Protocols. Introduction

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1 SPREAD-STACI study: A protocol for a randomized multicenter clinical trial comparing urgent with delayed endarterectomy in symptomatic carotid artery stenosis Gaetano Lanza 1 *, Stefano Ricci 2, Francesco Speziale 3, Danilo Toni 4, Enrico Sbarigia 3, Carlo Setacci 5, Carlo Pratesi 6, Francesco Somalvico 7, Augusto Zaninelli 8, and Gian Franco Gensini 9 Rationale In patients with >50% carotid artery stenosis (as measured by North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria) suffering a transient ischemic attack or a minor ipsilateral stroke, carotid endarterectomy exerts maximum benefits, when performed within the first 15 days from the initial ischemic symptom. It is also known that the probability of a major stroke spikes within the first few days after a transient ischemic attack/minor stroke and then flattens out in the following days and weeks. It could be hypothesized that urgent carotid endarterectomy has greater benefit than delayed procedure. Aims Demonstrate that urgent carotid endarterectomy is more effective than delayed interventions. Design Centers employing neurolgist/stroke physicians and vascular surgeons will enroll TIA or minor stroke patients with >50 % carotid artery stenosis (Nascet criteria), randomized in two groups: 1) urgent carotid endarterectomy (within 48 hours) and 2) delayed carotid endarterectomy ( operated between 48 hours and 15 days after onset of symptoms) Risk factors will be evaluated at enrollment. Correspondence: Gaetano Lanza*, Vascular Surgery Department, IRCCS MultiMedica Hospital, Viale Piemonte, 70, Castellanza, Italy. gaetano.lanza@multimedica.it 1 Vascular Surgery Department, IRCCS MultiMedica Hospital, Castellanza, Italy 2 Department of Neurology, ASL 1 Citta di Castello and Branca, Italy 3 Vascular Surgery Department, Policlinico Umberto I, La Sapienza University, Rome, Italy 4 Emergency Department Stroke Unit, Policlinico Umberto I, La Sapienza University Rome, Italy 5 Vascular Endovascular Surgery Unit, Department of Surgery, University of Siena, Italy 6 Vascular Surgery Unit, University of Florence, Italy 7 Biostatistics Service, IRCCS Multimedica Hospital, Sesto San Giovanni, Italy 8 School of Medicine, University of Florence, Italy 9 Department of Critical Care, University of Florence, Italy Conflicts of Interest: None declared. DOI: /j x TIA will be classified by ABCD2 scoring system,and minor stroke by National Institutes of Health Stroke Scale (NIHSS) scores. The study will last 90 days per patient,starting from their initial symptom,and the follow-up will be performed by an indipendent neurologist. A total of 456 patients (228 / group) is needed to observe an absolute difference of 10% between groups. Outcomes Primary end-point is reduction in all types of stroke, AMI or death in urgent endarterectomy groupo compared to delayed ones. Secondary end-points are: Reduction of ipsilateral ischemic stroke in group 1 with respect to Group 2 Identification of predictive risk factors and Confirmation of no different rate for hemorragic/ ischemiccomplications between groups. Key words: randomized clinical trial, stroke prevention, symptomatic carotid stenosis, urgent vs. delayed carotid endarterectomy Introduction The two main surgical trials on carotid artery stenosis conducted in the 1980s North American Symptomatic Carotid Endarterectomy Trial (NASCET) (1) and European Carotid Surgery Trial (ECST) (2) demonstrated the net benefit afforded by carotid endarterectomy (CEA), with respect to medical therapy alone, in patients with >50% carotid stenosis (as measured by the NASCET criteria) that had been symptomatic for minor stroke, transient ischemic attacks (TIA), or amaurosis fugax in the previous six-months. The benefit was discernible as a reduction in the five-year risk of recurring stroke and death. Recent revision of NASCET and ECST datasets demonstrated that the benefit of CEA is superior (Number Needed to Treat or NNT, 5) in patients operated on within the first twoweeks from the initial ischemic event than in patients having undergone surgery after >12 weeks from the initial ischemic event (NNT, 125): in other words, CEA is more effective the earlier it is performed (3). International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012,

2 The risk of experiencing a major stroke becomes high soon after experiencing a TIA or a minor stroke: the rate of this risk is 10% in the first week and 15% in the first 30 days not dissimilar to the risk of infarction after unstable angina and remains between 15% and 20% after 60 days (4). Further data have shown that, respectively, 17% and 43% of TIAs occur on the same day and only one-week before a major stroke, indicating that TIAs should be classified as a medical emergency (5). Validated models are available today that grade the risk of a major stroke occurring after a TIA. These models can aid in the detection of TIA patients that are under the greatest risk and, thus, that would benefit more from urgent medical and/or surgical intervention. The ABCD2 scoring system is an example of such a model: in this model, age >60 years = 1 point, arterial pressure >140/90 = 2 points, focal hypomotility = 2 points, dysphasia = 1 point, duration of the symptom >60 mins = 2 points and between 10 and 59 mins = 1 point, and diabetes = 1 point; the patient is considered to be low risk when the score totals 0 3 points, at moderate risk when the score is 3 4 points, and high risk when the score totals 6 7 points (6). It is also known that TIA/minor stroke patients that have significant atherosclerosis of the carotid arteries are those at the greatest risk of recurring stroke. In a meta-analysis of four studies conducted on a total of 1709 TIA/minor stroke patients, the subgroup of patients presenting with concomitant carotid atherosclerosis (which comprised 17% of all the patients) had recurring stroke in 37% of cases (7). In a population study on patients with symptomatic carotid stenosis, 50 99% of which were candidate for CEA, respectively 21% and 32% had had a recurring stroke within two-weeks and 12 weeks from the initial ischemic event; in half of these patients, stroke was either disabling or fatal (8). In another population study on symptomatic carotid stenosis, more than 50% of patients had a high risk of stroke after being subjected to delayed CEA (9). More recently, CEA was conducted successfully on acute stroke patients presenting with critical, ipsilateral stenosis of the carotid artery, as long as they did not have any serious neurological deficits; the intervention limited, or even prevented, greater ischemic cerebral damage in these patients (10). It could be presumed, therefore, that in patients presenting with >50% carotid artery stenosis (NASCET criteria), the benefit afforded by CEA in terms of a reduced risk of mortality or recurring stroke is greater when the procedure is performed within the first 48 h from the onset of symptoms and on patients with the highest risk scores. Moreover, in neurologically stable TIA/minor stroke patients, the risk of post-cea complications was shown to be as good in patients operated on within the first week from the onset of ischemic symptoms as those that were operated on at a later date (11). However, to date, there is insufficient evidence on the greater benefit afforded by conducting CEA very early on, i.e., within 48 h from initial ischemic symptom. Proof to this end would indicate CEA as an urgent procedure in patients with symptomatic carotid artery stenosis. We therefore have formulated a study having the following primary and secondary objectives: Primary objective: demonstrate that in patients presenting with symptomatic carotid artery stenosis (ranging between 51% and 99%, according to NASCET criteria), CEA is more effective (in terms of a significantly reduced risk of any type of stroke, myocardial infarction, or death within a 90-day observation period from the initial ischemic symptom) when performed as an urgent procedure (i.e. within 48 h from the initial ischemic symptom) than when performed after the first 48 h but before 15 days from the initial ischemic symptom (delayed CEA). Secondary objectives: demonstrate in patients with symptomatic carotid artery stenosis that urgent CEA is more effective in terms of significantly reducing the risk of ipsilateral stroke within a 90-day observation period from the initial ischemic symptom than delayed CEA identification of any subgroup of symptomatic carotid stenosis patients that might benefit more from urgent CEA than from the delayed procedure, and verification that urgent CEA is as safe as delayed CEA as an indication for patients presenting with symptomatic carotid stenosis, in terms of the risk of postoperative complications such as cerebral hemorrhaging or ischemia, cardiac events, or death. Methods Design G. Lanza et al. The present proposal is a multicentre, comparative, randomized study, with a blind follow-up at 90 days conducted by an independent neurologist/stroke physician. The proposed protocol conforms to the Good Clinical Practice (GCP) and has been approved by the Ethics Committee of IRCCS Multi- Medica Hospital. Only medical centers that have a neurology department or an internal medicine department with referent neurologists/ stroke physicians and a vascular surgery unit with referent vascular surgeons can participate. All referents must report their center s and their own experience and casuistry. In particular, vascular surgeons must present documentation on how many CEAs/year their centers have performed in the previous three-years, including their rates of perioperative complications (stroke, myocardial infarction, death). Neurologists/stroke physicians will conduct neurological examination of patients admitted within only a few hours from their first symptom of cerebral TIA, amaurosis fugax, or minor stroke, and that present with stenosis of the ipsilateral carotid artery ranging between 51% and 99%, as assessed with NASCET criteria on echo-color-doppler (ECD), computed tomographic angiography (CTA), or magnetic resonance angiography (MRA) scans of the supra-aortic trunk. The date 82 International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012, 81 85

3 G. Lanza et al. of admission is indicated as T 0. Consenting, informed patients will be randomly ascribed either to a group receiving CEA within 48 h (urgent CEA group) or between 48 h and 15 days (delayed CEA group) from their initial ischemic symptom. Vascular surgeons will then carry out the operation on the patients at the time instructed (T 1). The neurologists/stroke physicians will annotate the surgical variables and conduct neuroimaging assessment and clinical examination for each patient on discharge (T 2). Independent neurologists/stroke physicians will conduct a 90-day examination (T 3) and report the outcome. The variables to be annotated and registered in the CRF are given in Table 1: neurological variables of the initial ischemic symptom are to be recorded at T 0, i.e., either the ABCD2 score for TIAs, the presence/absence of amaurosis fugax, or the NIHSS grade for minor stroke; any new event having occurred during the perioperative period is to be recorded at T 2;any new event having occurred during the follow-up period is to be recorded at T 3. For each patient, the degree of carotid artery stenosis is to be assessed for both sides of the neck, in accordance with the criteria set out by NASCET, by ECD (see Table 2), and/or CTA and/or MRA. The echolucency (> or <25%) of the carotid plaques is to be recorded at T 0 (and at T 3, if present) for both sides of the neck. Table 1 Variables to be noted at the various time points of the study Variable 90-day Enrolment CEA Discharge follow-up (T 0) (T 1) (T 2) (T 3) Randomization X Neurologic-related X X X Degree of stenosis X X X Parenchymal lesions X X X Operation-related X Cardiac-related X X Death X X Risk factors X X CEA, carotid endarterectomy. Protocols The maximum diameter of damaged cerebral parenchyma is to be measured by either computed tomography (perfusion) or magnetic resonance (diffusion) at T 0,T 2, and T 3, the lesions identified as being either ischemic or hemorrhagic, and the process distinguished as being either terminated or in evolution. The surgery variables are: time (in days) from the initial ischemic symptom to CEA, in patients of the delayed CEA group; the use of shunts and/or patches; type of anesthesia (local or general); and any variations in cerebral monitoring (electroencephalogram or EEG, SomatoSensory Evoked Potentials or SSEP, TransCranial or TC Doppler). The cardiological variables are any clinical and/or imaging event of an ischemic nature observed in the myocardium, or any cardiac event of any other nature, appearing after T 0. In the case of death, date and the apparent or known cause are to be noted at T 2 or T 3. The risk factors and related variables are: coronary disease history of at least one episode of myocardial ischemia or previous myocardial infarction, documented by instrumental procedures atrial fibrillation electrocardiogram traces showing specific signs peripheral steno-occlusive arteriopathy patient presenting with the specific clinical symptoms and signs chronic renal insufficiency creatininemia >1 5 mg/dl or creatinine clearance <90 ml/min smoking patient declaring that he/she smokes or used to smoke diabetes mellitus patient taking medication for diabetes (oral hypoglycemics or insulin) and/or presenting with fasting basal glycemia >126 mg/dl at least twice arterial hypertension patient on at least one antihypertensive drug and/or presenting with, or has had, blood pressure >140/90 mmhg hypercholesterolemia patient on hypocholesterolemics and/or statins and presenting with cholesterolemia >240 mg/ dl, and patient taking oral antiplatelet or anticoagulation agents and/or statins. Table 2 Equivalence between the degree of carotid stenosis, measured by angiography and using NASCET criteria, and echo-doppler velocimetry Carotid artery stenosis (%) PSV ICA (m/s) EDV ICA (m/s) PSV ICA/PSV CCA 0 29 <1 1 <0 4 < <0 4 < > <0 4 < > >2 1 > > >2 1 >1 4 > Absent Absent Absent PSV, peak systolic velocity; ICA, internal carotid artery; EDV, end-diastolic velocity; CCA, common carotid artery; NASCET, North American Symptomatic Carotid Endarterectomy Trial. International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012,

4 G. Lanza et al. Patient population inclusion and exclusion criteria Inclusion criteria stenosis ranging between 51% and 99% (as measured with NASCET criteria) of the carotid artery bifurcation and/or origin of the internal carotid artery, diagnosed by ECD and/or CTA and/or MRA TIA or minor stroke (NIHSS 5) occurring ipsilaterally to the carotid stenosis and within only the previous few hours from admission Unimpaired consciousness and a neurologically stabile status no CT or MR evidence of areas of cerebral ischemia; or the presence of areas of cerebral ischemia <25 mm in diameter age years American Society of Anesthesiologists (ASA) risk score <4 informed consent possibility of performing CEA within 48 h from onset of the initial ischemic symptom (TIA, amaurosis fugax, or minor stroke), and possibility to attend a follow-up at least 90 days from the initial symptom. Exclusion criteria stenosis <50% (as measured with NASCET criteria) at the carotid artery bifurcation and/or at the origin of the internal carotid artery, diagnosed by ECD and/or CTA and/or MRA thrombosis or carotid dissection NIHSS >5 cerebral hemorrhage impaired consciousness or a neurologically unstable status cancer, any disease with an adverse prognosis, major cardiopathy, or any other severe neurological pathology CT or MR evidence of areas of cerebral ischemia >25 mm in diameter CT or MR evidence of cerebral lesions of uncertain origin recurring TIA or stroke in evolution age <45 years or >90 years ASA risk score = 4 no informed consent inability to perform CEA within 48 h from the onset of the initial ischemic symptom inability to attend a follow up at 90 days from the initial ischemic symptom, and previous CEA or stenting of the carotid artery under investigation Randomization Randomization of enrolled patients will be carried out via the online computerized service available at staci.it, run by the Vascular Surgery Department, University La Sapienza, Rome, Italy. Randomization will be stratified by center and balanced between the arms: (1) CEA performed within 48 h from the onset of ischemic symptoms (urgent CEA); and (2) CEA performed after 48 h, but before 15 days, from the onset of ischemic symptoms (delayed CEA). Treatment or intervention Routine procedures for the execution of CEA will be followed by participating centers. All patients will receive best medical therapy (oral antiplatelet drugs and medication aimed at risk factors) throughout the observation period. Primary outcomes The primary outcome is a significant drop in the rate of any type of stroke, myocardial infarction, and death in the urgent CEA group with respect to the delayed CEA group. Secondary outcomes A significant drop in the rate of ipsilateral stroke in the urgent CEA group with respect to the delayed CEA group. the possible identification of predictive risk factors of cardio-cerebrovascular events in the 90-day observation period. the confirmation that urgent CEA is as safe as delayed CEA as an indication for patients presenting with symptomatic >50% carotid stenosis, in terms of the risk of postoperative complications such as cerebral hemorrhaging or ischemia, cardiac events, and death. Data monitoring body Data monitoring will be carried out externally from each participating center by the Data Monitoring Committee: R. Sterzi (neurologist), A. Bignamini (statistician), and V. Toso (neurologist). Sample size Calculation of the exact number of cases needed to verify the hypothesis carried by this planned study is hindered by the lack of data on the difference in efficacy of urgent and delayed CEA. However, from the experience gained on CEA by a number of vascular surgery centers in Italy, it emerges that ~15% of patients presenting with >50% carotid stenosis and operated on within 2-weeks experience events. Therefore, using the two groups, continuity corrected chi-square test of equal proportions (nquery Advisor), and assuming that 5% and 15% of patients will experience an event respectively within 48 h and after 48 h from the onset of the initial ischemic symptom (power (1-beta), 90%; two-tailed error risk (alpha), 5%), we calculated that a sample size of 228 patients/ group (inclusive of an extra 10% to accommodate possible 84 International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012, 81 85

5 G. Lanza et al. Protocols losses due to incompletely collected data), for a total of 456 patients, will be required for this study in order to obtain an absolute difference of 10% (15%-5%). Statistical analyses The proposed study design is coherent with those used to analyze the difference between two groups, and was considered the best at the time of planning. The analyses will be carried out for: intention to treat, including all of the randomized patients per protocol, to evaluate all randomized patients that pass the inclusion/exclusion criteria and that complete the follow-up period set out by the study Statistical analyses will be carried out with spss v.18 software (spss Inc., Chicago, IL, USA). A two-tailed significance will be set at 5%(P < 0 05) in order to: reject the null hypothesis (H 0 = no difference between the urgent CEA group and the delayed CEA group), and verify any differences found between the urgent CEA group and the delayed CEA group. The demographic, clinical, and anamnesis data will be presented with the usual statistics: mean, standard deviation, standard error of measurement, median, 95% confidence interval, and contingency tables stratified per group for the various studied characteristics. Appropriate parametric and nonparametric techniques will be used to verify the homogeneity of the data from each group: discrete variables will be analyzed with chi-square and Fisher s exact tests; continuous variables will be analyzed with thet-test for independent data and the Mann Whitney test, after having verified normal distribution with the Kolmogorov Smirnov test; and homogeneity among participating centers will be analyzed with one-way analysis of variance (ANOVA) or the Kruskal Wallis test, in order to exclude the hypothesis that the data cannot be collated. Primary outcomes Chi-square or Fisher s exact tests will be used to find any significant difference between the urgent CEA group and the delayed CEA group. Relative risk will be calculated to quantify the rates in the two groups with 95% CI (Confidence Interval). Secondary outcomes Quantitative variables will be presented with descriptive statistics, whereas variations in time and between the two groups will be analyzed with two-way ANOVA (between within ANOVA) or with the Wilcoxon and Mann Whitney tests. Discrete variables (reduction in ipsilateral stroke, major cardiovascular events, risk factors) will be reported in contingency tables and analyzed with McNemar, chi-square, and Fisher s exact tests. Finally, a model of logistical regression will be used to evidence any relation between the covariate, dependent variable (the event) and possible predictive variables or those that might influence the appearance of the event (variables in the anamneses, echography indices, NIHSS grades, or the risk factors defined in this protocol), quantifying the risk by the odds ratio. Study organization and funding The Stroke Prevention and Educational Awareness Diffusion group for Italian guidelines ( and the Surgical Treatment of Acute Cerebral Ischemia Italian group ( aim to assess the utility of employing CEA as an urgent procedure (i.e. within 48 h from the initial ischemic symptom) for the treatment of symptomatic carotid stenosis. Because the proposed study does not entail the use of therapies or methodologies that are not routine, participating centers should not require supplementary funding or extra insurance cover to carry it out. All costs incurred for data analysis will be handled by IRCCS MultiMedica Hospital. References 1 North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. NEnglJMed1991; 325: European Carotid Surgery Trialists Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe or mild carotid stenosis. Lancet 1991; 337: Rothwell PM, Eliasziw M, Gutnikov SA et al., for the Carotid Endarterectomy Trialists Collaboration. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361: Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk after TIA or minor stroke. BMJ 2004; 328: Rothwell PM. Transient ischaemic attacks: time to wake up. Heart 2007; 93: Johnston SC, Rothwell PM. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369: Lovett JK, Coull A, Rothwell PM, on behalf of the Oxford Vascular Study. Early risk of recurrent stroke by aetiological subtype: implications for stroke prevention. Neurology 2004; 62: Fairhead JF, Mehta Z, Rothwell PM. Population-based study of delays in carotid imaging and surgery and the risk of recurrent stroke. Neurology 2005; 65: Blaser T, Hofmann K, Buerger T et al. Risk of stroke, transient ischaemic attack, and vessel occlusion before endarterectomy in patients with symptomatic severe carotid stenosis. Stroke 2002; 33: Sbarigia E, Toni D, Speziale F, Acconcia MC, Fiorani P. Early carotid endarterectomy after ischemic stroke: the results of a prospective multicenter Italian study. Eur J Vasc Endovasc Surg 2006; 32: Rerkasem K, Rothwell PM. Systematic review of the operative risks of carotid endarterectomy for recently symptomatic stenosis in relation to the timing of surgery. Stroke 2009; 40: International Journal of Stroke 2011 World Stroke Organization Vol 7, January 2012,