Alison Halliday, lead author of the Asymptomatic Carotid Surgery Trial (ACST), has revealed the commencement of a new randomised controlled trial with two prongs, ACST-2. The announcement was made at the annual meeting of the European Society for Vascular Surgery (ESVS), in Helsinki, Finland.
Halliday and the trial management group of the ACST, said ACST-2 would randomise appropriate patients with asymptomatic disease to surgery vs stenting. The investigators said that as ACST I has shown that at six-years surgery is superior to non-intervention, the new challenge for ACST-2 is to compare stenting to surgery as ‘gold standard’.
Patient eligibility will be based in unilateral or bilateral carotid artery stenosis appropriate for surgery or stenting (only one side allowed in trial). In addition, only patients fit for and willing to have surgery or stenting and accessible for follow-up to five-years (mostly by telephone) will be included, where both the doctor and patient are ‘substantially uncertain’ whether the patient should have carotid endarterectomy or carotid stenting.
The primary analysis will be clinical myocardial infarction, stroke and death within 30 days of surgery or stenting and long-term (five-year) survival free of stroke. Secondary analysis will include rates of symptomatic restenosis and cost-effectiveness. Each centre involved in the study should have a neurologist or stroke physician, vascular surgeon or neurosurgeon and interventionalist. The researchers will only use CE marked devices, usually with cerebral protection.
Previously, the Stenting and Angioplasty with Protection in Patients at HIgh Risk for Endarterectomy (SAPPHIRE) Trial demonstrated equivocal results (although there did seem to be a reduction in myocardial infarction with stenting). Halliday commented, “Much larger randomised trials are now needed to assess the benefits and risks of stenting versus surgery reliably. We hope ACST-2 will provide an answer to the question: Is stenting safer than surgery for treating asymptomatic carotid stenosis?”
However, the formation of the Transatlantic Asymptomatic Carotid Intervention Trial (TACIT) announced earlier this year, has highlighted a potential conflict. TACIT will study all-risk patients, assigning these patients to one of three treatment arms. The first arm will provide optimal medical therapy alone, consisting of antiplatelet, antilipidemic and antihypertensive therapy, as well as tight glycemic control and tobacco cessation efforts. The second arm will provide optimal medical therapy plus carotid endarterectomy. The third arm will provide optimal medical therapy plus carotid artery stenting, with embolic protection using commercially available devices at the time of trial initiation.
Dr Barry Katzen, Miami, lead investigator of TACIT, said, “We are seeking to answer whether there is still a role for best medical therapy in the carotids and whether intervention in asymptomatic patients with severe carotid artery stenosis is the right treatment.”
TACIT will comprise 100 sites, equally divided between the US and Europe, and will enrol at least 2,400 patients: 850 patients in each of the revascularisation arms and 700 patients in the medical treatment arm alone. The primary endpoint is the three-year rate of all strokes and death. Secondary endpoints include transient ischaemic attack, myocardial infarction, economic cost and quality-of-life analysis, neurocognitive function, and duplex stenosis progression. Anticipated initiation of enrolment is early 2007. Major findings of the study will be reported after completion of three-year follow-up in all patients.
As carotid revascularisation is one of the most frequently practiced procedures in the US and Europe, the ramifications of both TACIT and ACST on clinical practice are seen as vital.
The ACST is a 10-year prospective study involving 3,120 patients from 126 hospitals in 30 countries. Half the patients were allocated to carotid endarterectomy, the other half to no intervention. Many of the patients were receiving medical therapy (antiplatelets, anti-hypertensives, anticoagulants, and cholesterol-lowering drugs). Patients were eligible for randomization into ACST if they had, in the opinion of the collaborators, tight carotid artery stenosis in the index artery and if they were asymptomatic, in other words, had no ipsilateral carotid territory symptoms of either stroke or transient cerebral ischaemia in the previous six months. The doctor and the patient both had to be substantially uncertain about the benefits of having immediate endarterectomy for the patient to be included. The patients were followed-up on a yearly basis and major events, either death or stroke, had to be reported to the ACST office for subsequent audit. Deferral of carotid endarterectomy was until the patient seemed to need an operation, for example if they had transient ischaemic attacks. Average follow-up of patients was 4.0 years.
Presenting the six-year results from ACST, Halliday said, “The results demonstrate that immediate surgery is the best option for some patients with severe narrowing of the carotid artery. As we can see this has had a direct effect upon practice.”
The ACST investigators revealed that the six-year risk of events (including second and third events) among men allocated CEA was around half that of patients assigned to no intervention (7.4% vs. 13.9%). For women, the six-year risk of events (including second and third events) allocated carotid endarterectomy vs no intervention was 7.8 vs. 11.8%. Unlike the smaller Asymptomatic Carotid Atherosclerosis Study (ACAS), ACST showed that women do benefit from immediate surgery. Also in contrast to ACAS, equal benefit in preventing both disabling and non-disabling stroke was shown by ACST. Follow-up of patients will continue to 2008 for the 10-year results. The investigators warned that subgroup analysis should be interpreted cautiously and at ten years subgroup analysis should provide definite results.They have also revealed a dramatic change in practice across Europe as highlighted by the proportions of asymptomatic patients managed in ACST centres in different parts of Europe. An analysis of the centres demonstrated that the proportions of asymptomatic patients treated had risen in ACST centres across Europe.
In an, as yet, unpublished editorial in the European Journal of Vascular and Endovascular Surgery Dr Peter Gaines and M S Randall, Sheffield, UK discuss the merits of carotid trials.
In the editorial they argue, “It is generally considered, particularly by stroke physicians, that best medical therapy has progressed considerably since, the major CEA trials. Whether this renders carotid endarterectomy obsolete cannot currently be answered since, in both the ACST and ACAS Trials that best medical therapy was not mandated or prescribed. The role of best medical therapies should recognise that the introduction of current concepts in antiplatelet therapy, statins, ACE inhibitors and appropriate blood pressure control may confer some advantages over the historical understanding of the natural history of asymptomatic disease. However, to suggest that surgical intervention remains of value simply because clinicians and surgeons are poor at prescribing modern concepts of best medical therapy is a poor argument.”
They conclude, “Perhaps more time and effort should be dedicated to the introduction and maintenance of optimal therapy rather than pursuing an asymptomatic stenosis on which to operate. In addition, the concept that, because there is a lag phase in the benefit conferred by best medical therapy in patients with carotid disease, then carotid endarterectomy is advantageous, surely does not stand up to close scrutiny. There is also a lag phase in the benefit of carotid endarterectomy since, any long-term benefit from active intervention is delayed because of the initial peri-surgical complication rate. The simple answer, therefore, is that we have no data at present to suggest carotid artery stenting is of benefit over and above best medical therapy in patients with asymptomatic carotid disease. Perhaps, since, surgical trials did not deliver what is now considered to be best medical therapy, the same can also be said of carotid endarterectomy in asymptomatic disease. Surely this discussion opens the way for a trial of both carotid artery stenting and carotid endarterectomy versus best medical therapy.”