European Journal of Neurology 2014, 21: 1251–1257
doi:10.1111/ene.12461
CME ARTICLE
Safety of early endarterectomy in patients with symptomatic carotid artery stenosis: an international multicenter study G. Tsivgoulisa,b,c, C. Krogiasd, G. S. Georgiadise, R. Mikulikc,f, A. Safourisg, S. H. Mevesd, nyc,f, R. Staffah, S. G. Papageorgioua, A. H. Katsanosi, sa K. Voumvourakisa, M. Har j k A. Lazaris , A. Mumme , M. Lazaridese and S. N. Vasdekisj a
Second Department of Neurology, ‘Attikon’ Hospital, University of Athens, School of Medicine, Athens; bDepartment of Neurology,
Democritus University of Thrace, School of Medicine, Alexandroupolis, Greece; cInternational Clinical Research Center, St Anne’s University Hospital in Brno, Brno, Czech Republic; dDepartment of Neurology, St Josef Hospital, Ruhr University, Bochum, Germany; e
Department of Vascular Surgery, Democritus University of Thrace, School of Medicine, Alexandroupolis, Greece; fDepartment of
Neurology, St Anne’s University Hospital and Medical Faculty of Masaryk University, Brno, Czech Republic; gStroke Unit, Department of Neurology, Brugmann University Hospital, Brussels, Belgium; h2nd Department of Surgery, St Anne’s University Hospital, and Faculty of Medicine, Masaryk University, Brno, Czech Republic; iDepartment of Neurology, University of Ioannina, School of Medicine, Ioannina; jVascular Unit, 3rd Surgical Department, ‘Attikon’ Hospital, University of Athens, School of Medicine, Athens, Greece; and k
Department of Vascular Surgery, St Josef Hospital, Ruhr University, Bochum, Germany
Keywords:
carotid artery, carotid endarterectomy, early, stroke Received 2 February 2014 Accepted 7 April 2014
Background and purpose: Although the latest recommendations suggest that carotid endarterectomy (CEA) should be performed in symptomatic carotid artery stenosis (sCAS) patients within 2 weeks of the index event, only a minority of patients undergo surgery within the recommended time-frame. The aim of this international multicenter study was to prospectively evaluate the safety of early CEA in patients with sCAS in everyday clinical practice settings. Methods: Consecutive patients with non-disabling acute ischaemic stroke (AIS) or transient ischaemic attack (TIA) due to sCAS (≥70%) underwent early (≤14 days) CEA at five tertiary-care stroke centers during a 2-year period. Primary outcome events included stroke, myocardial infarction (MI) or death occurring during the 30-day follow-up period and were defined according to the International Carotid Stenting Study criteria. Results: A total of 165 patients with sCAS [mean age 69 10 years; 69% men; 70% AIS; 6% crescendo TIA; 8% with contralateral internal carotid artery (ICA) occlusion] underwent early CEA (median elapsed time from symptom onset 8 days). Urgent CEA (≤2 days) was performed in 20 cases (12%). The primary outcomes of stroke and MI were 4.8% [95% confidence interval (CI) 1.5%–8.1%] and 0.6% (95% CI 0%–1.8%). The combined outcome event of non-fatal stroke, non-fatal MI or death was 5.5% (95% CI 2.0%–9.0%). Crescendo TIA, contralateral ICA occlusion and urgent CEA were not associated (P > 0.2) with a higher 30-day stroke rate. Conclusions: Our findings indicate that the risk of early CEA in consecutive unselected patients with non-disabling AIS or TIA due to sCAS is acceptable when the procedure is performed within 2 weeks (or even within 2 days) from symptom onset.
Introduction Recent American Heart Association (AHA) and American Academy of Neurology guidelines [1–3] as Correspondence: G. Tsivgoulis, Iras 39, Gerakas Attikis, 15344 Athens, Greece (tel.: +306937178635; fax: +302105832471; e-mail: [email protected]). This is a Continuing Medical Education article, and can be found with corresponding questions on the Internet at http://www.efns.org/ EFNSContinuing-Medical-Education-online.301.0.html. Certificates for correctly answering the questions will be issued by the EFNS.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
well as other international recommendations [4,5] advocate that carotid endarterectomy (CEA) should be performed within 2 weeks of the index event in patients with symptomatic carotid artery stenosis (sCAS), since pooled analyses [6,7] from endarterectomy trials indicate that the benefit from surgery is greatest in those randomized to CEA within 14 days from their most recent symptomatic event. However, available data indicate that only a minority of patients undergo surgery within the recommended time-frame [8–10]. This may be related to delays in patients’
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diagnostic work-up and referrals, but it is mainly attributed to a traditional reluctance of surgeons to operate due to a perceived higher incidence of complications with early CEA [11]. Moreover, the safety of early CEA in unselected sCAS patients has not been established outside the settings of randomized controlled trials, since there are certain reports showing unacceptable rates of peri-procedural morbidity or mortality in sCAS patients who underwent early (≤14 days from symptom onset) [12,13] or urgent (≤2 days from symptom onset) CEA [14]. Finally, a recent systematic review of endarterectomy studies demonstrated high complication rates in crescendo transient ischaemic attack (TIA) patients with sCAS who underwent early CEA [15]. In view of the former considerations the aim of this international multicenter study was to prospectively evaluate the safety of early CEA in patients with sCAS in everyday clinical practice settings. It was also investigated whether urgent CEA performed within 2 days from the index event, a history of crescendo TIA or the presence of contralateral internal carotid artery (ICA) occlusion were associated with a higher risk of peri-procedural complications.
Methods Study population
Consecutive patients presenting with symptoms of acute ischaemic stroke (AIS) or TIA due to sCAS in five university tertiary-care stroke centers (Alexandroupolis and Athens, Greece; Bochum, Germany; Brno, Czech Republic; Brussels, Belgium) fulfilling the following inclusion criteria during the 2-year study period (June 2011–May 2013) were prospectively evaluated: (i) ≥70% stenosis in symptomatic carotid artery diagnosed on baseline carotid duplex evaluation by two or more independent investigators (using the Society of Radiologists in Ultrasound Consensus Criteria) [16]; (ii) a symptomatic index event defined as non-disabling [modified Rankin Scale (mRS) score of 0–2] AIS or TIA according to AHA recommendations [2]; (iii) CEA performed for revascularization of sCAS within 2 weeks from symptom onset; (iv) absence of radiation-induced carotid artery stenosis. Carotid endarterectomy was offered as the first-line therapy in all patients with sCAS (>70%) in the participating centers. Patients who did not consent to undergo carotid surgery and preferred to be treated either with medical therapy or with carotid artery stenting were excluded from the present analyses. All patients were included in a computerized data bank,
and their demographic characteristics, vascular risk factors, and clinical and neuroimaging findings during hospitalization and after discharge were documented as previously described in similar studies by our international collaborative group [17–19]. Stroke severity on hospital admission and at discharge was evaluated using the National Institutes of Health Stroke Scale (NIHSS) score. Crescendo TIAs were defined as a succession of TIAs in which succeeding TIAs were more severe or more frequent [15,20]. Stroke-in-evolution was defined as a stroke with progressive neurological deficits (quantified by serial NIHSS scores) over 1 or 2 days [21]. Contralateral ICA stenosis (50%–99%) and contralateral ICA occlusion was documented in all cases. The present study was approved by the Ethics Committee/Institutional Review Board of our institutions. All patients signed standard informed consent forms for CEA and were informed about potential peri-procedural risks. Carotid endarterectomy
The five participating centers had extensive previous experience in CEA for sCAS [18,22–25]. All patients referred to carotid surgery were evaluated by an attending level stroke neurologist (G.T., C.K., R.M., A.S., K.V.) who determined symptomatic status of the carotid artery stenosis and functional status of AIS patients using the mRS score. Patients with disabling stroke (mRS grades 3–5) were treated conservatively according to AHA recommendations [2]. Anesthetic and operative techniques, intra-operative monitoring, intra-operative blood pressure control and anticoagulation procedures were performed according to the operating surgeon’s discretion. Time to intervention was defined as the number of days between the qualifying neurological event and the day of surgery. Urgent CEA was performed in cases that were operated within the first 48 h from symptom onset. Definitions of outcome events
All patients were re-evaluated by a stroke neurologist within the first 24 h of carotid surgery and at the end of the 30-day follow-up period. The primary outcome events of interest included any stroke, death or procedural myocardial infarction (MI) during the first 30 days following the index event. All outcome events were diagnosed by a stroke neurologist, who assessed all patients both pre- and post-operatively, and were defined according to the International Carotid Stenting Study (ICSS) criteria [26]. More specifically, stroke was defined as a rapidly developing clinical syndrome © 2014 The Author(s) European Journal of Neurology © 2014 EAN
Early CEA in symptomatic carotid stenosis
of focal disturbance of cerebral function lasting more than 24 h or leading to death with no apparent cause other than that of vascular origin [26]. Brain imaging demonstrating a new lesion involving a different anatomical site or vascular territory from the index event was mandatory to support the diagnosis of peri-procedural stroke during the 30-day follow-up period. Stroke was classified as disabling if there was an increase in the mRS score to 3 or more, attributable to the event at 30 days after onset [26]. Ischaemic stroke was classified based on etiopathogenetic mechanisms into the following subgroups according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria: large artery atherosclerotic stroke (LAA), cardioembolic stroke, small artery occlusion or lacunar infarction, infarction of other determined origin and infarction of undetermined cause [27]. Myocardial infarction was defined by the presence of two of the following three criteria: (i) specific cardiac enzymes more than twice the upper limit of normal; (ii) history of chest discomfort for at least 30 min; (iii) the development of specific abnormalities (e.g. Q waves) on a standard 12-lead electrocardiograph [26]. Secondary events of interest were cranial nerve palsies and neck hematomas requiring surgery, transfusion or extended hospital stay [26]. Secondary prevention therapies during hospitalization and the follow-up period were determined by stroke neurologists at each participating center according to AHA recommendations [1]. Statistical analyses
Continuous parametric and non-parametric data are presented as mean standard deviation or as median (range) respectively. Non-continuous variables are presented as percentages. Statistical comparisons were performed between subgroups of patients using the v2 test (or Fisher’s exact test) and the unpaired t test (or Mann–Whitney U test) as indicated. The Kaplan–Meier product limit method was used to estimate the cumulative probability of peri-procedural stroke, MI or death after 30 days from the index event. Differences in stroke-free survival between different groups of patients were assessed for statistical significance with the log-rank test. Finally, Cox proportional hazards regression models were used to identify factors that increased the 30-day risk of stroke as well as the 30-day risk of stroke or death. In the initial univariate analyses the potential associations of all candidate variables (demographic characteristics, vascular risk factors, clinical and neuroimaging findings, time to intervention, crescendo TIA, urgent CEA) with the outcome events of interest were investigated. All © 2014 The Author(s) European Journal of Neurology © 2014 EAN
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factors that contributed to the outcome event in the univariate analyses at P values 50%, % Median admission NIHSS score, points (IQR) Median elapsed time between symptom onset and CEA, days (IQR, range) Urgent CEA performed within 2 days from symptom onset, % Median length of hospitalization, days (IQR, range)
69 (10) 69 70 30 6 86 33 9 56 45 30 8 22 3 (3) 7 (6, 1–14) 12 11 (8, 3–31)
AIS, acute ischaemic stroke; TIA, transient ischaemic attack; ICA, internal carotid artery; CEA, carotid endarterectomy; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale. Table 2 Baseline characteristics in patients who underwent urgent (0 –2 days of symptom onset) and early (3–14 days of symptom onset) carotid endarterectomy (CEA)
Baseline characteristic Mean age, years (SD) Male gender, % Index event AIS, % TIA, % Crescendo TIA, % Hypertension, % Diabetes mellitus, % Atrial fibrillation, % Hypercholesterolemia, % Current smoking, % Coronary artery disease, % Contralateral ICA occlusion, % Contralateral ICA stenosis >50%, % Median admission NIHSS score, points (IQR)
Urgent CEA (0–2 days of symptom onset)
Early CEA (3 14 days of symptom onset)
P
70 (12) 55
68 (10) 71
0.595 0.146
65 35 15 90 30 10 50 50 35
70 30 4 86 34 8 57 44 30
0.626
5
8
0.999a
10
24
0.251a
5 (7)
3 (3)
0.080a 0.743a 0.736 0.679a 0.580 0.621 0.612
0.209
AIS, acute ischaemic stroke; TIA, transient ischaemic attack; ICA, internal carotid artery; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale. aFisher’s exact test.
24 h following CEA. LAA was identified as the most common underlying stroke etiology (n = 7; 88% of all strokes). The diagnosis was confirmed in all cases by
Stroke Disabling stroke (mRS score of 0–2) Non-disabling stroke (mRS score of 3–6) Myocardial infarction Death Cranial nerve palsy Neck hematoma Non-fatal stroke or death Non-fatal stroke or non-fatal myocardial infarction or death Disabling stroke or myocardial infarction or death
N (%)
30-day cumulative rate,a % (95% CI)
8 (4.8) 3 (1.8)
4.8 (1.5–8.1) 1.9 (0–4.1)
5 (3.0)
3.0 (0.5–5.5)
1 1 11 6 9 9
(0.6) (0.6) (6.7) (3.6) (5.5) (5.5)
4 (2.4)
0.6 0.6 Not Not 5.5 5.5
(0–1.8) (0–1.8) applicable applicable (2.0–9.0) (2.0–9.0)
2.4 (0–4.8)
mRS, modified Rankin Scale. aCalculated using the Kaplan–Meier product limit method.
neuroimaging studies showing new or first-ever ischaemic lesions occurring in the territory of the operated ICA. There was one case of hyperperfusion hemorrhage (12%). Two cases of acute common carotid artery and ICA thrombosis (25%) occurring during the first 24 h following carotid surgery that were treated with emergent carotid artery thrombectomy were documented (Fig. 1). The 30-day event rate of disabling stroke was 3.0% (95% CI 0.5%–5.5%). One case of death (0.6%, 95% CI 0%–1.8%) due to an extensive acute MI complicated by pulmonary infections was documented. The combined outcome event rate of non-fatal stroke, non-fatal MI or death was 5.5% (2.0%–9.0%). The combined outcome event rate of non-fatal disabling stroke, non-fatal MI or death was 2.4% (95% CI 0%–4.8%). There was no difference across (P > 0.2) the five participating centers in the 30-day rates of stroke and in the 30-day rates of non-fatal stroke, non-fatal MI or death. The rates of cranial nerve palsy and neck hematoma were 6.7% and 3.6% respectively. The univariate associations of baseline characteristics with the outcome events of stroke and stroke or death are presented in Table 4. Crescendo TIA, contralateral ICA occlusion and urgent CEA were not associated (P > 0.2) with a higher rate of peri-procedural events. None of the baseline characteristics was associated with a higher 30-day stroke rate (P > 0.2). Gender (P = 0.137) and diabetes mellitus (P = 0.162) tended to be associated with the outcome event of stroke or death and were included as candidate variables in the multivariate Cox regression models. Neither female gender (HR 2.27; 95% CI 0.57–9.01; © 2014 The Author(s) European Journal of Neurology © 2014 EAN
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Figure 1 Peri-procedural stroke following carotid endarterectomy in a 61-year-old man with right symptomatic carotid artery stenosis >70% (index event: transient ischaemic attack). Baseline magnetic resonance imaging with diffusion weighted imaging was negative for acute ischaemic stroke. Eight hours following early carotid endarterectomy (performed at the ninth day of ictus) the patient developed left hemiparesis and mild dysarthria (NIHSS score 6). Emergent carotid duplex disclosed the presence of thrombus in the right common carotid artery (a, b: longitudinal and transverse B-mode images) and right internal carotid artery. The patient underwent emergent carotid thrombectomy that resulted in successful removal of a long thrombus from the right common and internal carotid arteries (c). Follow-up brain magnetic resonance imaging at 7 days showed a small right putaminal infarction (d, axial FLAIR sequence). The patient had an mRS score of 1 at 3 months.
Table 4 Univariate associations of baseline characteristics with 30-day stroke rate and 30-day combined stroke and mortality rate 30-day stroke
30-day stroke and mortality
Factor
Yes (n = 8)
No (n = 157)
P
Yes (n = 9)
No (n = 156)
P
Age, years (mean SD) Male gender, % AIS as index event, % Crescendo TIA, % Median admission NIHSS score, points (IQR) Median elapsed time between symptom onset and CEA, days (IQR, range) Urgent CEA performed within 2 days from symptom onset, % Hypertension, % Diabetes mellitus, % Hypercholesterolemia, % Atrial fibrillation, % Coronary artery disease, % Current smoking, % Confirmation of ICA stenosis by angiography, %
70 11 50.0 62.5 12.5 3 (5) 7 (9)
68 10 70.1 70.1 5.1 3 (3) 7 (6)
0.752 0.254 0.699 0.368 0.798 0.910
71 11 44.4 66.7 11.1 4 (4) 9 (10)
68 10 70.5 69.9 5.1 3 (3) 7 (6)
0.512 0.137 0.999 0.404 0.888 0.609
0.250 0.601 0.443 0.304 0.999 0.999 0.732 0.437
25.0 100 55.6 66.7 0 33.3 44.4 88.9
25.0 100 50.0 75.0 0 25.0 37.5 87.5
11.2 85.4 32.5 54.8 8.9 30.6 45.2 68.2
11.2 85.3 32.1 55.1 9.0 30.1 44.9 67.9
0.299 0.363 0.162 0.732 0.999 0.999 0.999 0.277
AIS, acute ischaemic stroke; TIA, transient ischaemic attack; NIHSS, National Institutes of Health Stroke Scale; IQR, interquartile range; CEA, carotid endarterectomy; ICA, internal carotid artery.
P = 0.247) nor diabetes mellitus (HR 2.04; 95% CI 0.51–8.16; P = 0.313) were independently associated with a higher 30-day rate of stroke or death on multivariate Cox regression analyses. Consequently no independent predictor of higher risk of peri-procedural events could be identified in our cohort. © 2014 The Author(s) European Journal of Neurology © 2014 EAN
The 30-day event of stroke in patients who underwent urgent CEA (n = 20) was 10.0% (n = 2). There was no difference between the rate of peri-procedural stroke between patients who underwent urgent (n = 20) and delayed (>14 days; n = 18) carotid surgery during the study period (10.0% vs. 5.6%;
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P = 0.999 by Fisher’s exact test). Similarly, the 30-day event of stroke in patients who underwent urgent (0– 2 days of symptom onset) CEA (10.0%) was similar to the 30-day event of stroke in patients who underwent early (3–14 days of symptom onset) CEA (4.1%; P = 0.260). After conducting a post hoc power analysis it was estimated that for the given effect size (4.1% vs. 10% rates of peri-procedural stroke in urgent and early CEA) and for the given prevalence ratio of early/urgent CEA (7.25/1) a sample of 1320 CEA performed within 14 days (160 cases of urgent CEA and 1160 cases of early CEA) would be required to detect a higher rate of peri-procedural stroke in urgent CEA in comparison with early CEA with a power of 80% and a two-tailed a of 0.05.
Discussion Our study showed that the peri-operative risk of CEA in sCAS patients with a recent non-disabling AIS or TIA was not increased if carotid surgery was performed within 14 days of a qualifying neurological event. The rate of peri-procedural complications was not elevated even in certain sCAS subgroups of potential high surgical risk [14,15,21] including patients who were operated in the acute phase (≤48 h) of cerebral ischaemia and individuals with crescendo TIAs or contralateral ICA occlusion. The optimal timing of CEA after TIA or AIS remains a timely and controversial issue. Despite compelling evidence from randomized controlled trials documenting that CEA is safe and most effective when performed within 2 weeks from the index event [7], most vascular surgeons are reluctant to undertake carotid surgery immediately after the symptomatic event. Consequently, the majority of sCAS patients are operated with substantial time delays in everyday clinical practice settings [8,9]. The main theoretical arguments supporting the delay of CEA include (i) conversion of pre-existing infarct into intracerebral hemorrhage due to reperfusion/hyperperfusion injury [11,13,28], (ii) increased vulnerability of recently infarcted brain tissue to peri-procedural cerebral ischaemia induced by carotid clamping or profound blood pressure decreases [11,13,28] and (iii) greater vulnerability of carotid plaques in the acute phase of cerebral ischaemia resulting in higher peri-procedural risk of distal embolization during plaque removal [14]. Moreover, individual studies reporting institutional [12,13,29] or multicenter [21,30] experience have reported an increased risk of peri-procedural stroke or death when CEA was performed within the first 2– 4 weeks of the index event. Finally, there are growing concerns regarding the safety of CEA in crescendo
TIAs [15,21] and during the first 2 days [14] of acute cerebral ischaemia. Our findings contradict the previous reports [13,29] arguing in favor of delaying carotid surgery beyond the 2-week time window recommended by international guidelines. Our observations are in line with the experience of Italian [31,32], German [33], Danish [34] and North American [35,36] investigators underscoring the safety of early CEA during the first weeks after the qualifying neurological event. In agreement with the recent literature [14,32,34,36], the feared increase in the risk of hyperperfusion hemorrhage following early CEA was not found and the risk was extremely low (0.6%) in our study population. Furthermore, crescendo TIAs and urgent (≤48 h) CEA were not associated with a higher risk of peri-procedural events. However, these findings should be interpreted in the light of the limited sample size in the two sCAS subgroups (nine cases of crescendo TIAs and 20 cases of urgent CEA). Our study has limitations including the observational design and the absence of a uniform intra-operative protocol. Moreover, the absence of central adjudication of outcome events should be acknowledged. In addition, no formal sample size estimation was performed prior to study initiation. Moreover, since ICSS definitions were used for outcome events, some cases of asymptomatic MIs may have been missed. In addition, plaque characteristics (echogenicity, stability or ulceration) were not accounted for in our analyses and these parameters may have contributed to peri-operative risks associated with early CEA. Also, the sample size of the group of urgent CEA was small (n = 20), albeit comparable to the limited studies available in the relevant literature [12,13]. Last but not least, patients with ≥70% stenosis in the symptomatic carotid artery were included since both North American and European guidelines advocate CEA in this subgroup using a grade I/level A recommendation [2–5]. An equally important group that was not evaluated in the present study and deserves further investigation includes patients with symptomatic 50%–69% carotid artery stenosis, since the reluctance of vascular surgeons to operate early in this specific subgroup may be even greater. On the other hand, certain strengths of this report should be recognized. First and most important, our observations in a consecutive series of patients reflect ‘real-life’ clinical experience in several countries. Secondly, serial evaluations (before and after carotid surgery) of sCAS patients were performed by independent stroke neurologists, who were responsible for the diagnosis and classification of both symptomatic status and peri-procedural complications. Thirdly, the © 2014 The Author(s) European Journal of Neurology © 2014 EAN
Early CEA in symptomatic carotid stenosis
possibility of selection bias was minimized since all operations were performed by a few experienced surgeons with high yearly volumes, whilst all referrals were made by the same attending vascular neurologists at each participating center. In conclusion, our findings indicate that the risk of early CEA in consecutive unselected patients with non-disabling stroke or TIA due to sCAS is acceptable when the procedure is performed within 2 weeks as well as within 2 days from symptom onset. Our prospective, multicenter experience provides reassurance that an expedited CEA can be safely performed in the acute (≤2 days) or subacute (3–14 days) phase of acute cerebral ischaemia in patients with sCAS and support current international recommendations advocating that expectant management and delayed
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surgery are not justified in patients with a recent nondisabling symptomatic event and ipsilateral significant carotid stenosis.
Acknowledgements Dr Georgios Tsivgoulis, Dr Robert Mikulik and Dr Michal Hars any have been supported by the European Regional Development Fund – Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123).
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
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2 weeks of minor ischemic stroke: a prospective study. J Vasc Surg 2008; 48: 595–600. 33. Schneider C, Johansen K, K€ onigstein R, Metzner C, Oettinger W. Emergency carotid thromboendarterectomy: safe and effective. World J Surg 1999; 23: 1163– 1167. 34. Shahidi S, Owen-Falkenberg A, Hjerpsted U, Rai A, Ellemann K. Urgent best medical therapy may obviate the
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need for urgent surgery in patients with symptomatic carotid stenosis. Stroke 2013; 44: 2220–2225. 35. Paty PS, Darling RC 3rd, Feustel PJ, et al. Early carotid endarterectomy after acute stroke. J Vasc Surg 2004; 39: 148–154. 36. Brinjikji W, Rabinstein AA, Meyer FB, Piepgras DG, Lanzino G. Risk of early carotid endarterectomy for symptomatic carotid stenosis. Stroke 2010; 41: 2186–2190.
doi:10.1111/ene.12461
CME ARTICLE
Safety of early endarterectomy in patients with symptomatic carotid artery stenosis: an international multicenter study G. Tsivgoulisa,b,c, C. Krogiasd, G. S. Georgiadise, R. Mikulikc,f, A. Safourisg, S. H. Mevesd, nyc,f, R. Staffah, S. G. Papageorgioua, A. H. Katsanosi, sa K. Voumvourakisa, M. Har j k A. Lazaris , A. Mumme , M. Lazaridese and S. N. Vasdekisj a
Second Department of Neurology, ‘Attikon’ Hospital, University of Athens, School of Medicine, Athens; bDepartment of Neurology,
Democritus University of Thrace, School of Medicine, Alexandroupolis, Greece; cInternational Clinical Research Center, St Anne’s University Hospital in Brno, Brno, Czech Republic; dDepartment of Neurology, St Josef Hospital, Ruhr University, Bochum, Germany; e
Department of Vascular Surgery, Democritus University of Thrace, School of Medicine, Alexandroupolis, Greece; fDepartment of
Neurology, St Anne’s University Hospital and Medical Faculty of Masaryk University, Brno, Czech Republic; gStroke Unit, Department of Neurology, Brugmann University Hospital, Brussels, Belgium; h2nd Department of Surgery, St Anne’s University Hospital, and Faculty of Medicine, Masaryk University, Brno, Czech Republic; iDepartment of Neurology, University of Ioannina, School of Medicine, Ioannina; jVascular Unit, 3rd Surgical Department, ‘Attikon’ Hospital, University of Athens, School of Medicine, Athens, Greece; and k
Department of Vascular Surgery, St Josef Hospital, Ruhr University, Bochum, Germany
Keywords:
carotid artery, carotid endarterectomy, early, stroke Received 2 February 2014 Accepted 7 April 2014
Background and purpose: Although the latest recommendations suggest that carotid endarterectomy (CEA) should be performed in symptomatic carotid artery stenosis (sCAS) patients within 2 weeks of the index event, only a minority of patients undergo surgery within the recommended time-frame. The aim of this international multicenter study was to prospectively evaluate the safety of early CEA in patients with sCAS in everyday clinical practice settings. Methods: Consecutive patients with non-disabling acute ischaemic stroke (AIS) or transient ischaemic attack (TIA) due to sCAS (≥70%) underwent early (≤14 days) CEA at five tertiary-care stroke centers during a 2-year period. Primary outcome events included stroke, myocardial infarction (MI) or death occurring during the 30-day follow-up period and were defined according to the International Carotid Stenting Study criteria. Results: A total of 165 patients with sCAS [mean age 69 10 years; 69% men; 70% AIS; 6% crescendo TIA; 8% with contralateral internal carotid artery (ICA) occlusion] underwent early CEA (median elapsed time from symptom onset 8 days). Urgent CEA (≤2 days) was performed in 20 cases (12%). The primary outcomes of stroke and MI were 4.8% [95% confidence interval (CI) 1.5%–8.1%] and 0.6% (95% CI 0%–1.8%). The combined outcome event of non-fatal stroke, non-fatal MI or death was 5.5% (95% CI 2.0%–9.0%). Crescendo TIA, contralateral ICA occlusion and urgent CEA were not associated (P > 0.2) with a higher 30-day stroke rate. Conclusions: Our findings indicate that the risk of early CEA in consecutive unselected patients with non-disabling AIS or TIA due to sCAS is acceptable when the procedure is performed within 2 weeks (or even within 2 days) from symptom onset.
Introduction Recent American Heart Association (AHA) and American Academy of Neurology guidelines [1–3] as Correspondence: G. Tsivgoulis, Iras 39, Gerakas Attikis, 15344 Athens, Greece (tel.: +306937178635; fax: +302105832471; e-mail: [email protected]). This is a Continuing Medical Education article, and can be found with corresponding questions on the Internet at http://www.efns.org/ EFNSContinuing-Medical-Education-online.301.0.html. Certificates for correctly answering the questions will be issued by the EFNS.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
well as other international recommendations [4,5] advocate that carotid endarterectomy (CEA) should be performed within 2 weeks of the index event in patients with symptomatic carotid artery stenosis (sCAS), since pooled analyses [6,7] from endarterectomy trials indicate that the benefit from surgery is greatest in those randomized to CEA within 14 days from their most recent symptomatic event. However, available data indicate that only a minority of patients undergo surgery within the recommended time-frame [8–10]. This may be related to delays in patients’
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diagnostic work-up and referrals, but it is mainly attributed to a traditional reluctance of surgeons to operate due to a perceived higher incidence of complications with early CEA [11]. Moreover, the safety of early CEA in unselected sCAS patients has not been established outside the settings of randomized controlled trials, since there are certain reports showing unacceptable rates of peri-procedural morbidity or mortality in sCAS patients who underwent early (≤14 days from symptom onset) [12,13] or urgent (≤2 days from symptom onset) CEA [14]. Finally, a recent systematic review of endarterectomy studies demonstrated high complication rates in crescendo transient ischaemic attack (TIA) patients with sCAS who underwent early CEA [15]. In view of the former considerations the aim of this international multicenter study was to prospectively evaluate the safety of early CEA in patients with sCAS in everyday clinical practice settings. It was also investigated whether urgent CEA performed within 2 days from the index event, a history of crescendo TIA or the presence of contralateral internal carotid artery (ICA) occlusion were associated with a higher risk of peri-procedural complications.
Methods Study population
Consecutive patients presenting with symptoms of acute ischaemic stroke (AIS) or TIA due to sCAS in five university tertiary-care stroke centers (Alexandroupolis and Athens, Greece; Bochum, Germany; Brno, Czech Republic; Brussels, Belgium) fulfilling the following inclusion criteria during the 2-year study period (June 2011–May 2013) were prospectively evaluated: (i) ≥70% stenosis in symptomatic carotid artery diagnosed on baseline carotid duplex evaluation by two or more independent investigators (using the Society of Radiologists in Ultrasound Consensus Criteria) [16]; (ii) a symptomatic index event defined as non-disabling [modified Rankin Scale (mRS) score of 0–2] AIS or TIA according to AHA recommendations [2]; (iii) CEA performed for revascularization of sCAS within 2 weeks from symptom onset; (iv) absence of radiation-induced carotid artery stenosis. Carotid endarterectomy was offered as the first-line therapy in all patients with sCAS (>70%) in the participating centers. Patients who did not consent to undergo carotid surgery and preferred to be treated either with medical therapy or with carotid artery stenting were excluded from the present analyses. All patients were included in a computerized data bank,
and their demographic characteristics, vascular risk factors, and clinical and neuroimaging findings during hospitalization and after discharge were documented as previously described in similar studies by our international collaborative group [17–19]. Stroke severity on hospital admission and at discharge was evaluated using the National Institutes of Health Stroke Scale (NIHSS) score. Crescendo TIAs were defined as a succession of TIAs in which succeeding TIAs were more severe or more frequent [15,20]. Stroke-in-evolution was defined as a stroke with progressive neurological deficits (quantified by serial NIHSS scores) over 1 or 2 days [21]. Contralateral ICA stenosis (50%–99%) and contralateral ICA occlusion was documented in all cases. The present study was approved by the Ethics Committee/Institutional Review Board of our institutions. All patients signed standard informed consent forms for CEA and were informed about potential peri-procedural risks. Carotid endarterectomy
The five participating centers had extensive previous experience in CEA for sCAS [18,22–25]. All patients referred to carotid surgery were evaluated by an attending level stroke neurologist (G.T., C.K., R.M., A.S., K.V.) who determined symptomatic status of the carotid artery stenosis and functional status of AIS patients using the mRS score. Patients with disabling stroke (mRS grades 3–5) were treated conservatively according to AHA recommendations [2]. Anesthetic and operative techniques, intra-operative monitoring, intra-operative blood pressure control and anticoagulation procedures were performed according to the operating surgeon’s discretion. Time to intervention was defined as the number of days between the qualifying neurological event and the day of surgery. Urgent CEA was performed in cases that were operated within the first 48 h from symptom onset. Definitions of outcome events
All patients were re-evaluated by a stroke neurologist within the first 24 h of carotid surgery and at the end of the 30-day follow-up period. The primary outcome events of interest included any stroke, death or procedural myocardial infarction (MI) during the first 30 days following the index event. All outcome events were diagnosed by a stroke neurologist, who assessed all patients both pre- and post-operatively, and were defined according to the International Carotid Stenting Study (ICSS) criteria [26]. More specifically, stroke was defined as a rapidly developing clinical syndrome © 2014 The Author(s) European Journal of Neurology © 2014 EAN
Early CEA in symptomatic carotid stenosis
of focal disturbance of cerebral function lasting more than 24 h or leading to death with no apparent cause other than that of vascular origin [26]. Brain imaging demonstrating a new lesion involving a different anatomical site or vascular territory from the index event was mandatory to support the diagnosis of peri-procedural stroke during the 30-day follow-up period. Stroke was classified as disabling if there was an increase in the mRS score to 3 or more, attributable to the event at 30 days after onset [26]. Ischaemic stroke was classified based on etiopathogenetic mechanisms into the following subgroups according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria: large artery atherosclerotic stroke (LAA), cardioembolic stroke, small artery occlusion or lacunar infarction, infarction of other determined origin and infarction of undetermined cause [27]. Myocardial infarction was defined by the presence of two of the following three criteria: (i) specific cardiac enzymes more than twice the upper limit of normal; (ii) history of chest discomfort for at least 30 min; (iii) the development of specific abnormalities (e.g. Q waves) on a standard 12-lead electrocardiograph [26]. Secondary events of interest were cranial nerve palsies and neck hematomas requiring surgery, transfusion or extended hospital stay [26]. Secondary prevention therapies during hospitalization and the follow-up period were determined by stroke neurologists at each participating center according to AHA recommendations [1]. Statistical analyses
Continuous parametric and non-parametric data are presented as mean standard deviation or as median (range) respectively. Non-continuous variables are presented as percentages. Statistical comparisons were performed between subgroups of patients using the v2 test (or Fisher’s exact test) and the unpaired t test (or Mann–Whitney U test) as indicated. The Kaplan–Meier product limit method was used to estimate the cumulative probability of peri-procedural stroke, MI or death after 30 days from the index event. Differences in stroke-free survival between different groups of patients were assessed for statistical significance with the log-rank test. Finally, Cox proportional hazards regression models were used to identify factors that increased the 30-day risk of stroke as well as the 30-day risk of stroke or death. In the initial univariate analyses the potential associations of all candidate variables (demographic characteristics, vascular risk factors, clinical and neuroimaging findings, time to intervention, crescendo TIA, urgent CEA) with the outcome events of interest were investigated. All © 2014 The Author(s) European Journal of Neurology © 2014 EAN
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factors that contributed to the outcome event in the univariate analyses at P values 50%, % Median admission NIHSS score, points (IQR) Median elapsed time between symptom onset and CEA, days (IQR, range) Urgent CEA performed within 2 days from symptom onset, % Median length of hospitalization, days (IQR, range)
69 (10) 69 70 30 6 86 33 9 56 45 30 8 22 3 (3) 7 (6, 1–14) 12 11 (8, 3–31)
AIS, acute ischaemic stroke; TIA, transient ischaemic attack; ICA, internal carotid artery; CEA, carotid endarterectomy; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale. Table 2 Baseline characteristics in patients who underwent urgent (0 –2 days of symptom onset) and early (3–14 days of symptom onset) carotid endarterectomy (CEA)
Baseline characteristic Mean age, years (SD) Male gender, % Index event AIS, % TIA, % Crescendo TIA, % Hypertension, % Diabetes mellitus, % Atrial fibrillation, % Hypercholesterolemia, % Current smoking, % Coronary artery disease, % Contralateral ICA occlusion, % Contralateral ICA stenosis >50%, % Median admission NIHSS score, points (IQR)
Urgent CEA (0–2 days of symptom onset)
Early CEA (3 14 days of symptom onset)
P
70 (12) 55
68 (10) 71
0.595 0.146
65 35 15 90 30 10 50 50 35
70 30 4 86 34 8 57 44 30
0.626
5
8
0.999a
10
24
0.251a
5 (7)
3 (3)
0.080a 0.743a 0.736 0.679a 0.580 0.621 0.612
0.209
AIS, acute ischaemic stroke; TIA, transient ischaemic attack; ICA, internal carotid artery; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale. aFisher’s exact test.
24 h following CEA. LAA was identified as the most common underlying stroke etiology (n = 7; 88% of all strokes). The diagnosis was confirmed in all cases by
Stroke Disabling stroke (mRS score of 0–2) Non-disabling stroke (mRS score of 3–6) Myocardial infarction Death Cranial nerve palsy Neck hematoma Non-fatal stroke or death Non-fatal stroke or non-fatal myocardial infarction or death Disabling stroke or myocardial infarction or death
N (%)
30-day cumulative rate,a % (95% CI)
8 (4.8) 3 (1.8)
4.8 (1.5–8.1) 1.9 (0–4.1)
5 (3.0)
3.0 (0.5–5.5)
1 1 11 6 9 9
(0.6) (0.6) (6.7) (3.6) (5.5) (5.5)
4 (2.4)
0.6 0.6 Not Not 5.5 5.5
(0–1.8) (0–1.8) applicable applicable (2.0–9.0) (2.0–9.0)
2.4 (0–4.8)
mRS, modified Rankin Scale. aCalculated using the Kaplan–Meier product limit method.
neuroimaging studies showing new or first-ever ischaemic lesions occurring in the territory of the operated ICA. There was one case of hyperperfusion hemorrhage (12%). Two cases of acute common carotid artery and ICA thrombosis (25%) occurring during the first 24 h following carotid surgery that were treated with emergent carotid artery thrombectomy were documented (Fig. 1). The 30-day event rate of disabling stroke was 3.0% (95% CI 0.5%–5.5%). One case of death (0.6%, 95% CI 0%–1.8%) due to an extensive acute MI complicated by pulmonary infections was documented. The combined outcome event rate of non-fatal stroke, non-fatal MI or death was 5.5% (2.0%–9.0%). The combined outcome event rate of non-fatal disabling stroke, non-fatal MI or death was 2.4% (95% CI 0%–4.8%). There was no difference across (P > 0.2) the five participating centers in the 30-day rates of stroke and in the 30-day rates of non-fatal stroke, non-fatal MI or death. The rates of cranial nerve palsy and neck hematoma were 6.7% and 3.6% respectively. The univariate associations of baseline characteristics with the outcome events of stroke and stroke or death are presented in Table 4. Crescendo TIA, contralateral ICA occlusion and urgent CEA were not associated (P > 0.2) with a higher rate of peri-procedural events. None of the baseline characteristics was associated with a higher 30-day stroke rate (P > 0.2). Gender (P = 0.137) and diabetes mellitus (P = 0.162) tended to be associated with the outcome event of stroke or death and were included as candidate variables in the multivariate Cox regression models. Neither female gender (HR 2.27; 95% CI 0.57–9.01; © 2014 The Author(s) European Journal of Neurology © 2014 EAN
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Figure 1 Peri-procedural stroke following carotid endarterectomy in a 61-year-old man with right symptomatic carotid artery stenosis >70% (index event: transient ischaemic attack). Baseline magnetic resonance imaging with diffusion weighted imaging was negative for acute ischaemic stroke. Eight hours following early carotid endarterectomy (performed at the ninth day of ictus) the patient developed left hemiparesis and mild dysarthria (NIHSS score 6). Emergent carotid duplex disclosed the presence of thrombus in the right common carotid artery (a, b: longitudinal and transverse B-mode images) and right internal carotid artery. The patient underwent emergent carotid thrombectomy that resulted in successful removal of a long thrombus from the right common and internal carotid arteries (c). Follow-up brain magnetic resonance imaging at 7 days showed a small right putaminal infarction (d, axial FLAIR sequence). The patient had an mRS score of 1 at 3 months.
Table 4 Univariate associations of baseline characteristics with 30-day stroke rate and 30-day combined stroke and mortality rate 30-day stroke
30-day stroke and mortality
Factor
Yes (n = 8)
No (n = 157)
P
Yes (n = 9)
No (n = 156)
P
Age, years (mean SD) Male gender, % AIS as index event, % Crescendo TIA, % Median admission NIHSS score, points (IQR) Median elapsed time between symptom onset and CEA, days (IQR, range) Urgent CEA performed within 2 days from symptom onset, % Hypertension, % Diabetes mellitus, % Hypercholesterolemia, % Atrial fibrillation, % Coronary artery disease, % Current smoking, % Confirmation of ICA stenosis by angiography, %
70 11 50.0 62.5 12.5 3 (5) 7 (9)
68 10 70.1 70.1 5.1 3 (3) 7 (6)
0.752 0.254 0.699 0.368 0.798 0.910
71 11 44.4 66.7 11.1 4 (4) 9 (10)
68 10 70.5 69.9 5.1 3 (3) 7 (6)
0.512 0.137 0.999 0.404 0.888 0.609
0.250 0.601 0.443 0.304 0.999 0.999 0.732 0.437
25.0 100 55.6 66.7 0 33.3 44.4 88.9
25.0 100 50.0 75.0 0 25.0 37.5 87.5
11.2 85.4 32.5 54.8 8.9 30.6 45.2 68.2
11.2 85.3 32.1 55.1 9.0 30.1 44.9 67.9
0.299 0.363 0.162 0.732 0.999 0.999 0.999 0.277
AIS, acute ischaemic stroke; TIA, transient ischaemic attack; NIHSS, National Institutes of Health Stroke Scale; IQR, interquartile range; CEA, carotid endarterectomy; ICA, internal carotid artery.
P = 0.247) nor diabetes mellitus (HR 2.04; 95% CI 0.51–8.16; P = 0.313) were independently associated with a higher 30-day rate of stroke or death on multivariate Cox regression analyses. Consequently no independent predictor of higher risk of peri-procedural events could be identified in our cohort. © 2014 The Author(s) European Journal of Neurology © 2014 EAN
The 30-day event of stroke in patients who underwent urgent CEA (n = 20) was 10.0% (n = 2). There was no difference between the rate of peri-procedural stroke between patients who underwent urgent (n = 20) and delayed (>14 days; n = 18) carotid surgery during the study period (10.0% vs. 5.6%;
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P = 0.999 by Fisher’s exact test). Similarly, the 30-day event of stroke in patients who underwent urgent (0– 2 days of symptom onset) CEA (10.0%) was similar to the 30-day event of stroke in patients who underwent early (3–14 days of symptom onset) CEA (4.1%; P = 0.260). After conducting a post hoc power analysis it was estimated that for the given effect size (4.1% vs. 10% rates of peri-procedural stroke in urgent and early CEA) and for the given prevalence ratio of early/urgent CEA (7.25/1) a sample of 1320 CEA performed within 14 days (160 cases of urgent CEA and 1160 cases of early CEA) would be required to detect a higher rate of peri-procedural stroke in urgent CEA in comparison with early CEA with a power of 80% and a two-tailed a of 0.05.
Discussion Our study showed that the peri-operative risk of CEA in sCAS patients with a recent non-disabling AIS or TIA was not increased if carotid surgery was performed within 14 days of a qualifying neurological event. The rate of peri-procedural complications was not elevated even in certain sCAS subgroups of potential high surgical risk [14,15,21] including patients who were operated in the acute phase (≤48 h) of cerebral ischaemia and individuals with crescendo TIAs or contralateral ICA occlusion. The optimal timing of CEA after TIA or AIS remains a timely and controversial issue. Despite compelling evidence from randomized controlled trials documenting that CEA is safe and most effective when performed within 2 weeks from the index event [7], most vascular surgeons are reluctant to undertake carotid surgery immediately after the symptomatic event. Consequently, the majority of sCAS patients are operated with substantial time delays in everyday clinical practice settings [8,9]. The main theoretical arguments supporting the delay of CEA include (i) conversion of pre-existing infarct into intracerebral hemorrhage due to reperfusion/hyperperfusion injury [11,13,28], (ii) increased vulnerability of recently infarcted brain tissue to peri-procedural cerebral ischaemia induced by carotid clamping or profound blood pressure decreases [11,13,28] and (iii) greater vulnerability of carotid plaques in the acute phase of cerebral ischaemia resulting in higher peri-procedural risk of distal embolization during plaque removal [14]. Moreover, individual studies reporting institutional [12,13,29] or multicenter [21,30] experience have reported an increased risk of peri-procedural stroke or death when CEA was performed within the first 2– 4 weeks of the index event. Finally, there are growing concerns regarding the safety of CEA in crescendo
TIAs [15,21] and during the first 2 days [14] of acute cerebral ischaemia. Our findings contradict the previous reports [13,29] arguing in favor of delaying carotid surgery beyond the 2-week time window recommended by international guidelines. Our observations are in line with the experience of Italian [31,32], German [33], Danish [34] and North American [35,36] investigators underscoring the safety of early CEA during the first weeks after the qualifying neurological event. In agreement with the recent literature [14,32,34,36], the feared increase in the risk of hyperperfusion hemorrhage following early CEA was not found and the risk was extremely low (0.6%) in our study population. Furthermore, crescendo TIAs and urgent (≤48 h) CEA were not associated with a higher risk of peri-procedural events. However, these findings should be interpreted in the light of the limited sample size in the two sCAS subgroups (nine cases of crescendo TIAs and 20 cases of urgent CEA). Our study has limitations including the observational design and the absence of a uniform intra-operative protocol. Moreover, the absence of central adjudication of outcome events should be acknowledged. In addition, no formal sample size estimation was performed prior to study initiation. Moreover, since ICSS definitions were used for outcome events, some cases of asymptomatic MIs may have been missed. In addition, plaque characteristics (echogenicity, stability or ulceration) were not accounted for in our analyses and these parameters may have contributed to peri-operative risks associated with early CEA. Also, the sample size of the group of urgent CEA was small (n = 20), albeit comparable to the limited studies available in the relevant literature [12,13]. Last but not least, patients with ≥70% stenosis in the symptomatic carotid artery were included since both North American and European guidelines advocate CEA in this subgroup using a grade I/level A recommendation [2–5]. An equally important group that was not evaluated in the present study and deserves further investigation includes patients with symptomatic 50%–69% carotid artery stenosis, since the reluctance of vascular surgeons to operate early in this specific subgroup may be even greater. On the other hand, certain strengths of this report should be recognized. First and most important, our observations in a consecutive series of patients reflect ‘real-life’ clinical experience in several countries. Secondly, serial evaluations (before and after carotid surgery) of sCAS patients were performed by independent stroke neurologists, who were responsible for the diagnosis and classification of both symptomatic status and peri-procedural complications. Thirdly, the © 2014 The Author(s) European Journal of Neurology © 2014 EAN
Early CEA in symptomatic carotid stenosis
possibility of selection bias was minimized since all operations were performed by a few experienced surgeons with high yearly volumes, whilst all referrals were made by the same attending vascular neurologists at each participating center. In conclusion, our findings indicate that the risk of early CEA in consecutive unselected patients with non-disabling stroke or TIA due to sCAS is acceptable when the procedure is performed within 2 weeks as well as within 2 days from symptom onset. Our prospective, multicenter experience provides reassurance that an expedited CEA can be safely performed in the acute (≤2 days) or subacute (3–14 days) phase of acute cerebral ischaemia in patients with sCAS and support current international recommendations advocating that expectant management and delayed
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surgery are not justified in patients with a recent nondisabling symptomatic event and ipsilateral significant carotid stenosis.
Acknowledgements Dr Georgios Tsivgoulis, Dr Robert Mikulik and Dr Michal Hars any have been supported by the European Regional Development Fund – Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123).
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
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