Clinical Trial Service Unit, University of Oxford, Oxford. ACST-2 an update

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1 English version of ACST-2 ein Update Eine große, einfache randomisierte Studie zum Vergleich der Karotisendarteriektomie mit dem Karotisstenting zur Schlaganfallprävention bei asymptomatischen Patienten Gefässchirurgie : DOI 1.17/s Springer-Verlag Berlin Heidelberg 213 R. Bulbulia 1 A. Halliday 2 1 Clinical Trial Service Unit, University of Oxford, Oxford 2 Nuffield Department of Surgical Sciences, John Radcliffe Hospital University of Oxford, Headington, Oxford ACST-2 an update A large, simple randomised trial to compare carotid endarterectomy versus carotid artery stenting to prevent stroke in asymptomatic patients Ischaemic stroke is a leading cause of premature death and major morbidity in the developed world. In the UK, over 1, strokes occur annually, and over 3, people are living with moderate or severe disability due to strokes, costing the National Health Service (NHS) around 3 billion per annum. Whilst the majority of ischaemic strokes are due to occlusive cerebrovascular disease, around 15 2% of strokes are associated with significant carotid artery stenoses, and over 1 million people in Europe have severe stenosis in one or both carotid arteries [1, 2]. The management of patients with carotid artery stenosis has been the subject of extensive research over the last 3 years. In the 198s, two large trials [NASCET (North American Symptomatic Caro tid Endarterectomy Trial) and ECST (European Carotid Surgery Trial)] were conducted which showed conclusively that carotid endarterectomy in patients with a symptomatic stenosis significantly reduced the risk of subsequent stroke [3, 4]. During the 199s, another pair of carotid trials [ACST (Asymptomatic Caro tid Surgery Trial) and ACAS (Asymptomatic Carotid Atherosclerosis Study)] demonstrated a substantial reduction in stroke risk associated with carotid endarterectomy in patients with an asymptomatic stenosis [5-7]. During the 2s, several trials (largely in symptomatic populations) have compared carotid artery stenting with carotid endarterectomy [8-11]. Whilst the results of these head-to-head studies have been less clear than earlier trials, there is evidence that, in the short term, surgery is safer than stenting in most symptomatic patients, but emerging evidence suggests that the long-term durability of both procedures may be similar [12]. Currently, in the 21s, there are two key areas of uncertainty in the management of patients with carotid artery disease: F With improvements in contemporary medical therapy (CMT) is any intervention justified in patients with asymptomatic stenosis? F When intervention is indicated, is stenting better than surgery? Both of these questions have generated lively debate amongst vascular surgeons, interventionalists and stroke specialists, but, unfortunately, views have become polarised. At times, editorial comment and hypothesis-generating studies (which are frequently small, non-randomised or both) have been given unwarranted prominence over large high-quality randomised trials. It is therefore very reassuring that, during the 21s, several large randomised trials are now funded (with three actively recruiting), aimed at directly addressing both these areas of substantial uncertainty. Treatment of asymptomatic patients Randomised evidence supports carotid intervention in selected patients The first Asymptomatic Carotid Surgery Trial (ACST-1) and a parallel trial in North America investigated the role of carotid endarterectomy in around 5 patients with significant carotid artery stenosis, but with no stroke or stroke-like symptoms during the previous 6 months. In ACST-1 ( ) over 3 patients (134 of whom were from German-speaking countries: Germany (n=98), Austria (n=3) and Switzerland (n=6)] were randomised between medical treatment only (i.e. deferral of surgery) or medical treatment and immediate surgery. Whilst CEA involved a 3% periprocedural risk of stroke or death, allocation to immediate CEA resulted in a substantial reduction in the risk of stroke during a 1-year followup period (. Fig. 1), with 62 participants allocated immediate CEA suffering a dis- Funding. The UK National Institute of Health Research (NIHR) Health Technology Assessment Programme and the BUPA Foundation, a UK medical research charity. In addition the University of Oxford s Clinical Trial Service Unit (CTSU) has provided some assistance free of charge. Professor Halliday s research is funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme. Gefässchirurgie

2 Any type of stroke or perioperative death Any type of non-perioperative stroke %risk (±SE) 2 Gain at 5 years: 4.1% (1.1), p =.1 1 years: 4.6% (1.7), p = % 2 Gain at 5 years: 5.9% (1.), p <.1 1 years: 6.1% (1.7), p = % 1 1.9% 13.4% 1 1.% 1.8% 6.9% 4.1% a 5 1 Years 5 1 Years Perioperative events/ceas (%) + other events Events/person years Years 5 Years 5 1 Years 5 Years /159 (2.9%) + 56 /23 (.%) /654 (.9% pa) 43/342 (1.4% pa) 44/36 (3.9%) /87 (2.3%) + 48 b 14/6553 (2.1% pa) 48/33 (1.6% pa) Fig. 1 9 The 1-year risk of a any stroke or perioperative death and b any non-perioperative stroke. (Adapted from [6]) On statin before stroke: stroke or perioperative death 2 Gain at %risk (±SE) 5 years: 2.1% (1.1), p =.5 1 years: 5.% (2.), p = % 2 On statin before stroke: non-perioperative stroke Gain at 5 years: 3.4% (1.), p =.5 1 years: 5.8% (1.9), p = % 1 7.% 9.6% 1 6.1% 7.6% 4.9% a 2.8% 5 1 Years 5 1 Years Perioperative events/ceas (%) + other events Events/person years Years 5 Years 5 1 Years 5 Years /993 (2.2%) + 25 /15 (.%) /4478 (.6% pa) 2/2145 (.9% pa) 9/259 (3.5%) /69 (2.9%) + 32 b 56/4483 (1.1%pa) 32/284 (1.5% pa) Fig. 2 9 The 1-year risks amongst those on statins before stroke. (Adapted from [6]) AHA Carotid Disease Management Guidelines (211) It is reasonable to perform CEA in asymptomatic patients who have > 7% stenosis (Evidence Level: A) Prophylactic CAS might be considered in highly selected patients with asymptomatic carotid stenosis (Evidence Level: B) Society for Vascular Surgery Carotid Guidelines (211) Asymptomatic > 6% stenosis should be considered for CEA (Evidence Level: A) CAS should not be performed except as part of an on-going clinical trial (Evidence Level: B) NICE Carotid Intervention Guidelines (211) NICE encourages clinicians either to enter patients into the ACST-2 trial, or to submit data to the Endovascular Carotid Register Fig. 3 9 Carotid intervention guidelines. (Adapted from [13, 14]) abling or fatal stroke versus 14 amongst those allocated deferral of CEA, and a further 37 vs. 84 participants had a non-disabling stroke. Therefore, combining perioperative events and strokes, the net risks were 6.9% vs. 1.9% at 5 years (gain 4.1%; p<.1) and 13.4% vs. 17.9% at 1 years (gain 4.6%; p=.9). The beneficial effects of immediate CEA were similar in men and women up to 75 years of age, though not for older patients. During ACST-1, the medical management of patients was similar in both groups, and most were on long-term 2 Gefässchirurgie 7 213

3 Abstract Zusammenfassung antihypertensive and antiplatelet therapy. Whilst cholesterol-lowering therapy is now widely used, this was not the case in the early 199s, and the proportion of participants on statins rose from <1% in 1993 to >8% when final follow-up concluded in However, both for patients on statin therapy and those not, allocation to immediate CEA roughly halved the non-perioperative stroke rate (. Fig. 2). In summary, appropriate medical treatment with antiplatelet, antihypertensive and cholesterol-lowering medicines significantly reduces the risk of heart attacks and strokes in all patients at increased vascular risk. But, the results from ACST-1 provide reliable evidence that carotid endarterectomy can be used to reduce still further the risk that a carotid artery stenosis will cause a stroke in selected patients [5, 6]. Contemporary medical therapy (CMT) alone vs. CMT plus carotid intervention trials Currently, two large trials [SPACE-2 (Stent-Protected Angioplasty versus Carotid Endarterectomy) and CREST-2 (Carotid Revascularization Endarterectomy versus Stenting Trial)] are funded and aim to randomise large numbers of patients with asymptomatic carotid stenosis to either CMT or CMT and carotid intervention. These trials will probably report results in the early 22s, but, in the interim, substantial numbers of patients will undergo carotid interventions for asymptomatic disease. CEA vs. CAS? This is a highly relevant question now, and is likely to become even more important in the 22s. Around 1, carotid procedures are performed on asymptomatic patients in the United States each year, with a further 6, done in Europe, and the choice of intervention (i.e. stenting or surgery) varies across countries and seems to be influenced largely by the personal preference of the treating clinician. Accordingly, if an asymptomatic stenosis is detected by an interventional cardiologist during coronary angiography, it is highly like- Gefässchirurgie : DOI 1.17/s Springer-Verlag Berlin Heidelberg 213 R. Bulbulia A. Halliday ACST-2 an update. A large, simple randomised trial to compare carotid endarterectomy versus carotid artery stenting to prevent stroke in asymptomatic patients Abstract Introduction. ACST-2 is a large and simple stream-lined trial which aims to compare both the early hazards and long-term durability of carotid endarterectomy (CEA) versus carotid artery stenting (CAS) in asymptomatic patients with high-grade carotid artery stenosis. Methods. Patients are eligible for ACST-2 if they have a severe carotid artery stenosis and intervention is clearly indicated, with both CEA and CAS practicable, but where there is substantial uncertainty as to which intervention is best. Collaborating surgeons and stenters may use their usual techniques and any CE-marked devices are permitted. Results. ACST-2 aims to recruit several thousand patients by 219. To date, over 12 patients have been randomised by study collaborators working in 79 centres across 25 countries. Italy is the top recruiting country, followed by the UK and Sweden. Interim blinded analyses reveal a 1% rate of serious 3- day postprocedure complications (disabling stroke, myocardial infarction or death). Discussion. ACST-2 is the only trial designed to reliably compare the short-term hazards and long-term benefits of CEA versus CAS in asymptomatic patients, and it complements other carotid trials which compare intervention versus medical management (e.g. SPACE-2). If, as seems likely, these trials show benefit from carotid intervention in addition to contemporary medical management in selected patients, then whether to perform CEA or CAS will remain a highly relevant question, and one only ACST-2 can answer. Keywords Carotid artery stenosis Stroke Carotid stenting Carotid endarterectomy Randomised controlled trial ACST-2 ein Update. Eine große, einfache randomisierte Studie zum Vergleich der Karotisendarteriektomie mit dem Karotisstenting zur Schlaganfallprävention bei asymptomatischen Patienten Zusammenfassung Einleitung. Der Asymptomatic Carotid Surgery Trial 2 (ACST-2) ist eine groß und einfach angelegte Studie mit dem Ziel, sowohl die frühen Risiken als auch die langfristige Beständigkeit der Karotisendarteriektomie (CEA) und des Karotisstentings (CAS) an asymptomatischen Patienten mit hochgradiger Karotisstenose zu vergleichen. Methoden. Patienten kommen für den ACST-2 infrage, wenn sie eine schwerwiegende Karotisstenose aufweisen und eine Intervention klar indiziert ist, wobei sowohl die CEA als auch das CAS durchführbar ist, aber beträchtliche Unsicherheit hinsichtlich der besseren Intervention besteht. Teilnehmende Chirurgen und Stenting-Spezialisten können ihre gewohnten Verfahren anwenden. Der Einsatz jeglicher CE-gekennzeichneter Geräte ist erlaubt. Ergebnisse. In ACST-2 sollen bis 219 mehrere tausend Patienten eingeschlossen werden. Bislang haben die Studienmitarbeiter an 79 Zentren in 25 Ländern über 12 Patienten randomisiert. Italien ist das Land mit den meisten Rekrutierungen, gefolgt vom Vereinigten Königreich und Schweden. Verblindete Interimanalysen ergaben eine 1%ige Rate ernster Komplikationen in den ersten 3 Tagen nach Eingriff (schwerer Schlaganfall, Myokardinfarkt oder Tod). Diskussion. Der ACST-2 ist die einzige Studie, die für den verlässlichen Vergleich der kurzfristigen Risiken und langfristigen Vorteile der CEA gegenüber dem CAS bei a symptomatischen Patienten konzipiert wurde. Zudem ergänzt er andere Karotisstudien, welche den interventionellen Ansatz mit dem medikamentösen Management vergleichen, z. B. Stent-Protected Angioplasty versus Carotid Endarterectomy 2 (SPACE-2). Falls diese Studien bei ausgewählten Patienten einen Nutzen der Karotisintervention zusätzlich zur modernen medikamentösen Behandlung aufzeigen, was wahrscheinlich ist, wird die Frage, ob eine CEA oder ein CAS durchgeführt werden sollte, ihre hohe Relevanz behalten und nur der ACST-2 kann darauf eine Antwort geben. Schlüsselwörter Karotisstenose Schlaganfall Karotisstenting Karotisendarteriektomie Randomisierte, kontrollierte Studie Gefässchirurgie

4 best to intervene will be of critical importance, and only ACST-2 can directly answer this clinically relevant question. Substantial uncertainty as to whether CAS is better than CAS Carotid artery stenting (CAS) is a minimally invasive alternative method of treating carotid artery stenosis, and might be more acceptable to patients than conventional surgery, but there is limited evidence about the safety and long-term efficacy of CAS compared to CEA in asymptomatic patients. In CREST, the 3- day stroke and death rate for the 1182 asymptomatic patients was 1.4% (CEA) vs. 2.5% (CAS). And whilst this compares favourably with the 3% perioperative hazard observed in ACST-1, CREST randomised too few asymptomatic patients to provide reliable evidence as to how best to intervene in patients with significant carotid artery stenoses. This substantial uncertainty is reflected in several authoritative guidelines (. Fig. 3) which stress the need for large scale randomised trials directly comparing CEA and CAS in such patients [13, 14]. ACST-2 A large and simple randomised trial of CEA vs. CAS for stroke prevention Fig. 4 8 ACST-2 protocol summary. (Adapted from [16]) ly that the intervention of choice will be carotid stenting. Conversely, if the lesion is detected by a vascular surgeon who does not perform carotid stenting, then the patient will probably be offered CEA. By randomising several thousand patients to either CEA or CAS during the 21s, ACST-2 will provide uniquely reliable evidence about both the early hazards and long-term efficacy of both procedures. This will not only help guide current practice, but if, as seems likely (given the results of ACST-1), SPACE-2 and CREST-2 confirm that carotid intervention (CAS or CEA) confers additional benefit over and above that achieved with CMT, then how ACST-2 is designed to maximise recruitment by minimising each collaborator s workload. It can be integrated easily into routine clinical care, as minimal information is required at randomisation and at the 1-month postprocedure follow-up, and these two forms are the only forms that routinely need completion by participating doctors. Annual follow-up (for at least 5 years) is by postal questionnaire and coordinated by the central ACST-2 office in Oxford (See Protocol Summary:. Fig. 4). ACST-2 aims to randomise several thousand patients with asymptomatic carotid artery stenosis in whom prompt intervention is indicated to either CEA or CAS (1:1 fashion). To be eligible for inclusion, both procedures should be practicable, and there should be substantial uncertainty (shared by both doctor and patient) 4 Gefässchirurgie 7 213

5 about whether CEA or CAS is the most appropriate choice of treatment. The primary objectives of ACST-2 are to compare F periprocedural risks (myocardial infarction [MI], stroke and death within the first month after the allocated CEA or CAS is attempted by an experienced practitioner) and F long-term (i.e. at least 5 years) prevention of stroke in subsequent year Ongoing recruitment: over 12 patients randomised ACST-2 began recruiting participants in February 28, and as of end July 213, ACST-2 collaborators working in 79 centres across 25 countries have randomised 1233 patients to either CEA (n=616) or CAS (n=617), making ACST-2 the largest investigator-led trial comparing carotid stenting with carotid surgery in asymptomatic patients. Italian centres have contributed the largest number of patients, followed by the UK and Sweden. To date, four German centres have recruited 61 patients into ACST-2, but we hope to substantially increase the number of collaborating sites in Germany, Austria and Switzerland which should enable large numbers of patients with asymptomatic carotid artery stenosis in whom some form of intervention is deemed necessary to be randomised to either CEA or CAS. To join ACST-2, a centre must have a collaborating neurologist (or stroke physician), a vascular surgeon and a carotid stenter, all of whom are responsible for patient recruitment, randomisation and 1-month follow-up. The stenter can be an interventional radiologist, cardiologist, surgeon or a physician with specialist training in carotid stenting. It is a trial requirement that vascular surgeons who may perform CEA in the trial and interventionalists who may perform CAS must already have a reasonable amount of successful experience with this procedure, and both groups qualifications and experience are assessed in a blinded fashion by a technical management committee which reviews the track records of prospective collaborators. This helps to ensure that the comparison in ACST-2 will be between CEA and CAS both performed to a high standard by experienced clinicians, and, on average, ACST-2 collaborators perform 82 CEA and 36 CAS (within and without the trial) each year. Whilst most vascular surgical centres perform CEA, not all have access to CAS on site. Therefore, collaborating centres can organise hub-and-spoke networks, with patient recruitment, randomisation and surgery occurring across the network, but CAS concentrated at a central hub, thereby maximising stenting expertise and ensuring high quality care. Randomisation can be done by telephone or via the web, with the intention of performing the allocated procedure as soon as possible (and ideally within the first month after randomisation). The choice of technique and equipment used is at the collaborators discretion, but should be appropriate for routine clinical practice (e.g. CE-marked stents). In contrast to many previous carotid stenting trials, a wide range of stents have been used to date in ACST-2, with Wallstent being the most commonly used device. Cerebral protection devices were used in almost all cases, with filters predominating. Local anaesthesia was used in 94% of patients receiving carotid stents, whereas roughly equal numbers of CEA were performed under general anaesthesia (56%) and local/regional anaesthesia (44%), and carotid patching was used in 5% of patients undergoing CEA. The use of cardiovascular risk factor reduction medications is recorded at randomisation and throughout follow-up. At entry into ACST-2, 93% of participants were on antiplatelet therapy, 89% on antihypertensive therapy and 85% on lipidlowering therapy, with even higher compliance rates anticipated with long-term follow-up. Interim results Blinded results for 1-month major procedural morbidity and mortality are available for the first 691 patients in ACST-2, and these show that, overall, CEA and CAS in the trial have a 1.% risk of disabling stroke and death [15]. Whilst the results on perioperative hazards for both CEA and CAS are of significant interest, the long-term durability of both procedures is also of fundamental importance. By following up large numbers of patients for at least 5 years, ACST-2 will provide reliable evidence about the long-term efficacy of CEA versus CAS. Vascular specialists contributions If, as we expect from the results of ACST-1, trials comparing carotid intervention vs. best medical management in the 21s (e.g. SPACE-2, CREST-2 and ECST-2) find in favour of intervention, how best to intervene in such patients will be of critical importance in the 22s. ACST-2 is the only trial in progress that directly compares CEA vs CAS, and hence answer this question reliably.» Evidence from vascular surgeons can help determine how to best manage patients in 22 When a vascular specialist is faced with a patient in clinic with a haemodynamically significant stenosis (e.g. 7 99%), there are a range of treatment options open for discussion. In some patients (either due to age, extensive comorbidity, limited life expectancy or patient preference) intervention may be inappropriate, in which case medical management is the only option. Sometimes, clinicians and patients may be uncertain as to whether any procedure is indicated, and in such circumstances randomisation into a trial (such as SPACE-2) comparing stenting or surgery with contemporary medical therapy is reasonable. There will, however, be substantial numbers of patients in whom some procedure is clearly indicated, but uncertainty exists as to whether stenting or surgery is best, and such patients should be considered for randomisation into ACST-2. Conclusion ACST-2 and SPACE-2 are complementary trials, and not competitive. Vascular specialists in Germany, Austria and Switzerland are currently in the unique position of being able to consider randomising the majority of patients undergoing carotid intervention for asymptomatic disease into one of two trials: Gefässchirurgie

6 F if uncertain as to whether intervention is indicated, then randomise into SPACE-2a/SPACE-2b; but F if intervention is clearly indicated but if uncertain as to whether it should be CAS or CEA, consider randomising into ACST-2. Over one-third of all carotid procedures in Europe are performed in Germanyspeaking countries, and enthusiastic participation in ACST-2 will help ensure we know how best to intervene in patients with asymptomatic carotid stenosis in the 22s. Corresponding address Compliance with ethical guidelines Prof. A. Halliday Nuffield Department of Surgical Sciences John Radcliffe Hospital University of Oxford Headley Way, OX3 9DU Headington, Oxford UK alison.halliday@nds.ox.ac.uk Conflict of interest. R. Bulbulia and A. Halliday state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies. References 1. Lopez AD, Mathers CD, Ezzati M (eds) et al (26) Global burden of disease & risk factors. Oxford University Press and The World Bank, Washington 2. Berry E, Kelly S, Westwood ME et al (22) The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review. Health Technol Assess 6(7) 3. European Carotid Surgery Trialists Collaborative Group (1991) MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (7 99%) or with mild ( 29%) carotid stenosis. Lancet 337: North American Symptomatic Carotid Endarterectomy Trial Collaborators (1991) Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade stenosis. N Engl J Med 325: MRC Asymptomatic Carotid Surgery Trial (AC- ST) Collaborative Group (24) Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial. Lancet 363: Halliday H, Harrison M, Hayter E et al (21) 1-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1) a multicentre randomized Trial. Lancet 376: Executive Committee for the Asymptomatic Carotid Atherosclerosis Study (1995) Endarterectomy for asymptomatic carotid stenosis. JAMA 273: Silver FL, Mackey A, Clark WM et al (211) Safety of stenting and endarterectomy by symptomatic status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). Stroke 42: Mas J-L, Chatellier G, Beyssen B, Branchereau A et al (26) Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 355: The SPACE Collaborative Group (26) 3 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomized non-inferiority trial. Lancet 368: International Carotid Stenting Study (ICSS) Investigators (21) Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomized controlled trial. Lancet 375: Featherstone RL, Doig D, Kennedy F et al (213) Equivalent long-term disability after carotid artery stenting and endartectomy in patients randomised in the International Carotid Stenting Study (ICSS). Cerebrovasc Dis 35(Suppl 3) 13. Smith, SC, Benjamin EJ, Bonow RO et al (211) AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 211 update. Circulation 124: NICE Interventional Procedures Guideline (IPG) 388: carotid artery stent placement for asymptomatic extracranial carotid stenosis (April 211) 15. ACST-2 Collaborative Group (213) Status update and interim results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2). EJVES (in press) ST-2_protocol_v4.2_Dec_27.pdf/view. Accessed 1 Sept Gefässchirurgie 7 213