European Journal of Vascular & Endovascular Surgery
Volume 37, Issue 6 , Pages 625-632, June 2009

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

  • A.R. Naylor

      Affiliations

    • The Department of Vascular Surgery at Leicester Royal Infirmary, Leicester, UK
    • Corresponding Author InformationCorresponding author. Department of Vascular Surgery, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK. Tel.: +44 116 252 3252; fax: +44 116 252 3179.
    • ,
  • P.A. Gaines

      Affiliations

    • The Sheffield Vascular Institute, Northern General Hospital, Sheffield, UK
    • ,
  • P.M. Rothwell

      Affiliations

    • The Stroke Prevention Research Unit, University Department of Clinical Neurology, the John Radcliffe Hospital, Oxford, UK

Received 16 January 2009; accepted 23 January 2009. published online 06 April 2009.

Article Outline

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: carotid endarterectomy, asymptomatic carotid disease, carotid stenting, medical therapy

 

“All professions are a conspiracy against the laity”

George Bernard Shaw (1856–1950)

Two randomised controlled trials (RCTs), the Asymptomatic Carotid Atherosclerosis Study (ACAS)1 and the Asymptomatic Carotid Surgery Trial (ACST)2, concluded that carotid endarterectomy (CEA) conferred a 50% relative risk reduction in the 5year 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 1. Five 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 5years 51 54
Any major stroke9.1%6.4%2.7%6.1%3.5%2.6%
No of ‘major strokes’ prevented per 1000 CEAs at 5years 27 26
Ipsilateral stroke11.0%5.1%5.9%5.1%*4.4%*1.1%
No of ipsilateral strokes prevented per 1000 CEAs at 5years 59
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 10year ACST data. In the CEA group it includes a 2.8% operative risk, n/a=no data available, ARR=absolute risk reduction at 5years.

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.3 In 2005, 135,701 carotid revascularisations were performed in the USA. Of these, 122,986 (92%) were in asymptomatic patients4; almost one tenth being by CAS. By contrast, only 20% of reconstructions in the UK are performed in asymptomatic patients (very few by CAS),5 while the Belgian Government will reimburse surgeons for performing CEA in asymptomatic patients but not following CAS.6

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.7 In 1997, a consortium of Canadian stroke neurologists campaigned against screening and intervention in asymptomatic patients.8 By 2003, some called for the RCTs to be repeated,9 while by 2008 some even felt that improvements in what constituted ‘best medical therapy’ meant that no-one need undergo any intervention at all.10 The lack of consensus was illustrated by a 2008 poll undertaken by the New England Journal of Medicine.11 A case scenario was presented (67year 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 2. Global variation in opinion on how a 67year 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.11 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.12 The important factors included; male gender, increasing age (especially >75years), hemispheric vs ocular symptoms, increasing medical co-morbidity, very recent symptoms (especially the first 2weeks), 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 >75years (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.13, 14 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.15 Commenting upon these predictions,15 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,4 122,986 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 5years 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 5years (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 5years would therefore be $319,551 and the parallel figure for preventing one ‘any stroke’ at 5years 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.16 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 5years 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%.17 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.18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 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.47 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.

  • View full-size image.
  • Figure 1 

    Annual 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,44 Touze45 and Rijbroek.46.

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,1 even when the operative risk was later excluded.48 ACST claimed that women gained significant benefit at 5years, but this only held true if the operative risk was excluded.49 When the operative risk was included, all significant benefit ceased.49 In the 2005 Cochrane Review,50 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 5year 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 75years.

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.51

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 10years that the trial recruited.2 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 5years of ACST would have been much lower than are currently recommended. Simvastatin (10mg 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 2002,52 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 75years 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 5year risks of ‘any’ and ‘ipsilateral’ stroke in these two trials. Note that between 1995 (when ACAS published) and 2004 (when ACST first published), the 5year 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 9year period. There were also proportional reductions in: (i) the 5year 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 5year risk of stroke in the 10year data currently being presented by ACST to national meetings. Table 3 shows that in the second 5year period of ACST (i.e. years 6–10), the 5year risk of ‘any’ stroke was now 7.2% (i.e. down 39% on the 11.8% reported in 2004), while the 5year risk of ipsilateral stroke in the second 5year period had fallen to 3.6% (down 32% from 5.3% in 2004).

Table 3. Temporal changes in the 5year risk of ‘any’ stroke and ‘ipsilateral’ stroke in ACAS and ACST
TrialYearsYear published‘Any’ stroke (%)‘Ipsilateral’ stroke (%)
ACAS1–5199517.511.0
ACST1–5200411.85.3a
ACST6–1020097.2a3.6a

a=derived from oral presentations of the 10year 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 1985.1, 2, 18, 21, 22, 25, 26, 28, 32, 34, 37, 39, 40, 44, 53 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%.32

  • View full-size image.
  • Figure 2 

    Annual 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.44.

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),54 but was 15% in patients with TCD evidence of embolisation. Larger studies are nearing completion and will greatly inform the debate.55 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 8years as compared with only 1.0% in patients with similar stenoses but no infarction.56 Similarly, patients randomised into a medical limb could undergo serial biomarker evaluation and/or novel imaging strategies including evaluation of intraplaque haemorrhage on MR57 or image normalised Grey Scale Median measurement using ultrasound.58 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 5–10years 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 4. Demographics and methodology of the randomised trials in asymptomatic patients
MethodologyACT 1ACST IITACITSPACE II
Type of trialaNon-inferiorityEquivalenceSuperioritySuperiority CEA/CAS vs BMT non-inferiority CAS vs CEA
Multi-centreYesYesYesYes
Recruiting countryNorth AmericaWorldwideNorth America & EuropeGermany, Austria, Switzerland
Treatment optionsbCAS vs CEACAS vs CEACAS vs CEA vs BMTCAS vs CEA vs BMT
Funding sourceAbbott VascularNHS R+D and HTAcNot yet determinedBMBF/DFG
Number intended to be in triale1858500025003640
Randomisation ratiosfCAS 3: CEA 1CAS 1: CEA 1CEA 1: CAS 1: BMT 1CEA 1550: CAS 1550: BMT 540
Randomisation started?YesYesNoNo
Track record of participantsgYesYesYesYes
Proctoring/mentoring allowedhNoNoNoNo
Stenosis rangei‘Severe’‘Severe’≥50%≥50% NASCET
Stenosis measurement methodjNASCETNASCET & ECSTNASCETNASCET & ECST
Stent used in studyXact Rapid Exchange™CE approvedkFDA/CE approvedkCE approvedk and approved by the CAS quality committee
Cerebral protection deviceobligatoryOptionalObligatoryoptional
TypeEmboshield™CE approvedkFDA/CE approvedkCE approvedk 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 1year ipsilateral stroke neurocognitive decline5year stroke (any/disabling)5year stroke rateEfficacy: 30-day any stroke or death plus 5year ipsilateral ischemic stroke
Contact detailswww.act1trial.comacst@sgul.ac.ukTACIT@SIRFoundation.orgNeurologie@med.uni-heidelberg.de

aNon-inferiority, equivalence, superiority.

bCarotid angioplasty (CAS), carotid endarterectomy (CEA), best medical therapy (BMT).

cNational Health Service Research Health Technology Assessment programme.

eNumber of patients that power calculation deems necessary for trial completion.

fRatio of CAS to CEA in trial.

gIs a track record review undertaken in order to select trial participants.

hDoes 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.

iRange of stenoses being randomised.

jStenosis measurement method; i.e. NASCET, ECST.

kFDA=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 5year period, but could begin if $20 million were committed over a 3year 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.

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Conflict of Interest 

None declared.

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PII: S1078-5884(09)00131-2

doi:10.1016/j.ejvs.2009.01.026

Refers to corrigendum:

  • Corrigendum to “Who Benefits Most from Intervention for Asymptomatic Carotid Stenosis: Patients or Professionals?” [Eur J Vasc Endovasc Surg 37, (2009) 625–632] , 31 August 2009

    A.R. Naylor, P.A. Gaines, P.M. Rothwell
    European Journal of Vascular & Endovascular Surgery November 2009 (Vol. 38, Issue 5, Page 657)

European Journal of Vascular & Endovascular Surgery
Volume 37, Issue 6 , Pages 625-632, June 2009

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