Currently, CEA is indicated for patients presenting a symptomatic carotid stenosis ≥ 50%, aiming at stroke prevention, if the rate of peri-procedural stroke or death is < 6% [1,2]. Based on a pooled analysis of randomized trials assessing CEA, the timing of carotid revascularization recommended is ≤ 14 days of the last ischemic symptom, if there is no contra-indication [1,2,4,5]. However, evidence suggests the earlier the CEA is performed after symptoms, the higher the risks of mortality or stroke, which may be higher than 10% [17—20]. In spite of that, according to Naylor based on data from The Carotid Endarterectomy Trialists Collaboration, performing a carotid revascularization procedure with a 10% risk within 2 weeks could prevent approximately 150 strokes per 1000 CEA, versus only 100 strokes if the procedure is performed after 4 weeks with a 3% risk [17,18].
174 Although CAS has become an acceptable alternative treatment to CEA, carotid revascularization within 2 weeks of symptoms is advocated mainly based on data extracted from CEA trials. Few studies have assessed safety data on CAS performed earlier after symptoms and those that did showed conflicting results [6—10]. In the present study, we reported clinical data of patients presenting carotid symptomatic stenosis who underwent CAS as a first intention treatment in a high-volume university hospital, outside randomized trials. Known limitations of observational studies that evaluate CAS are selection biases, because most patients treated with CAS usually are at a high risk or had a CEA contra-indicated [21,22]. The new insight of this study was to assess the clinical outcome data of patients who undergone CAS as a first intention revascularization treatment in a real clinical practice. In this study, an overall major complication rate (MACCE) of 4.7% (6/127) at 30 days was in accordance with the safe rates recommended after CAS for symptomatic patients (< 6%) [1,2]. The overall results reported showed a lower rate of poor outcomes, considering that 16 patients (12.6%) presenting severe neurological disability (mRS = 4) were included in the analysis. Moreover, compared to the late CAS, early CAS was associated with a non-significant higher frequency of any ipsilateral stroke (3.9% and 2.6%, P = 1.00) and MACCE (7.8% vs. 2.6%, P = 0.21) at 30 days. An analysis of these results in the perspective of the unbalanced baseline variables may explain the differences obtained. The baseline carotid stenosis grade was significantly higher in the early CAS group compared to the late CAS group (79.7 vs. 72.6, P = 0.01). In addition, the mean timing of CAS after the qualifying symptom had a huge discrepancy between the two groups. The mean timing for CAS in the early and late CAS groups was, respectively, 5.5 days vs. 127 days (P < 0.001). In the late CAS group, the mean time from symptoms to CAS was 4.2 months, relatively longer than the early CAS group, which could explain why the complication rates observed in that group were very similar with that obtained even among asymptomatic patients treated with CAS (< 3%). Another important issue was the occurrence of 2 deaths non-related to CAS procedures among patients of the early CAS group, which elevated the rate of MACCE to 7.8% (4/51). An analysis of the baseline variables TIA and stroke revealed that the higher prevalence of TIA in the early CAS group, and the tendency toward a high prevalence of stroke in the late CAS group, might reflect our institutional revascularization protocol. Accordingly to our protocol (Table 1), patients presenting TIA are usually treated as soon as possible, while patients presenting large strokes usually preclude an early carotid intervention, because of the potential risks of a symptomatic bleeding in the recent infracted tissue after an early carotid revascularization, or because patients presenting large strokes more frequently present acute clinical conditions, like infections. The aim of this study was to assess safety data on CAS within the first 14 days of the qualifying event using a comparator group of symptomatic patients who underwent CAS in a very late period after symptoms. Both primary and secondary outcomes did not significantly differ between the two groups, even in the setting of significant unbalance between the two groups regarding some clinically relevant baseline variables. However, because of the small sample size and the
L.H.d. Castro-Afonso et al. low rates of clinical events observed, we cannot make definitive conclusions regarding differences in clinical outcomes between the two groups. Despite of that, it is noteworthy that, in a setting which all patients were symptomatic, we included 15.6% patients presenting baseline mRS = 4, and patients were treated in a mean time of 5.5 days of symptoms, the outcomes obtained in the early CAS group may be considered encouraging. The major limitations of the study are the small sample size, which come from a single institution, the nonrandomized retrospective design, and the lack of a clinical and a surgical control groups. As CAS requires anticoagulation and antiplatelet therapies, on contrary to CEA, a surgical comparator group would be necessary to compare the incidence of iPH among patients treated within 2 weeks after ischemic strokes. The lack of a clinical comparator group is explained because we did not assess clinical outcomes, nor the incidence of recurrent ischemic events among patients who had not undergone CAS. Indeed, all patients who were not treated had a severe functional disability (mRS ≥ 5), an unstable and refractory clinical condition, or died in-hospital. Although CAS was performed as a first intention treatment modality to a broad range of patients, the external validity of the present study is limited by the single-center, the small sample size and by the low rates of clinical events observed. The small sample size and the lower rates of major clinical events found prevent us to make definitive conclusions regarding differences in clinical outcomes between the two groups.
Conclusion In this study, CAS seems to be safe when used as first intention revascularization treatment within 2 weeks of symptoms, if infarcted area is less than one third of the middle cerebral artery territory. Our results need to be confirmed by larger studies.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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