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Why is the management of asymptomatic carotid
disease so controversial?
A. Ross Naylor
*
The Department of Vascular Surgery at Leicester Royal Infirmary, Leicester, United Kingdom
article info
Article history:
Received 9 July 2014
Accepted 24 August 2014
Available online xxx
Keywords:
Asymptomatic carotid disease
Stroke
Carotid endarterectomy
Carotid artery stenting
abstract
Background: Despite level I evidence supporting a role for carotid endarterectomy (CEA) in
the management of patients with asymptomatic carotid disease, there is surprisingly little
international consensus regarding the optimal way to manage these patients.
Methods: Review of current strategies for managing asymptomatic carotid disease
Main findings: Those favouring a pro-interventional approach argue that: (i) until new
randomised trials demonstrate that best medical therapy (BMT) is better than CEA or ca-
rotid artery stenting (CAS) in preventing stroke, guidelines of practice should remain un-
changed; (ii) strokes secondary to carotid thromboembolism harboured a potentially
treatable asymptomatic lesion prior to the event. Because 80% of strokes are not preceded
by a TIA/minor stroke, CEA/CAS is the only way of preventing these strokes; (iii) screening
for carotid disease could identify patients with significant asymptomatic stenoses who
could undergo prophylactic CEA/CAS in order to prevent avoidable stroke; (iv) international
guidelines already advise that only ‘highly-selected’patients should undergo CEA/CAS; (v)
the 30-day risks of death/stroke after CEA/CAS are diminishing and this will increase long-
term stroke prevention and (vi) the alleged decline in annualized stroke rates in medically
treated patients is based upon flawed data.
Conclusions: The inescapable conclusion is that only a relatively small proportion of
asymptomatic patients benefit from prophylactic CEA/CAS. The key question, therefore,
remains; is society prepared to invest sufficient resources in identifying these ‘high risk for
stroke’patients so that they can benefit from aggressive BMT and CEA or CAS, leaving the
majority of lower risk patients to be treated medically?
©2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal
College of Surgeons in Ireland. Published by Elsevier Ltd. This is an open access article under
the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).
*Vascular Research Group, Division of Cardiovascular Sciences, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE27LX,
United Kingdom. Tel.: þ44 116 2523252; fax: þ44 116 2523179.
E-mail addresses: ross.naylor@uhl-tr.nhs.uk,arnaylor@hotmail.com.
Available online at www.sciencedirect.com
ScienceDirect
The Surgeon, Journal of the Royal Colleges
of Surgeons of Edinburgh and Ireland
www.thesurgeon.net
the surgeon xxx (2014) 1e10
Please cite this article in press as: Naylor AR, Why is the management of asymptomatic carotid disease so controversial?, The
Surgeon (2014), http://dx.doi.org/10.1016/j.surge.2014.08.004
http://dx.doi.org/10.1016/j.surge.2014.08.004
1479-666X/©2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by
Elsevier Ltd. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).
“Medicine's much hailed ability to help the sick is fast being
challenged by its propensity to harm the healthy”
Moynihan, Doust and Henry
1
Background statistics
What should one do with an incidental finding that might
predispose towards a fatal or disabling stroke? Stroke is the
third leading cause of death in the Western world and the
principle cause of permanent neurological disability. In the
United States, 600,000 first-ever strokes occur each year
(150,000 in the UK) and >140,000 Americans will die each year
following their stroke (50,000 in the UK).
2,3
In Europe; stroke is
responsible for 1.1 million deaths each year, making it the
second commonest cause of death
4
and more than half of all
stroke survivors remain dependent on others for everyday
activities.
5
In 2008, the total cost of stroke in the USA was $34
billion, while the cost of treating stroke between 2005 and 2050
in the USA is predicted to increase to $2 trillion.
6
Stroke costs
health providers in the European Union over 38 billion Euros
each year.
4
Stroke is, therefore, a major cause of death and disability,
as well as a huge drain on resources. Surely statistics such as
these demand a more aggressive approach towards preven-
tion, including the provision of carotid endarterectomy (CEA)
or carotid artery stenting (CAS) for the treatment of asymp-
tomatic carotid disease?
Stroke due to carotid disease
It is sometimes all too easy to focus attention on carotid dis-
ease as being a key cause of stroke, whilst forgetting that there
are many other important causes as well. Out of the next 100
strokes destined to occur in a typically Western community,
approximately 15% will be haemorrhagic (ie 15 of the 100),
while 85% will be ischaemic (85/100). About 20% of the 85
ischaemic strokes will affect the vertebrobasilar territory (17/
100), and 80% will affect the carotid territory (68/100). Of the 68
carotid territory, ischaemic strokes; about 50% (34/100) will
follow thromboembolism from the extracranial internal ca-
rotid artery (ICA); while 25% (17/100) will be due to small vessel
intracranial disease (lacunar stroke); 20% (14/100) will be car-
dioembolic and 5% (3/100) will have miscellaneous/rare
aetiologies.
3
Accordingly, about 34% of all strokes will follow ICA
thromboembolism. However, about two-thirds of these pa-
tients (about 20 of the next 100 strokes destined to happen)
will not have a ‘surgical’ICA stenosis >50%, leaving approxi-
mately 14 of the next 100 strokes being due to thromboem-
bolism from a previously asymptomatic (50e99%) ICA
stenosis. However, 20% of these patients (3/100) will suffer a
warning TIA prior to their stroke. This, therefore, leaves about
11 of the next 100 patients whose stroke was destined to be
due to thromboembolism from a previously (unheralded)
asymptomatic stenosis >50%.
If one now extrapolates these data into national practice;
this means that for the UK (with a population of 64 million
7
),
approximately 16,500 of the 150,000 new strokes happening
each year will follow thromboembolism from a previously
asymptomatic, significant ICA stenosis. In the USA (with a
population of 317 million
8
), 66,000 of 600,000 first-ever strokes
will follow thromboembolism from a previously asymptom-
atic, significant ICA stenosis. These then are the target cohorts
for invasive treatment (ie about 11% of all strokes overall) who
form the subject of the current debate. While 66,000 patients
with potentially preventable strokes sounds quite a large
number, it represents 0.02% of the entire US population and
only 0.07% of the 98 million US citizens currently aged over 50
years.
7
Randomised trials in asymptomatic patients
Following the introduction of CEA in 1954 for the prevention of
stroke in symptomatic patients,
9
an increasing proportion of
carotid interventions were undertaken in neurologically
asymptomatic patients (especially in the USA). However,
while some prominent surgeons were advocates of inter-
vening in asymptomatic patients,
10
this was not a universally
held opinion, especially amongst Neurologists. Throughout
the 1980s-1990s, the controversy deepened, until two land-
mark randomised trials (the Asymptomatic Carotid Athero-
sclerosis Study (ACAS) and the Asymptomatic Carotid Surgery
Trial (ACST) published in 1995 and 2004 respectively.
11,12
The vox populi interpretation of ACAS and ACST was that
CEA conferred a 50% relative risk reduction in the 5-year risk
of stroke from about 12% down to about 6%, with ACST
showing no evidence of benefit for CEA in patients aged >75
years.
12
ACAS observed no reduction in the five-year rate of
disabling stroke, while ACST (a much bigger trial) observed a
43% relative risk reduction in the five-year risk of disabling
stroke from 6.1% (BMT) down to 3.5% with CEA.
12
ACST is
the only trial to have published 10-year data
13
and showed
that immediate CEA conferred a 4.6% absolute risk reduc-
tion compared with medical therapy. This equates to 46
strokes being prevented at 10 years per 1000 operations (ie
about 95% of all of the CEA procedures were ultimately
unnecessary).
International guidelines
Despite having published their data 20 years ago (ACAS) and
10 years ago (ACST), both remain the cornerstones of every
contemporary international guideline of practice. In 2011, the
American Heart Association (AHA) published its updated
guidelines regarding the role of CEA and CAS in asymptomatic
patients.
14
They recommended that all patients with an
asymptomatic carotid stenosis should be screened for treat-
able risk factors, with the institution of appropriate lifestyle
changes and best medical therapy (BMT) (Class I, Level C). The
AHA advised that CEA might be considered in highly selected,
‘average risk’patients with 70e99% stenoses, provided the
procedural risk was <3% (Class IIa, Level B). In addition, the
2011 AHA guidelines were the first to suggest that CAS might
now be an alternative to CEA in highly selected, ‘average risk’
patients (Class IIb, Level B). The AHA concluded that the
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usefulness of CAS (as an alternative to CEA) in ‘high risk for
CEA’patients was uncertain (Class IIb, Level B).
14
AHA guidelines and contemporary practice
AHA Guidelines exert considerable influence around the
world. However, despite level I evidence supporting CEA,
there is actually surprisingly little consensus (in the interna-
tional community) regarding how best to treat asymptomatic
patients in the modern era.
This lack of consensus is reflected in the recommendations
of five other international guidelines that also published in
2011.
15e19
The ‘14-Society’Guidelines (prepared by a North
American multi-disciplinary guideline committee) published
recommendations that were very similar to the AHA.
15
By
contrast (but based upon the same literature base), the
Australia and New Zealand Guidelines advised that CEA
(alone) should be considered in highly selected, ‘average risk’
patients (Class I, Level A) and advised against any role for CAS.
They also recommended that BMT was the preferred option in
‘high-risk for CEA’patients.
16
NICE advised that CEA should be considered in highly
selected patients, but recognised that it was appropriate to
offer CAS within ongoing randomised trials. NICE provided no
guidance regarding the management of ‘high-risk for CEA’
patients.
17
The European Society of Cardiology (ESC) recom-
mended CEA for highly selected patients with 70e99% steno-
ses (Class IIa, Level A), but advised that it was reasonable to
offer CAS within high-volume centres who had audited pro-
cedural risks <3% (Class IIb, Level B).
18
Finally, the Society of
Vascular Surgery (who were partners in the 14-Society
Guidelines), recommended that only CEA should be consid-
ered in ‘average risk’patients (Class I, Level A) and that
medical therapy (but not CAS) was the preferred treatment for
‘high risk for CEA’asymptomatic patients.
19
This lack of consensus is reflected in wide variations in
worldwide practice. In the USA, 90% of revascularisations are
currently performed in asymptomatic patients, equating to
>120,000 CEA/CAS procedures each year.
20
At the other
extreme, no interventions were performed in asymptomatic
patients in a recent audit of practice from Denmark.
21
In the
UK, Finland, Sweden and Norway, the proportion of asymp-
tomatic patients undergoing CEA/CAS is 15e20%, increasing
to 33% for Australia, 40% for Hungary and Switzerland and
almost 70% in Italy.
21
At first sight, it would appear that some of the disagree-
ment relates to the role (or lack of) for CAS in some of the
guidelines, raising the inevitable question as to whether this
reflected inter-disciplinary ‘turf-wars’, rather than evidence.
However, focussing too much attention on the CAS debate
only serves to divert attention away from more deep-seated
concerns regarding the contemporary management of
asymptomatic carotid disease, most notably the emergence of
an expanded role for BMT. This is reflected in a recent NEJM
audit where 4669 respondents were asked to indicate how
they would manage a 67-year old non-smoking male with
hypertension, hyperlipidaemia and an asymptomatic 75% ICA
stenosis.
22
Overall; 49% of respondents recommended BMT,
compared with 31% for CEA and 20% for CAS. Interestingly,
there was an identical pattern of responses from the USA
where 47% recommended BMT, 36% preferred CEA, whilst 17%
recommended CAS.
The CREST trial
23
was singularly responsible for the AHA,
14-Society and ESC Guidelines advising that CAS might be an
alternative to CEA in highly selected patients. This was
despite the fact that CREST only randomised asymptomatic
patients in the latter half of the trial, because recruitment of
symptomatic patients (its original inclusion cohort) was flag-
ging. More important, CREST was never powered to determine
whether CEA or CAS was safer/preferable in asymptomatic
patients.
24
The updated AHA/14 Society guidelines invariably trig-
gered a request to the US Medicare and Medicaid Services that
they should now consider reimbursement for CAS in ‘average
risk’asymptomatic patients.
25
If successful, this would have
precipitated a major increase in the number of carotid
revascularisations performed each year in the USA.
26
How-
ever, a Technology Assessment, commissioned by the Centres
for Medicare and Medicaid Services,
27
concluded that despite
the AHA/14-Society guidelines being convinced that the evi-
dence supported an ‘alternative’role for CAS in asymptomatic
patients, the report's authors concluded that “the current state
of evidence was neither sufficiently robust for CAS,or applicable to
current clinical practice (CEA) to determine the optimal management
of patients with asymptomatic carotid disease”.
A Medicare Medicaid Expert Panel convened in January
2012
25
to consider all the available evidence. In response to the
question: “How confident are you that there is adequate evidence to
determine whether or not CAS or CEA or BMT alone is the favoured
strategy to decrease stroke or death in the average risk asymptom-
atic Medicare population”, the Expert Panel scored a mean of 1/5
for CEA; 1/5 for CAS and 4/5 for BMT (where 1/5 ¼low confi-
dence, 3 ¼intermediate confidence and 5/5 ¼high confi-
dence). The single biggest reason for the lack of confidence in
advocating confident roles for CEA and CAS, whilst according
a much higher confidence for BMT, was a growing awareness
that the annual risk of stroke in medically treated patients
with significant carotid stenoses appeared to be diminishing,
attributed to improvements in modern BMT (see later) that
were not available to patients when ACAS and ACST were
recruiting in the 1990s.
So; why the lack of consensus?
The reasons for the worldwide lack of consensus are multi-
factorial and are summarised in Table 1.
(1) current international guidelines are based on Level I
evidence
ACAS and ACST remain the two most influential rando-
mised trials comparing BMT with CEA in average risk,
asymptomatic patients. Both demonstrated a (small), but
significant benefit favouring CEA and advocates of interven-
tion argue that until new randomised trials are undertaken,
international guidelines of practice should not change. As the
AHA and NICE only use randomised trial evidence to deter-
mine practice guidelines, it is hard, therefore, to see how their
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recommendations can change. To paraphrase Beckman
28
:
“there is currently no level I evidence favouring best medical therapy
in asymptomatic patients”. Critics argue that the data from
ACAS and ACST are too historical and that there is now
compelling evidence that the annual risk of stroke on modern
BMT is diminishing, to the extent that CEA (CAS) might now
confer little or no benefit.
29
This controversy is reviewed in
greater detail later.
Two randomised trials (ACT-1 and ACST-2) are currently
recruiting patients and cannot include a medical limb. Their
methodology was conceived long before the current debate
regarding modern BMT reached its current intensity.
30
How-
ever, two multi-centre, contemporary randomised trials
comparing CAS with CEA in asymptomatic patients do plan to
include a third limb for evaluating the role of ‘modern’BMT
using the methodology of ‘two trials within one trial’
(ie CEA þBMT vs BMT, or CAS þBMT vs BMT). SPACE-2
has already started and will recruit 1636 patients into each
of its subtrials.
31
CREST-2 has not started recruiting, but
plans to randomise 1240 patients into each of the two sub-
studies.
32
Whilst the inclusion of a medical limb will certainly inform
the debate, there are persisting concerns regarding power. In
Raman's recent Technology Assessment, a meta-analysis
suggested that each limb of a study comparing intervention
with medical therapy would need 3000 participants in order to
have an 80% power of demonstrating the superiority of
revascularisation over BMT.
27
Unfortunately, SPACE-2 and
CREST-2 plan to recruit less than half of this number. Second;
in both ACAS and ACST, there was no association between
increasing stenosis severity and late stroke risk (ie stratifying
patients based upon stenosis severity cannot identify a ‘high
risk for stroke’subgroup within the medically treated cohort).
For this to be achieved, SPACE-2/CREST-2 will have to include
other imaging strategies in order to identify higher risk sub-
groups.
30
To date, there is no evidence that either trial has
sufficient funding to achieve this goal.
(2) 80% of strokes are not preceded by a TIA. Strokes due to
a carotid stenosis harboured a treatable asymptomatic
lesion prior to the event
This is, of course, perfectly true and is frequently cited in
the rationale for advocating a more aggressive approach to
prophylactic carotid revascularisation. Whilst 600,000 new
strokes occur each year in the USA, only about 11% (66,000)
will occur in patients who suffer an unheralded stroke sec-
ondary to thrombo-embolism from a previously asymptom-
atic ICA stenosis. However, what is often not considered is
that while disease progression has been reported to be asso-
ciated with TIA or stroke, in at least 50% of cases this
happened at the time of the event, rather than being evident
before the stroke. Upon review, it is not uncommon to find
that the ultrasound surveillance scan immediately preceding
the stroke showed a ‘non-surgical’stenosis (<50%), which
then became more acutely severe around the time of plaque
disruption and overlying thrombus formation.
33
In effect, it
does not necessarily follow that all ‘previously asymptomatic’
individuals had a ‘surgical stenosis’at the ultrasound scan
that preceded their stroke (ie when they could have been
referred for treatment).
In addition, even if it were possible to identify and then
treat all patients with asymptomatic stenoses by CEA (or CAS),
it is a salutary fact that about 95% of all strokes would still
occur. This is because about 90% of all strokes have an alter-
native cause (see earlier). ACAS and ACST showed that CEA
reduced the 5-year risk of stroke by about 50%, so that only
half of the 11% of strokes due to a previously asymptomatic
stenosis could ever have been prevented (ie about 5% overall),
leaving the other 95% of all strokes destined to occur. How-
ever, given the logistics of actually finding these patients, it is
likely that an aggressive policy of screening and offering CEA/
CAS to asymptomatic patients could only ever prevent about
1e2% of all strokes.
34
It should also be borne in mind that up to
half of all strokes that occur ipsilateral to a previously
Table 1 eWhat are the controversies that contribute towards the current lack of consensus in the management of
asymptomatic carotid disease?.
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asymptomatic stenosis are not actually due to embolisation
from the stenosis itself, but are lacunar or cardioembolic in
origin.
35
If, however, it became possible to identify a smaller ‘high-
risk for stroke’cohort of patients with asymptomatic carotid
stenoses, it would be perfectly reasonable to actively target
these patients for aggressive BMT and CEA/CAS. Unfortu-
nately (as will be seen) we have no externally validated means
of achieving this goal.
30
(3) screening could identify patients with significant
asymptomatic stenoses, thereby enabling early in-
terventions to prevent avoidable stroke
Despite there being no official recommendation supporting
carotid screening in the USA, there has been a 27% increase in
non-invasive carotid imaging in Medicare patients between
2001e6,
36
suggesting that some form of ‘unofficial screening’
is taking place. The US Preventive Services Taskforce
(USPSTF), the AHA, the 14-Society and the Society for Vascular
Surgery (SVS) advise against screening for carotid disease in
the general population, although the SVS does support selec-
tive screening in patients with vascular risk factors.
14,15,19,37
By contrast, Life Line Screening
®
, a private screening com-
pany, advises that everyone aged over 50 years (or aged >40
years with risk factors) should undergo annual carotid
screening.
38
According to Thapar, there are five reasons for undertaking
screening for the presence of asymptomatic carotid disease: (i)
to select patients for revascularisation; (ii) to monitor risk
factor control and medical therapy; (iii) to quantify ipsilateral
stroke rates whilst on BMT; (iv) to validate new technologies
for identifying the vulnerable plaque and (v) for randomising
patients within trials.
39
The USPSTF has just updated its 2007
recommendation and concluded that; “there are still no
eligible studies that provide direct evidence that screening for
ACS reduces fatal or non-fatal stroke”and they continue to
recommend against routine and selective carotid screening.
37
Somewhat controversial was the USPSTF evaluation of the
role of Duplex ultrasound as a potential screening tool for
identifying patients with significant, asymptomatic carotid
disease.
37
The USPSTF observed that the accuracy of ultra-
sound varies considerably (especially in inexperienced hands)
and that its indiscriminate use in a low prevalence population
could result in a large number of false positives. USPSTF cited
an example where the screening of 100,000 adults with an
asymptomatic stenosis prevalence of 1% would yield 893 true
positives, but 7920 false positives. Even if all the patients with
false positive tests underwent MRA corroboration, 792 pa-
tients with false positive stenoses might still be considered
candidates for CEA/CAS (ie almost as many as the 893 true
positives).
37
Some, like the SVS, have advocated carotid screening in
selected cohorts where the prevalence of a 50e99% stenosis is
expected to be higher. For example, the prevalence of finding a
50e99% stenosis in patients with peripheral arterial disease is
about 25%, compared to 15% in patients with ischaemic heart
disease and 12% in patients with an aortic aneurysm.
40
At first
sight, therefore, it might seem appropriate to perform a ca-
rotid scan in claudicants in order to optimise both yield and
resource utilisation. However, Thapar has calculated that
screening all 60-year old claudicants in the UK with a ‘one off’
carotid Duplex scan in the outpatient clinic would cost about
£17 million. If all patients with a 70e99% stenosis then un-
derwent CEA, this would prevent about 230 strokes annually,
which represents only 0.2% of the annual UK stroke burden.
40
In practice, 143 claudicants would need to undergo a carotid
scan in order to identify 20 surgical candidates with a 70e99%
stenosis in order to prevent 1 stroke at 10 years. This process
would cost £76,000 per stroke prevented
40
and is neither
clinically effective nor cost-effective.
An alternative approach to evaluating the impact of
asymptomatic carotid stenosis (relative to other risk factors) is
to use the Population Attributable Risk (PAR). In an editorial
accompanying the 2014 USPSTF recommendations on carotid
screening, Goldstein reported that the PAR for asymptomatic
carotid stenosis was only about 0.7%.
41
This statistical asso-
ciation is tiny (by comparison) with a PAR of >95% for hyper-
tension, 12e14% for cigarette smoking and 9% for
hyperlipidaemia. Goldstein concluded that the prevalence of
an asymptomatic carotid stenosis >70% would need to be
about 14 times higher before the PAR was similar to that of
hyperlipidaemia.
41
The main reason why routine/selective carotid screening
has not been recommended by the USPSTF is a perception
that too many (otherwise low risk) people will undergo
unnecessary and/or possibly injurious interventions, with
relatively little prospect of gaining benefit in terms of stroke
prevention. For example; the 10-year ACST data suggest
that only 46 strokes would be prevented at 10 years for
every 1000 CEAs performed (see earlier). This therefore
means that 95% of all patients underwent an ultimately
unnecessary procedure.
Accordingly, the vast majority of patients with an asymp-
tomatic carotid stenosis will not suffer a fatal or disabling
stroke. In the SMART study, the annual risk of myocardial
infarction in patients with an asymptomatic 50e99% carotid
stenosis was almost five times higher than the annual risk of
suffering a stroke (3.6%pa for MI vs 0.8%pa for stroke).
42
If it
were possible to develop imaging algorithms for identifying
smaller cohorts of ‘high-risk for stroke’asymptomatic pa-
tients, in whom to target aggressive BMT and CEA/CAS, it
would then become more reasonable to offer high quality
medical therapy and risk factor control to the remaining pa-
tients (ie the majority) who face a lower risk of stroke in the
long-term, with the added benefit of reducing their long-term
cardiac risk as well. Until this paradigm shift in thinking
happens, it is unlikely that any official body will recommend
routine or selective carotid screening.
(4) The AHA already recognises that only ‘highly selected’
asymptomatic patients should undergo CEA or CAS
Virtually every AHA guideline since 1995 has advised that
only ‘highly selected’patients should undergo CEA. Unfortu-
nately, the AHA has never specifically defined what this term
means and there is widespread scepticism as to whether
anyone really pays any attention to this caveat. In the 2011
updated recommendations, the AHA advised clinicians that;
“the selection of asymptomatic patients for carotid revascularization
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should be guided by an assessment of comorbid conditions and life
expectancy,as well as other individual factors, and should include a
thorough discussion of the risks and benefits of the procedure with an
understanding of patient preferences”(Class I;Level of Evidence
C).
14
This recommendation remains steeped in non-specific
caveats that are really of little help to the practising clini-
cian. By contrast, the USPSTF concluded that there was no
current validated way of identifying ‘high-risk for stroke’pa-
tients and no externally validated or reliable risk stratification
tools for distinguishing people who were at a greater or lesser
risk of suffering a stroke if treated medically.
37
As a consequence, the practising clinician has no objective
way of advising patients whether they are more or less likely
to suffer a stroke (except beyond advising that patients aged
>75 years gain no significant benefit from CEA
12
) and it is
difficult to see how ‘patient preferences’can be appropriately
‘informed’during the consent process. Thus, while authors
continue to advocate ‘individualized approaches to manage-
ment’, this often simply means that the patient is expected to
live 5 years.
43
It has also been observed that 50% of CAS pro-
cedures undertaken by Cardiologists in Medicare beneficiaries
in the USA were undertaken at the same time as a cardiac
catheterization, ie patients underwent carotid and coronary
angiograms simultaneously. The authors of this report
concluded that; “this raised the possibility that the routine finding
of a significant carotid stenosis by Cardiologists may have influenced
patient selection”.
44
Hardly a ringing endorsement of the AHA's
recommendation about treating ‘highly selected’patients!
Finally, in a recent review of the American College of Sur-
geons National Quality Improvement Programme, 12,631
neurologically asymptomatic patients underwent CEA. How-
ever (and notwithstanding AHA advice dating back to 1995
that only highly selected patients should undergo CEA), 20%
had significant life-limiting conditions that compromised
their chances of living five years.
45
Is it surprising, therefore,
that Stroke Physicians and Neurologists remain extremely
sceptical about the ability (willingness) of Surgeons and In-
terventionists to identify and treat ‘highly selected’patients?
(5) The risks of CEA and CAS are getting lower and this will
make any interventions more effective in the future.
This is a regularly quoted reason for justifying CEA and CAS
in asymptomatic patients in the current era. The rationale is
that if the procedural risks following CEA/CAS could be
reduced to almost zero, surely this would not harm patients
and would justify large-scale interventions?
Centres who wished to randomise patients within ACAS
and ACST had to submit a track record detailing their per-
formance before they were accepted into the trial. In the case
of ACAS, 40% of surgeon applicants were rejected.
46
This
inevitably led to concerns that the trial results might not be
generalisable into routine clinical practice. After ACAS re-
ported that the death/stroke rate after CEA was a highly
commendable 2.3%,
11
audits were undertaken to see whether
these excellent outcomes were reproduced in ‘the real world’.
In a review of 46 published series with Neurologist adjudicated
outcomes, the mortality rate was ten times higher (1.11%)
compared with the 0.14% risk reported in ACAS. Similarly, in 8
published series, the death/stroke rate after CEA was 4.5%,
compared to the 2.3% in ACAS.
47
This and several multi-state
audits in the USA have consistently shown that ‘real-world’
practice rarely mimics that seen in RCTs.
48,49
More recently, it has been claimed that the risks following
CEA and CAS have reduced,
50
leading to claims that this will
greatly enhance the overall benefit of intervening (ie facili-
tating greater stroke prevention).
34,52
Unfortunately, however
attractive this hypothesis might superficially seem, it is un-
likely to make any material difference to overall patient benefit.
Table 2 shows a reanalysis of the 5 and 10-year data from ACAS
and ACST. Modelling the 2.3% procedural risk observed in
ACAS, CEA prevented 59 strokes at 5 years per 1000 operations
(ie 941 (94%) underwent an ultimately unnecessary procedure).
If the ACAS data are now modelled for a 0% procedural risk, the
number of strokes prevented per 1000 operations increases to
82, but this still means that 918 patients (92%) underwent an
ultimately unnecessary intervention.
32,49
Exactly the same
principle applies to the five and 10-year ACST data (Table 2).
Modelling for a 0% procedural risk in ACST would mean that 74
strokes would now be prevented at 10 years per 1000 CEAs,
meaning that 93% were unnecessary).
34,52
One is always pleased to acknowledge evidence of re-
ductions in procedural risk. Unfortunately, this will do little to
reduce the proportion of unnecessary interventions in
asymptomatic patients, which currently costs US Health
Providers about $2 billion each year.
52
(6) The apparent decline in stroke risk on medical therapy
is based upon flawed data
This is one of the most contentious and controversial is-
sues in the current debate about the optimal management of
patients with asymptomatic carotid disease. A number of
systematic reviews and meta-analyses have reported a sus-
tained decline in annual rates of stroke in patients with
asymptomatic carotid stenoses treated medically. Abbott has
reported that the annual rate of ipsilateral stroke in patients
with a 50e99% stenosis fell from 2.2% per annum in 1995 to 1%
in 2005, while the annual rate of ‘any stroke’fell from 3.5% to
2.2%.
29
In Raman's meta-regression analysis of 26 published
studies, the rate of ipsilateral stroke was significantly lower in
studies that closed recruitment between 2000 and 2010 (1.13%
stroke rate per annum), compared with 2.38%pa in those
studies that recruited prior to 2000.
27
Interestingly, this temporal decline in the annual rate of
stroke has also coincided with a 30% decline in the rate of
myocardial infarction, attributed to improvements in medical
therapy and better risk factor control.
53
In addition, the po-
tential for ‘modern’BMT to confer greater benefit than was
previously considered possible is exemplified by the decision
to prematurely stop the SAMMPRIS trial.
54
This RCT compared
aggressive BMT (antiplatelet therapy, intensive management
of risk factors and lifestyle modification) versus aggressive
BMT plus stenting of intracranial stenoses. At a median of 32
months, 15% of the medical group versus 23% of the stented
group had suffered a stroke (p¼0.025) and the trial was
stopped. The absolute differences in the primary endpoint
were 7.1% at 1 year, 6.5% at year 2 and 9% at year 3.
Despite the benefit of aggressive BMT in the SAMMPRIS
trial and the declining prevalence of MI with improvements in
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medical therapy, meta-analyses suggesting a parallel decline
in the annual risk of stroke in medically treated patients with
asymptomatic carotid stenoses have been criticised as being
‘flawed’because some of the constituent studies included
patients with ‘sub-surgical’50e70% stenoses that might have
carried a lower risk of stroke in the long-term, thereby con-
founding meaningful interpretation of the data.
51
More specific to this debate, critics have (not unreasonably)
argued that no randomised trial has corroborated this decline
in stroke risk on medical therapy, whilst voicing concerns
regarding patient compliance with medication.
51
In fact,
many of these concerns have already been addressed; it was
just that we had not realised it. Figure 1 shows changing
trends in the annual rates of ipsilateral and ‘any’stroke in
observational and randomised studies reporting annualized
stroke rates in medically treated patients, stratified for year of
publication and severity of the baseline stenosis.
34
As can be
seen, there has been a sustained decline in the annual rate of
stroke in medically treated patients, including those patients
who were randomised to medical therapy within ACST and
ACAS. In addition, the sustained decline in the annual stroke
risk was evident in studies that included less severe stenosis
categories (ie 50e99%), as well as those with more severe
stenoses (ie 70e99%).
Table 3 shows more objective evidence of a progressive
reduction in annualized stroke rates in medically treated
Table 2 eEffect of modelling the procedural risk to 0% on preventing long-term stroke in ACAS and ACST*.
Reproduced with permission from Naylor AR, Sillesen H, Schroeder TV. Clinical and Imaging features associated with an increased risk of early
and late stroke in patients with asymptomatic carotid disease. Eur J Vasc Endovasc Surg (in press).
Fig. 1 eAnnualized rates of stroke in medically treated patients with asymptomatic carotid stenosis stratified for year of
publication and baseline severity of stenosis. A sustained decrease in the annual rates of ipsilateral and any stroke has
occurred over the past two decades. This decline is evident in both randomized and nonrandomized studies and across all
stenosis severities. Reproduced with permission from Naylor,A.R.Time to rethink management strategies in asymptomatic
carotid disease.Nature Reviews Cardiology 2011;9:116e124.
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patients who were randomised within ACAS and ACST.
34,52
Unfortunately, nobody really noticed this at the time of pub-
lication because readers failed to observe that the two trials
were reporting different primary endpoints
52
(ACAS primarily
reported the ipsilateral stroke rate, while ACST reported ‘any
stroke’). In the original 1995 ACAS publication, the five-year
risk of ‘any’stroke in medically treated patients was 17.5%
(ie 3.5% per annum).
11
When ACST reported in 2004,
12
the five-
year risk of ‘any’stroke had already declined to 11.8% (ie 2.4%
pa). When ACST reported its 10-year data in 2010,
13
the five-
year risk of ‘any’stroke for the second five-year period had
declined even further to 7.2% (ie 1.4% pa).
The same phenomenon was also evident in the successive
changes in 5-year prevalences of ipsilateral stroke in medi-
cally treated patients (Table 3). ACAS reported a five-year risk
of ipsilateral stroke of 11.0% (2.2%pa) in medically treated
patients.
11
By 2004, when ACST reported its first five-year
data, the 5-year risk of ipsilateral stroke was 5.3% (1.1%pa).
52
When ACST reported its 10-year data, the rate of ipsilateral
stroke for the second five-year period had now fallen to 3.6%
(ie 0.7%pa).
52
Accordingly, the data from Fig. 1 and Table 3 suggest that
there has been a 60e70% decline in the annual rates of ‘any’
and ‘ipsilateral’stroke in both randomised and non-
randomised studies, irrespective of baseline stenosis severity.
In conclusion
The controversy about how best to manage patients with
asymptomatic carotid disease is not going to go away. Given
that the AHA and other prominent guideline groups still
recommend that CEA (CAS) be considered in ‘highly selected’
patients, it is an inevitable fact of life that surgeons and in-
terventionists will harbour concerns about medico-legal
exposure should they advise against offering an intervention
and that patient then suffers a stroke.
However, the available evidence does suggest that there
has been a decline in the annual risk of stroke in patients
treated medically. This will be proved/disproved in the
ongoing randomised trials, but these will not report for at least
another 5 years. However, even if SPACE-2 and CREST-2 do
corroborate the declining risk of stroke on modern medical
therapy, it is inevitable that a small subgroup of patients
(perhaps 10e20%) will still prove to be ‘high risk for stroke’and
it is important that we have the capacity to identify these
patients and target them with aggressive medical therapy as
well as CEA/CAS. This will, however, require clinicians to
commit to performing a series of studies (either within new
natural history cohorts or within the two ongoing randomised
trials) in order to develop imaging algorithms that can be
validated for identifying these truly high-risk patients. A
number of imaging parameters/algorithms are currently
available for external validation,
55
but there is still no sign that
any of these are to be evaluated within SPACE-2 or CREST-2.
The spectre at the feast……
Notwithstanding the enduring controversy regarding the role
of CEA/CAS in preventing stroke, the situation could become
even more controversial with the publication of studies sug-
gesting an ‘association’between asymptomatic carotid dis-
ease and cognitive decline. A recent systematic review
reported that 9/10 studies involving 763 patients with a >50%
asymptomatic carotid stenosis and 6308 non-carotid stenosis
controls, reported an association between an asymptomatic
carotid stenosis and cognitive impairment.
56
More recently,
an Italian study has reported that patients with severe bilat-
eral (asymptomatic) carotid stenoses may be at risk of devel-
oping cognitive impairment.
57
In both the systematic review
56
and Buratti's paper,
57
it was very unclear whether this was a
causal association (ie secondary to silent embolisation or
hypoperfusion) or (more likely) to the fact that most of the risk
Table 3 eTemporal changes in the 5 year risk of ‘any’and ‘ipsilateral’stroke in medically treated patients randomised
within ACAS and ACST.
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factors associated with carotid stenosis (eg diabetes, smoking,
hypertension) are also risk factors for cognitive decline.
To date, the literature does not support a carotid embolic
role for dementia, though this may not stop some from
advocating a role for CEA/CAS in the future. Purandare
observed spontaneous cerebral emboli in 40% of Alzheimer
patients and 37% of those with vascular dementia, compared
with 15% of age-matched controls.
58
Interestingly, these
emboli were not derived from extracranial carotid stenoses,
which were equally prevalent in dementia and control sub-
jects. In these patients, a venous to arterial shunt (suggestive
of a patent foramen ovale) was demonstrated in 32% of Alz-
heimer patients and 29% of vascular dementia patients. In
addition, the same group has subsequently reported no as-
sociation between spontaneous cerebral embolisation and
cognitive decline in elderly patients without dementia.
59
Conflict of interest
None.
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