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Who Benefits Most from Intervention for Asymptomatic Carotid Stenosis: Patients or Professionals?

Open ArchivePublished:April 06, 2009DOI:https://doi.org/10.1016/j.ejvs.2009.01.026

      Abstract

      Although there is level I evidence supporting the role of carotid endarterectomy (CEA) in patients with asymptomatic disease, opinion remains polarised regarding what constitutes optimal management, especially as carotid artery stenting (CAS) has emerged as a less invasive alternative. Reasons for this lack of consensus amongst surgeons, interventionists, neurologists and stroke physicians include our continued inability to identify ‘high risk for stroke' patients in whom to target costly therapies. For example, recent data from the USA suggest that up to $21 billion is being spent each year on ultimately ‘unnecessary' interventions. Second, is growing evidence that improvements in what now constitutes modern ‘best medical therapy' has significantly reduced the risk of stroke compared to that observed in ACAS and ACST. If true, this will compromise risk:benefit analyses used in national and international guidelines.
      At a time when evidence suggests that up to 94% of interventions may not benefit the patient, the authors urge that at least one of the randomised trials comparing CEA with CAS in asymptomatic patients includes an adequately powered third limb for BMT. Timely investment now could optimise patient care and resource utilisation for all of us in the future.

      Keywords

      “All professions are a conspiracy against the laity”George Bernard Shaw (1856–1950)
      Two randomised controlled trials (RCTs), the Asymptomatic Carotid Atherosclerosis Study (ACAS)
      • Executive Committee for the Asymptomatic Carotid Atherosclerosis Study
      Endarterectomy for asymptomatic carotid artery stenosis.
      and the Asymptomatic Carotid Surgery Trial (ACST)
      Asymptomatic Carotid Surgery Trial Collaborators
      The MRC Asymptomatic Carotid Surgery Trial (ACST): carotid endarterectomy prevents disabling and fatal carotid territory strokes.
      , concluded that carotid endarterectomy (CEA) conferred a 50% relative risk reduction in the 5 year risk of ‘stroke’ from approximately 12% down to 6% (Table 1). However, despite level I (Grade A) evidence supporting intervention, the management of patients with asymptomatic carotid disease continues to polarise opinion around the world.
      Table 1Five year risks of the main outcomes from ACAS and ACST, including the operative risk
      ACASACST
      BMTCEAARRBMTCEAARR
      Any stroke17.5%12.4%5.1%11.8%6.4%5.4%
      No of ‘any strokes’ prevented per 1000 CEAs at 5 years5154
      Any major stroke9.1%6.4%2.7%6.1%3.5%2.6%
      No of ‘major strokes’ prevented per 1000 CEAs at 5 years2726
      Ipsilateral stroke11.0%5.1%5.9%5.1%*4.4%*1.1%
      No of ipsilateral strokes prevented per 1000 CEAs at 5 years59
      Major ipsilateral stroke6.0%3.4%2.6%n/an/an/a
      BMT = best medical therapy, CEA = carotid endarterectomy, * data derived from presentations about the 10 year ACST data. In the CEA group it includes a 2.8% operative risk, n/a = no data available, ARR = absolute risk reduction at 5 years.
      It is inevitable, of course, that practice will reflect political/financial priorities within health systems, but the magnitude of variation seems remarkable, especially as it is based upon an interpretation of the same published data. The Iberian Medical Tourism Network, for example, suggests that the indications for carotid artery stenting (CAS) in asymptomatic patients are “essentially the same as for standard open CEA” and its website will quote for both interventions. In 2005, 135,701 carotid revascularisations were performed in the USA. Of these, 122,986 (92%) were in asymptomatic patients
      • McPhee J.T.
      • Schanzer A.
      • Messina L.M.
      • Eslami M.H.
      Carotid artery stenting has increased rates of post-procedure stroke, death and resource utilization than does carotid endarterectomy in the United States 2005.
      ; almost one tenth being by CAS. By contrast, only 20% of reconstructions in the UK are performed in asymptomatic patients (very few by CAS),

      2008 Great Britain and Ireland Carotid Endarterectomy Audit: Generic Trust Report. http://www.vascularsociety.org.uk.

      while the Belgian Government will reimburse surgeons for performing CEA in asymptomatic patients but not following CAS.

      Endovasculaire behandeling van Carotisstenose. KCE Reports vol. 13A. Federaal Kenniscentrum voor de Gezondheidszorg, Centre Federal d'Expertise des Soins de Sante; 2005.

      Enthusiasm for intervening is highest amongst those surgeons, radiologists and cardiologists who promote their procedures and lowest amongst neurologists and stroke physicians. As early as 1996, Barnett questioned whether the available evidence justified the huge increase in CEA numbers following publication of ACAS.
      • Barnett H.J.M.
      • Eliasziw M.
      • Meldrum H.E.
      • Taylor D.W.
      Do the facts and figures warrant a tenfold increase in the performance of carotid endarterectomy on asymptomatic patients?.
      In 1997, a consortium of Canadian stroke neurologists campaigned against screening and intervention in asymptomatic patients.
      • Perry J.R.
      • Szalai J.P.
      • Norris J.W.
      Consensus against both endarterectomy and routine screening for asymptomatic carotid artery stenosis: The Canadian Stroke Consortium.
      By 2003, some called for the RCTs to be repeated,
      • Chaturvedi S.
      Should the multicenter carotid endarterectomy trials be repeated?.
      while by 2008 some even felt that improvements in what constituted ‘best medical therapy’ meant that no-one need undergo any intervention at all.
      • Abbott A.
      Asymptomatic carotid artery stenosis: it's time to stop operating.
      The lack of consensus was illustrated by a 2008 poll undertaken by the New England Journal of Medicine. A case scenario was presented (67 year old non-smoking male with hypertension, hyperlipidaemia and a 70–80% NASCET derived asymptomatic carotid stenosis) and three experts advised on how he should be managed. Having considered the ‘expert's’ advice, almost 5000 readers then voted their own recommendations. Interestingly, almost half (49%) said they would treat the patient medically, 32% recommended CEA, while 19% said they would perform CAS. Table 2 shows that the most frequent response from every continent (including North America) was a recommendation for conservative management.
      Table 2Global variation in opinion on how a 67 year old non-smoking male with hypertension, hyperlipidaemia and a 70–80% asymptomatic stenosis should be managed (*)
      ContinentRespondentsBMT (%)CAS (%)CEA (%)
      North American = 2227471736
      Europen = 1161481933
      South American = 545492526
      Asia & Russian = 425562420
      Australia & Oceanian = 118561430
      African = 39443126
      (*) based on data from an on-line vote run by the New England Journal of Medicine. BMT = best medical therapy, CAS = carotid artery stenting, CEA = carotid endarterectomy.
      So why, despite two large RCTs, is opinion still so polarised? The main reasons include: (i) our continued inability to identify ‘high risk for stroke’ patients in whom to target costly (and potentially risky) interventions; and (ii) a belief that improvements in what now constitutes ‘best medical therapy’ may have significantly reduced the risk of stroke compared to that observed in ACAS and ACST. A third and more controversial reason (to which George Bernard Shaw would undoubtedly subscribe) is the fact that intervening in asymptomatic patients remains a major source of income to surgeons and interventionists around the world.
      Following publication of the symptomatic trials, it was possible to identify subgroups of patients who were at increased risk of suffering a stroke on medical therapy but not at significantly increased operative risk.
      • Naylor A.R.
      • Rothwell P.M.
      • Bell P.R.F.
      Overview of the principal results and secondary analyses from the European and the North American randomised trials of carotid endarterectomy.
      The important factors included; male gender, increasing age (especially >75 years), hemispheric vs ocular symptoms, increasing medical co-morbidity, very recent symptoms (especially the first 2 weeks), irregular vs smooth plaques, increasing degrees of stenosis (but not subocclusion), contralateral occlusion, tandem intracranial disease and a failure to recruit intracranial collaterals. By contrast, other than ACST observing that CEA conferred no significant benefit in patients aged >75 years (a finding currently ignored by many surgeons and interventionists), few conclusions regarding who might benefit most (and least) from intervention for asymptomatic stenosis were forthcoming.
      The need to target CEA/CAS towards high risk (for stroke) asymptomatic patients cannot be overstated. Even if it were possible to identify and then operate upon every single patient with an asymptomatic 60–99% stenosis in the whole population, fewer than 5% of all strokes in the population would be prevented.
      • Hankey G.J.
      Asymptomatic carotid stenosis: how should it be managed?.
      • Naylor A.R.
      Time is brain!.
      The cost of screening and intervention would, however, be enormous and would undoubtedly draw funds from other more cost-effective preventive strategies. The following section will deal with current practice in the USA (largely because they have published most data), but there are important messages for many other health systems.
      The Centres for Medicare and Medicaid Services predict that US Healthcare spending will nearly double to $4.3 trillion by 2017, i.e. about 20% of GDP. Commenting upon these predictions, Professor Brian Rubin observed that “publically funded healthcare in the USA was about to be hit by the ‘perfect storm’ and that difficult decisions lay ahead, hopefully driven by evidence based studies as to which therapies offer an adequate return on investment.” So where does the management of asymptomatic carotid disease feature in any discussions regarding an ‘adequate return on investment’?
      Using the US statistics,
      • McPhee J.T.
      • Schanzer A.
      • Messina L.M.
      • Eslami M.H.
      Carotid artery stenting has increased rates of post-procedure stroke, death and resource utilization than does carotid endarterectomy in the United States 2005.
      122,986 revascularisations in asymptomatic patients were performed in 2005 (91% CEA, 9% CAS). Because McPhee published an estimate of total hospital costs in his paper, it is now possible to model the financial implications (total hospital costs) against the late benefits (strokes prevented) for this cohort of patients. Using the ACAS data summarised in Table 1, 59 ipsilateral strokes will be prevented at 5 years by performing 1000 CEAs assuming a 2.3% procedural risk. The parallel figure for ‘any strokes’ prevented is 51. If these values are now applied to the 2005 national data, this means that 7256 ipsilateral strokes would be prevented at 5 years (59 × 122.986). Conversely, this means that 115,730 patients (94%) underwent an unnecessary procedure. Using the US definition of a billion, this equates to a $21 billion cost to the US Health Services for ‘unnecessary interventions’ in that calendar year. The cost incurred for preventing one ipsilateral stroke at 5 years would therefore be $319,551 and the parallel figure for preventing one ‘any stroke’ at 5 years would be $369,685.
      However, these data were modelled upon the procedural risks observed in ACAS (2.3%). If 30-day risk data from the 2004 US Multistate CEA audit were used instead, the benefits and costs change considerably.
      • Kresowik T.F.
      • Bratzler D.W.
      • Kresowik R.A.
      Multistate improvement in process and outcomes of carotid endarterectomy.
      In this audit, the procedural risk of stroke and death in asymptomatic patients was 3.8%. If this is a truer reflection of ‘real world’ practice, the number of ipsilateral strokes prevented per 1000 CEAs at 5 years falls to 44, the total number of strokes prevented in the cohort of 122,986 patients falls to 5411 (i.e. 117,575 would undergo an unnecessary procedure), leading to an average total hospital cost of $428,510 per stroke prevented.
      So who might benefit most (and least) from prophylactic intervention? Unfortunately, neither ACAS nor ACST have really been able to help. Contrary to assumptions before the trials commenced, neither has demonstrated any relationship between stenosis severity and late stroke risk (i.e. the total opposite of the symptomatic trials). Despite this, some advocates of intervention still feel that it is almost unethical not to intervene in patients with 80–99% stenoses, as opposed to 60–79%.
      • Wholey M.H.
      • Barbato J.E.
      • Al-Khoury G.E.
      Treatment of asymptomatic carotid disease with stenting: Pro.
      This conclusion is not, however, supported by any other natural history study. Figure 1 details the annual risk of ipsilateral stroke in 26 natural history studies relative to the degree of stenosis measured when the patient entered the study.
      • Norris J.W.
      • Zhu C.Z.
      • Bornstein N.M.
      • Chambers B.R.
      Vascular risks of asymptomatic carotid disease.
      • Autret A.
      • Pourcelot L.
      • Saudeau D.
      • Marchal C.
      • Bertrand P.
      • de Boisvilliers S.
      Stroke risk in patients with carotid stenosis.
      • O'Holleran L.W.
      • Kennelly M.M.
      • McClurken M.
      • Johnson J.M.
      Natural history of asymptomatic carotid plaque: five year follow-up study.
      • Bock R.W.
      • Gray-Weale A.C.
      • Mock P.A.
      • App S.M.
      • Robinson D.A.
      • Irwig L.
      • et al.
      The natural history of asymptomatic carotid artery disease.
      • Mansour M.A.
      • Mattos M.A.
      • Faught W.E.
      • Hodgson K.J.
      • Barkmeier L.D.
      • Ramsey D.E.
      • et al.
      The natural history of moderate 50–79% internal carotid artry stenosis in symptomatic, non-hemispheric and asymptomatic patients.
      • Rockman C.B.
      • Riles T.S.
      • Lamparello P.J.
      • Giangola G.
      • Adelman M.A.
      • Stone D.
      • et al.
      Natural history and management of the asymptomatic, moderately stenosed internal carotid artery.
      • Shanik G.D.
      • Moore D.J.
      • Leahy A.
      • Grouden M.C.
      • Colgan M.P.
      Asymptomatic carotid stenosis: a benign lesion?.
      • Hobson R.W.
      • Weiss D.G.
      • Fields W.S.
      • Goldstone J.
      • Moore W.S.
      • Towne J.B.
      Efficacy of carotid endarterectomy for asymptomatic carotid stenosis: the Veterans Affairs Co-operative Study Group.
      • Satiani B.
      • Porter R.M.
      • Biggers K.M.
      • Das B.M.
      Natural history of non-operated significant carotid stenosis.
      • Ellis M.R.
      • Franks P.J.
      • Cuming R.
      • Powell J.T.
      • Greenhalgh R.M.
      Prevalence, progression and natural history of asymptomatic carotid stenosis: is there a place for carotid endarterectomy?.
      • Mackey A.E.
      • Abrahamowicz M.
      • Langlois Y.
      • Battista R.
      • Simard D.
      • Bourque F.
      Outcome of asymptomatic patients with carotid disease.
      • Ford C.S.
      • Frye J.L.
      • Toole J.F.
      • Lefkowitz D.
      Asymptomatic carotid bruit and stenosis: a prospective follow up study.
      • Hennerici M.
      • Hulsbomer H.B.
      • Hefter H.
      • Lammerts D.
      • Rautenberg W.
      Natural history of asymptomatic extracranial arterial disease: results of a long term prospective study.
      • Nadareishvili Z.G.
      • Rothwell P.M.
      • Beletsky V.
      • Pagniello A.
      • Norris J.W.
      Long term risk of stroke and other vascular events in patients with asymptomatic carotid stenosis.
      • Goessens B.M.B.
      • Visseran F.L.J.
      • Kappelle J.
      • Algra A.
      • van der Graaf Y.
      for the SMART Study Group
      Asymptomatic carotid artery stenosis and the risk of new vascular events in patients with manifest arterial disease: the SMART Study.
      • Inzitari D.
      • Eliasziw M.
      • Gates P.
      • Sharpe B.L.
      • Chan R.K.
      • Meldrum H.E.
      • et al.
      The causes and risk of stroke in patients with asymptomatic internal carotid artery stenosis: North American Symptomatic Carotid Endarterectomy Trial Collaborators.
      • Abbott A.L.
      • Chambers B.R.
      • Stork J.L.
      • Levi C.R.
      • Bladin C.F.
      • Donnan G.A.
      Embolic signals and prediction of ipsilateral stroke or transient ischaemic attack in asymptomatic carotid stenosis: a multicentre Prospective Cohort Study.
      • Tong Y.
      • Royle J.
      Outcome of patients with symptomless carotid bruits: a prospective study.
      • Dick P.
      • Sherif C.
      • Sabeti S.
      • Amighi J.
      • Minar E.
      • Schillinger M.
      Gender differences in outcome of conservatively treated patients with asymptomatic high grade carotid stenosis.
      European Carotid Surgery Trialists Collaborative Group
      Risk of stroke in the distribution of an asymptomatic carotid artery.
      • Longstreth W.T.
      • Shemanski L.
      • Lefkowitz D.
      • O'Leary D.H.
      • Polak J.F.
      • Wolfson S.K.
      Asymptomatic internal carotid artery stenosis defined by ultrasound and the risk of subsequent stroke in the elderly.
      • Johnson J.M.
      • Kennelly M.M.
      • Decesare D.
      • Morgan S.
      • Sparrow A.
      Natural history of asymptomatic carotid plaque.
      • Chambers B.R.
      • Norris J.W.
      Outcome in patients with asymptomatic neck bruit.
      • Meissner I.
      • Wiebers D.O.
      • Whisnant J.P.
      • O'Fallon W.M.
      The natural history of asymptomatic carotid artery occlusive lesions.
      • Mess W.
      • Steinke W.
      • Rautenberg W.
      • Hennerici M.
      Asymptomatic extracranial arterial disease.
      • Bogousslavsky J.
      • Despland P.A.
      • Regli F.
      Asymptomatic tight stenosis of the internal carotid artery: long term prognosis.
      Note that across a wide range of stenoses (including 80–99%), the annual risk of stroke rarely exceeded 3% and none exceeded 4%. One exception (not included in this figure) is a subgroup analysis in the ACSRS study which showed that patients with a 90–99% stenosis plus a history of contralateral TIA plus renal impairment faced a 6.5% annual risk of stroke.
      • Nicolaides A.N.
      • Kakkos S.K.
      • Griffin M.
      • Sabetai M.
      • Dhanjil S.
      • Tegos T.
      • et al.
      for the ACSRS Study Group. Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischaemic events: results from the ACSRS.
      All of the remaining patients in the 90–99% stenosis category incurred a 1% annual ipsilateral stroke risk. In reality the number of patients likely to fulfil all three of these high risk caveats is inconsequential.
      Figure thumbnail gr1
      Figure 1Annual rates of ipsilateral stroke in patients with an asymptomatic carotid stenosis stratified for stenosis severity at baseline. The authors acknowledge that many of the studies were sourced from Abbott,
      • Abbott A.L.
      • Bladin C.F.
      • Levi C.R.
      • Chambers B.R.
      What should we do with asymptomatic carotid stenosis?.
      Touze
      • Touze E.
      Natural history of asymptomatic carotid stenosis.
      and Rijbroek.
      • Rijbroek A.
      • Wisselink W.
      • Vriens E.M.
      • Barkhof F.
      • Lammertsma A.A.
      • Rauwerda J.A.
      Asymptomatic carotid artery stenosis: past, present and future.
      .
      More fundamentally, we have still not even determined whether women gain significant benefit from prophylactic CEA (or CAS). In ACAS, CEA conferred no benefit in females,
      • Executive Committee for the Asymptomatic Carotid Atherosclerosis Study
      Endarterectomy for asymptomatic carotid artery stenosis.
      even when the operative risk was later excluded.
      • Young B.
      • Moore W.S.
      • Robertson J.T.
      • Toole J.F.
      • Ernst C.B.
      • Cohen S.N.
      • et al.
      An analysis of peri-operative surgical mortality and morbidity in the Asymptomatic Carotid Atherosclerosis Study.
      ACST claimed that women gained significant benefit at 5 years, but this only held true if the operative risk was excluded.
      • Rothwell P.M.
      ACST: which subgroups will benefit most from carotid endarterectomy.
      When the operative risk was included, all significant benefit ceased.
      • Rothwell P.M.
      ACST: which subgroups will benefit most from carotid endarterectomy.
      In the 2005 Cochrane Review,

      Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD001923. DOI 10.1002/14651858. CD001923.pub2.

      males gained a highly significant 50% reduction in the risk of late stroke (OR 0.50, 95% CI 0.36–0.67), while CEA conferred no benefit in women (OR 1.0, 95% CI 0.6–1.7). The likely reason for the apparent lack of benefit in women is a combination of there being a slightly higher operative risk in women (4.0% vs 2.4% in ACST, 3.6% vs 1.7% in ACAS) in conjunction with a lower 5 year risk of stroke on medical therapy compared with men (8.7% vs 12.1% in ACAS; 7.5% vs 10.6% in ACST)). Accordingly, if one were to use ACAS and ACST data to predict who might fall into a category of being considered ‘higher risk for stroke’ on best medical therapy, they would have to be males under the age of 75 years.
      The second important reason underlying uncertainty about how best to manage patients with asymptomatic carotid disease is a growing belief that improvements in what now constitutes ‘best medical therapy’ may have reduced the natural history risk of stroke to levels below that observed in ACAS and ACST. This is a very important issue to be resolved as if the annual rate of fatal/major stroke falls below 1.1%, no benefit will ever accrue to any patient from CEA.
      • Arazi H.C.
      • Capparelli F.J.
      • Linetzky B.
      • Rebolledo F.P.
      • Augustovski F.
      • Wainsztein N.A.
      Carotid endarterectomy in asymptomatic stenosis: a decision analysis.
      In ACAS, ‘best medical therapy’ included advice to stop smoking, control of blood pressure and aspirin therapy. Unfortunately, ACAS did not publish data regarding changing trends in therapy or drug compliance, but relatively few will have received statins. By contrast, ACST has published considerable data on changes in medical therapy during the 10 years that the trial recruited.
      Asymptomatic Carotid Surgery Trial Collaborators
      The MRC Asymptomatic Carotid Surgery Trial (ACST): carotid endarterectomy prevents disabling and fatal carotid territory strokes.
      The majority (90%) received antiplatelet therapy throughout the study, while 70% were on antihypertensive therapy when the trial concluded in 2003. The most important change in practice was a progressive increase in the proportion of patients receiving statin therapy from 17% (1993–1996) to 58% by 2000–2003. By the end of 2003, 70% were taking statins and by 2008, the figure was over 90%. It is, however, important to note that by the midpoint of the trials duration (1997), fewer than 40% of ACST patients were taking statins. More importantly, the doses of statins used in the first 5 years of ACST would have been much lower than are currently recommended. Simvastatin (10 mg daily) was the most commonly used dose in the 1990s. Second, is a potential anomaly regarding the prescription of statins in women. Until the British Heart Protection Study published in 2002,
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo controlled trial.
      usual practice in the UK was to only prescribe statins to asymptomatic patients if they were male, had an elevated cholesterol level, were under the age of 75 years and had ischaemic heart disease. Accordingly, prior to 2002, a significant proportion of female patients were probably not receiving statin therapy.
      However, increasing statin use is only part of what constitutes the modern concept of ‘best medical therapy.’ Any future RCT (including a medical limb) would probably recommend even more aggressive blood pressure control using multiple therapeutic agents, especially in type II diabetics. There would be obligatory statin therapy at a relatively high dose, dual antiplatelet therapy (probably aspirin and dipyridamole as recommended by the American College of Chest Physicians), low dose ACE inhibition (now recommended by the AHA), more aggressive lifestyle modification advice (smoking cessation, exercise, diet) and the avoidance of hormone replacement therapy in women. No RCT has ever compared this modern concept of ‘best medical therapy’ with intervention in patients with asymptomatic carotid stenosis.
      What evidence is there that improvements in medical therapy are reducing the annual risk of stroke? Table 1 is a summary of the principal findings from ACAS and ACST, while Table 3 specifically focuses on temporal changes in the 5 year risks of ‘any’ and ‘ipsilateral’ stroke in these two trials. Note that between 1995 (when ACAS published) and 2004 (when ACST first published), the 5 year risk of ‘any stroke’ had declined from 17.5% in ACAS to 11.8% in ACST. This represents a 33% relative risk reduction during the 9 year period. There were also proportional reductions in: (i) the 5 year risk of any major stroke (down 33% from 9.1% in ACAS to 6.1% in ACST (Table 1)); and in (ii) ipsilateral stroke (down 52% from 11.0% in ACAS to about 5.3% in ACST (Table 3)). Interestingly, there is now evidence of a still further decline in the 5 year risk of stroke in the 10 year data currently being presented by ACST to national meetings. Table 3 shows that in the second 5 year period of ACST (i.e. years 6–10), the 5 year risk of ‘any’ stroke was now 7.2% (i.e. down 39% on the 11.8% reported in 2004), while the 5 year risk of ipsilateral stroke in the second 5 year period had fallen to 3.6% (down 32% from 5.3% in 2004).
      Table 3Temporal changes in the 5 year risk of ‘any’ stroke and ‘ipsilateral’ stroke in ACAS and ACST
      TrialYearsYear published‘Any’ stroke (%)‘Ipsilateral’ stroke (%)
      ACAS1–5199517.511.0
      ACST1–5200411.85.3
      =derived from oral presentations of the 10year ACST data.
      ACST6–1020097.2
      =derived from oral presentations of the 10year ACST data.
      3.6
      =derived from oral presentations of the 10year ACST data.
      a  = derived from oral presentations of the 10 year ACST data.
      Further evidence supporting a declining stroke risk (with time) comes from Figure 2 which shows the annual rate of ‘ipsilateral’ and ‘any’ stroke in 16 studies involving patients with 50–99% asymptomatic carotid stenoses published since 1985.
      • Executive Committee for the Asymptomatic Carotid Atherosclerosis Study
      Endarterectomy for asymptomatic carotid artery stenosis.
      Asymptomatic Carotid Surgery Trial Collaborators
      The MRC Asymptomatic Carotid Surgery Trial (ACST): carotid endarterectomy prevents disabling and fatal carotid territory strokes.
      • Norris J.W.
      • Zhu C.Z.
      • Bornstein N.M.
      • Chambers B.R.
      Vascular risks of asymptomatic carotid disease.
      • Bock R.W.
      • Gray-Weale A.C.
      • Mock P.A.
      • App S.M.
      • Robinson D.A.
      • Irwig L.
      • et al.
      The natural history of asymptomatic carotid artery disease.
      • Mansour M.A.
      • Mattos M.A.
      • Faught W.E.
      • Hodgson K.J.
      • Barkmeier L.D.
      • Ramsey D.E.
      • et al.
      The natural history of moderate 50–79% internal carotid artry stenosis in symptomatic, non-hemispheric and asymptomatic patients.
      • Hobson R.W.
      • Weiss D.G.
      • Fields W.S.
      • Goldstone J.
      • Moore W.S.
      • Towne J.B.
      Efficacy of carotid endarterectomy for asymptomatic carotid stenosis: the Veterans Affairs Co-operative Study Group.
      • Satiani B.
      • Porter R.M.
      • Biggers K.M.
      • Das B.M.
      Natural history of non-operated significant carotid stenosis.
      • Mackey A.E.
      • Abrahamowicz M.
      • Langlois Y.
      • Battista R.
      • Simard D.
      • Bourque F.
      Outcome of asymptomatic patients with carotid disease.
      • Goessens B.M.B.
      • Visseran F.L.J.
      • Kappelle J.
      • Algra A.
      • van der Graaf Y.
      for the SMART Study Group
      Asymptomatic carotid artery stenosis and the risk of new vascular events in patients with manifest arterial disease: the SMART Study.
      • Abbott A.L.
      • Chambers B.R.
      • Stork J.L.
      • Levi C.R.
      • Bladin C.F.
      • Donnan G.A.
      Embolic signals and prediction of ipsilateral stroke or transient ischaemic attack in asymptomatic carotid stenosis: a multicentre Prospective Cohort Study.
      European Carotid Surgery Trialists Collaborative Group
      Risk of stroke in the distribution of an asymptomatic carotid artery.
      • Johnson J.M.
      • Kennelly M.M.
      • Decesare D.
      • Morgan S.
      • Sparrow A.
      Natural history of asymptomatic carotid plaque.
      • Chambers B.R.
      • Norris J.W.
      Outcome in patients with asymptomatic neck bruit.
      • Abbott A.L.
      • Bladin C.F.
      • Levi C.R.
      • Chambers B.R.
      What should we do with asymptomatic carotid stenosis?.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • Langlois Y.
      • Bourque F.
      • Mackey A.
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing: The Asymptomatic Cervical Bruit Study Group.
      Once again, there is evidence of a sustained decline in the annual rate of stroke (ipsilateral and any) over the last two decades and which has continued since the publication of ACST in 2004. The most recent study (SMART) reported annual rates of ‘any stroke’ and ipsilateral stroke of <1%.
      • Goessens B.M.B.
      • Visseran F.L.J.
      • Kappelle J.
      • Algra A.
      • van der Graaf Y.
      for the SMART Study Group
      Asymptomatic carotid artery stenosis and the risk of new vascular events in patients with manifest arterial disease: the SMART Study.
      Figure thumbnail gr2
      Figure 2Annual rates of ipsilateral and ‘any’ stroke in patients with an asymptomatic 50–99% stenosis stratified by date of publication. The authors acknowledge that many of these studies were sourced from Abbott.
      • Abbott A.L.
      • Bladin C.F.
      • Levi C.R.
      • Chambers B.R.
      What should we do with asymptomatic carotid stenosis?.
      .
      We, therefore, believe that there is still considerable uncertainty about how best to manage patients with asymptomatic carotid disease. In our opinion, consensus will only be achieved if one of the trials evaluating CEA with CAS in asymptomatic patients includes an adequately powered third limb for medically treated patients. However, reliance only upon stenosis severity for patient selection may no longer be appropriate. More sophisticated methods are required in order to identify the relatively small subset of patients at highest risk of suffering a late stroke, in whom intervention is still likely to be more effective than best medical treatment alone. For example, Spence has shown that the annual risk of stroke was only 1% in patients with an asymptomatic 60–99% stenosis and no baseline evidence of embolisation on transcranial Doppler (TCD),
      • Spence D.J.
      • Tamayo A.
      • Lownie S.P.
      • Ng W.P.
      • Ferguson G.G.
      Absence of microemboli on transcranial Doppler identifies low risk patients with asymptomatic carotid stenosis.
      but was 15% in patients with TCD evidence of embolisation. Larger studies are nearing completion and will greatly inform the debate.

      The ACES Investigators. The Asymptomatic Carotid Emboli Study (ACES): study design and baseline results. Int J Stroke, in press.

      Similarly, something as simple as performing a CT scan (identifying pre-existing infarction) or looking at the patency of the circle of Willis may impart valuable information regarding long term prognosis. In a recent subgroup analysis from the ACSRS, patients with a 60–99% stenosis and an ipsilateral infarct on CT scan incurred a 3.6% annual rate of stroke over the ensuing 8 years as compared with only 1.0% in patients with similar stenoses but no infarction.

      Kakkos S, Sabetai M, Tegos T, Stevens J, Thomas D, Griffin M, et al. Silent embolic infarcts on computed tomography brain scans and risk of ipsilateral hemispheric events in patients with asymptomatic internal carotid artery stenosis. J Vasc Surg, in press.

      Similarly, patients randomised into a medical limb could undergo serial biomarker evaluation and/or novel imaging strategies including evaluation of intraplaque haemorrhage on MR
      • Altaf N.
      • MacSweeney S.T.
      • Gladman J.
      • Auer D.P.
      Carotid intraplaque haemorrhage predicts recurrent symptoms in patients with high-grade carotid stenosis.
      or image normalised Grey Scale Median measurement using ultrasound.
      • Nicolaides A.N.
      • Kakkos S.
      • Griffin M.
      • Sabetai M.
      • Dhanjil S.
      • Thomas D.J.
      • et al.
      Effect of image normalisation on carotid plaque classification and the risk of ipsilateral ischemic events: Results from the Asymptomatic Carotid Stenosis and Risk of Stroke Study.
      ACST and ACAS cannot be faulted for not having used these new techniques when they were recruiting, but we now need more discriminating investigative strategies for the future. Only then might it become possible to develop a predictive scoring system to enable the targeting of therapy to the most vulnerable patients.
      However, unless one of the planned RCTs includes an adequately powered third limb, the moment will be lost. The inevitable consequence will be that in 5–10 years time when the trials begin to report, we will continue to spend huge amounts of money on unnecessary treatments and we will have to make comparisons with natural history data derived from the medical limbs of trials started two or three decades earlier. Table 4 summarises the four trials intending to make a randomised comparison between CAS and CEA in asymptomatic patients. CREST (not mentioned in Table 4, but recently completed) included about 1000 asymptomatic patients and will report preliminary data later this year. They did not include a medical limb. ACT-1 has already started to recruit. It does not have a medical limb and only allows ‘elite’ interventionists and surgeons to participate. It is inevitable that there will be questions about the generalisability of its findings. ACST II has just started recruiting and plans to randomise 5000 patients. The authors accept that it may be difficult to change trial methodology at this late stage, but it is likely that the lack of a medical arm will be cited at a later date as being a major limitation. SPACE II is about to start in Germany, Austria and Switzerland. It is unique in that it has secured funding for a third medical limb, but it only plans to randomise 500 patients to medical treatment only. Unfortunately clinicians from outside these three countries cannot randomise patients (could that change?). Moreover, given past experience, it is likely that 500 patients will not be large enough to identify a clinically relevant high risk subgroup and there is no guidance (as yet) as to whether SPACE II plans to measure plasma biomarkers or use novel imaging strategies in their medically managed patients.
      Table 4Demographics and methodology of the randomised trials in asymptomatic patients
      MethodologyACT 1ACST IITACITSPACE II
      Type of trial
      Non-inferiority, equivalence, superiority.
      Non-inferiorityEquivalenceSuperioritySuperiority CEA/CAS vs BMT non-inferiority CAS vs CEA
      Multi-centreYesYesYesYes
      Recruiting countryNorth AmericaWorldwideNorth America & EuropeGermany, Austria, Switzerland
      Treatment options
      Carotid angioplasty (CAS), carotid endarterectomy (CEA), best medical therapy (BMT).
      CAS vs CEACAS vs CEACAS vs CEA vs BMTCAS vs CEA vs BMT
      Funding sourceAbbott VascularNHS R + D and HTA
      National Health Service Research Health Technology Assessment programme.
      Not yet determinedBMBF/DFG
      Number intended to be in trial
      Number of patients that power calculation deems necessary for trial completion.
      1858500025003640
      Randomisation ratios
      Ratio of CAS to CEA in trial.
      CAS 3: CEA 1CAS 1: CEA 1CEA 1: CAS 1: BMT 1CEA 1550: CAS 1550: BMT 540
      Randomisation started?YesYesNoNo
      Track record of participants
      Is a track record review undertaken in order to select trial participants.
      YesYesYesYes
      Proctoring/mentoring allowed
      Does your trial allow for less experienced CAS practitioners to randomise patients but be proctored by more experienced practitioners before being allowed to perform CAS independently within the trial.
      NoNoNoNo
      Stenosis range
      Range of stenoses being randomised.
      ‘Severe’‘Severe’≥50%≥50% NASCET
      Stenosis measurement method
      Stenosis measurement method; i.e. NASCET, ECST.
      NASCETNASCET & ECSTNASCETNASCET & ECST
      Stent used in studyXact Rapid Exchange™CE approved
      FDA=Food and Drug Administration approved, CE mark indicates that the product meets the requirements of all relevant European Directives.
      FDA/CE approved
      FDA=Food and Drug Administration approved, CE mark indicates that the product meets the requirements of all relevant European Directives.
      CE approved
      FDA=Food and Drug Administration approved, CE mark indicates that the product meets the requirements of all relevant European Directives.
      and approved by the CAS quality committee
      Cerebral protection deviceobligatoryOptionalObligatoryoptional
      TypeEmboshield™CE approved
      FDA=Food and Drug Administration approved, CE mark indicates that the product meets the requirements of all relevant European Directives.
      FDA/CE approved
      FDA=Food and Drug Administration approved, CE mark indicates that the product meets the requirements of all relevant European Directives.
      CE approved
      FDA=Food and Drug Administration approved, CE mark indicates that the product meets the requirements of all relevant European Directives.
      and approved by the CAS quality committee
      Dual antiplatelet therapyYesYesYesYes
      Endpoints30-day death/stroke/MI30-day death/stroke/MI30-day death/stroke/MISafety: 30-day death or any stroke
      >30-day to 1 year ipsilateral stroke neurocognitive decline5 year stroke (any/disabling)5 year stroke rateEfficacy: 30-day any stroke or death plus 5 year ipsilateral ischemic stroke
      Contact detailswww.act1trial.com[email protected][email protected][email protected]
      a Non-inferiority, equivalence, superiority.
      b Carotid angioplasty (CAS), carotid endarterectomy (CEA), best medical therapy (BMT).
      c National Health Service Research Health Technology Assessment programme.
      e Number of patients that power calculation deems necessary for trial completion.
      f Ratio of CAS to CEA in trial.
      g Is a track record review undertaken in order to select trial participants.
      h Does your trial allow for less experienced CAS practitioners to randomise patients but be proctored by more experienced practitioners before being allowed to perform CAS independently within the trial.
      i Range of stenoses being randomised.
      j Stenosis measurement method; i.e. NASCET, ECST.
      k FDA = Food and Drug Administration approved, CE mark indicates that the product meets the requirements of all relevant European Directives.
      The only other study is TACIT, which is the only trial planning to recruit patients into three large limbs, but it is struggling to secure funding. In addition to traditional endpoints, TACIT plans to evaluate neurocognitive changes, quality of life issues and carotid plaque characteristics. If it were funded, it would allow clinicians from around the world to randomise patients into either ACST II, TACIT or SPACE II according to patient preference and/or physician equipoise. At present, however, TACIT still needs to secure $60 million funding over a 5 year period, but could begin if $20 million were committed over a 3 year period (John Rundback, personal communication). Although these seem large sums of money, given that about $21 billion is currently being spent each year on unnecessary interventions in asymptomatic patients in the USA, it does seem disappointing that funding has not been forthcoming. Now would seem an ideal opportunity for health systems around the world to contribute relatively little towards a trial that could end up saving a lot of resources for all of us in the future.

      Conflict of Interest

      None declared.

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