Screening for Atherosclerotic Cardiovascular Risk
and Prevention of Heart Attacks and Strokes
Andrew Nicolaides MS, FRCS, FRCSE, PhD (Hon)
Introduction
Cardiovascular disease (CVD) is one of the most common causes of death in the
western world and stroke the most common cause of disability in women. Treatment
is a major financial burden to health services. Effective prevention has now become a
priority. The official aim in the UK is to reduce mortality from heart disease among
men under 75 by 40% (1). Is this possible?
Traditional methods of risk assessment for premature heart attacks and strokes
using conventional risk factors such as smoking, high blood pressure and blood
cholesterol and expressing the result as a 10 year Framingham Risk Score (FRS) or
Procam Risk Score (depending on the equation used) have produced moderate results.
Such methods do identify high risk groups, but if followed up these high risk groups
contain at best only 40% of the events that will occur in the subsequent 10 years. The
rest occur in the low risk groups. Why? We now know that 50% of those who develop
heart attacks and strokes do not have any of the conventional risk factors. Because of
this, epidemiologists and health care providers have been trying to determine whether
relatively simple tests can provide information over and above that obtained by
conventional risk factors and be practical and effective enough to be adopted for
general population screening.
Screening and improved selection of individuals for more effective prevention is
now possible because of the following: (a) preclinical (silent) deposits of cholesterol
in the arteries known as plaques develop slowly over several decades before they
rupture or obstruct an artery becoming clinically manifest, (b) screening methods are
now available for detecting the presence and severity of such plaques and (c) current
prophylaxis with aggressive risk factor modification can reduce morbidity and
mortality from heart attacks and strokes by 50%.
Screening for Preclinical Atherosclerosis
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Three methods are currently available: (a) measurement of ankle brachial index
(ABI), (b) coronary artery calcium scoring (CACS) using multislice CT-scanning
known as Electron Beam Tomography (EBT) and (c) ultrasonic arterial scanning..
Each method provides information that can improve the FRS to a lesser or greater
extent and has its advantages or disadvantages. This is because the information
obtained by each method is related to different characteristics of preclinical
atherosclerosis at different stages in time (earlier or later) in different vascular beds
with different significance and associated costs. This article summarises the efficacy
of each method and associated advantages and disadvantages in an attempt to answer
the questions which method or combination of methods and when should be used, and
most importantly what advice should be given to individuals once the results become
available.
Measurement of ABI
This consists of measurements of ankle and brachial systolic pressures with a handheld “pocket Doppler” and calculating the ratio of ankle pressure over brachial
pressure. This is the oldest and least expensive method. It was introduced in 1969 by
the vascular team at St Mary’s Hospital Medical School as a method of assessing the
severity of lower limb ischaemia and the response to medical or surgical therapy.
Subsequently, it became an epidemiological tool.
A recent meta-analysis has assessed the results of 16 general population cohort
studies (2) involving 24,955 men and 23,339 women. Asymptomatic individuals
without any history of CVD had their ABI measured at baseline and followed up to
detect cardiovascular events and mortality. The 10 year cardiovascular mortality in
men with low (abnormal) ABI (≤ 0.90) was 18.7% and in those with normal ABI
(1,11-1.40) was 4.4% (Hazard ratio [HR] 4.2; 95% CI 3.3 to 5.4). Corresponding
mortalities in women were 12.6% and 4.1%; HR 3.5; 95% CI 2.4 to 5.1). The
sensitivity and specificity of a low ABI (≤ 0.90) for predicting coronary heart disease
were 16.5% and 92.7%, for stroke 16.0% and 92.2% and for cardiovascular mortality
41.0% and 87.9% respectively. It is important to note that a low ABI is found in only
a small number in the younger groups e.g. 1.4% in those less than 50 years, 3.5% in
those 50-54, 12.7% in those 75 years or older and 22.6% in those 80 years or older
(3).
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It can be concluded that the ABI has the advantage of ease of use in a GP practice
by a doctor or a trained nurse in asymptomatic individuals over the age of 70 without
prior history of CVD or older than 50 with one additional CV risk factor (3). It is
inexpensive and takes 10-15 minutes. The finding of a low ABI (≤ 0.90) in an
individual without a prior history of CVD or diabetes is an indication for aggressive
risk factor modification as in patients with established vascular disease. A
disadvantage is its low sensitivity and its low yield in individuals younger than 55
years. This is because a low ABI is the result of advanced lower limb occlusive
arterial disease, albeit still asymptomatic, that occurs in older age groups. This is a
major drawback of ABI because it is particularly in the younger groups (40s and 50s)
when atherosclerosis is at its early stages that prophylaxis is likely to be most
effective.
CACS using multislice CT-scanning
A recent meta-analysis of six prospective studies has demonstrated that coronary
artery calcium score (CACS) obtained by computed tomography (CT) is an
independent predictor of future coronary events (5) i.e. it provides information over
and above that of the FRS. The risk of annual fatal myocardial infarction (MI) for
CACS (Agatson score) less than 100 is low (< 0.4%), for CACS 100-400 it is
moderate (1.3%) and for CACS 400 or higher it is high (2.4%). When compared to
individuals with CACS of zero the corresponding relative risks (RR) and 95% CI are
1.9 (1.3 to 2.8), 4.3 (3.1 to 6.1) and 7.8 (5.8 to 9.8) respectively. Although CACS is a
good predictor of coronary artery disease, it cannot identify those with non-calcific
unstable plaques (5). Also, the finding of a high CACS in the absence of any
significant coronary artery stenosis (> 50%) is common indicating the need to
improve predictive ability. Finally, CACS is related to atherosclerotic disease in the
coronary arteries and does not provide information on stroke risk.
On the basis of the available data the American College of Cardiology Foundation
and American Heart Association have stated in their guidelines (5) that screening is of
limited clinical value in individuals who are at low risk for coronary events i.e. FRS
less than 1.0% per year. However, in individuals with a FRS of 1-2% (10-20% in 10
years) the finding of CACS of 400 or greater would increase the risk to that noted
with diabetes or peripheral arterial disease (31). Thus, clinical decision making could
be altered by CACS measurement in individuals with an intermediate FRS.
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Individuals with a high FRS (≥ 2%) should be treated aggressively according to the
current NCEP III guidelines and do not require additional testing (31). The current
literature does not support the concept that high-risk asymptomatic individuals can be
safely excluded from prophylaxis even if CACS is zero.
A disadvantage of CACS is that it is expensive and the high radiation dose
associated with it does not allow repeated testing. Also, CACS does not provide
information on stroke risk.
Screening with Ultrasound
High resolution ultrasound can provide images of the arterial wall and plaques with
measurements of intima-media thickness (IMT), plaque thickness and plaque area at a
resolution of 0.2 mm. Several studies (3) have indicated that IMT can be used to study
the effect of risk factor modification in large groups and has become a validated
biomarker. However, it is only marginally better than conventional risk factors in
identifying individuals at increased risk. Thus, IMT is not a helpful test for risk
assessment in individuals. However, new ultrasonic arterial wall measurements such
as the presence and thickness of plaques (4-6) and plaque echolucency (6-8) not only
in the carotid but also in the common femoral have been shown to be stronger
predictors of risk with a relative risk (RR) of 3.0 to 5.0.
Two prospective studies have shown that carotid plaque area is a better predictor
of future myocardial infarction than IMT (9-10). In the Tromsø study (9), IMT, total
plaque area and plaque echolucency were measured in 6226 men and women aged 25
to 84 years with no previous MI followed for 6 years. The adjusted RR and 95% CI
between the highest plaque area tertile versus no plaque was 1.56 (1.04 to 2.36) in
men and 3.95 (2.16 to 7.19) in women. The adjusted corresponding RR and 95% CI
for IMT was 1.73 (0.98 to 3.06) in men and 2.86 (1.07 to 7.65) in women. Plaque
echolucency (low collagen content) indicating plaque instability was also associated
with increased risk of MI. In the study performed in Canada (10) carotid plaque areas
from 1686 patients followed for up to 5 years were categorised into 4 quartiles. The
combined 5 year risk of stroke, myocardial infarction and vascular death by quartiles
of plaque area was: 5.6%, 10.7%, 13.9% and 19.5%.
Our own study performed in a subgroup of the British Regional Heart Study (425
men and 375 women) has demonstrated that the presence and number of plaques in
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the carotid and common femoral bifurcations have a stronger association with
prevalence of clinical cardiovascular disease than carotid IMT (5).
In a subsequent ongoing study, 2000 individuals over the age of 40 are being
screened for conventional risk factors, clinical and preclinical cardiovascular disease
and followed-up for 5 years (11). Both carotid and both common femoral bifurcations
are scanned with ultrasound. In the first 762 individuals, evidence of clinical
cardiovascular disease was present in 113 (14.8%). After adjustment for conventional
risk factors the association of total plaque area (TPA) (sum of all plaque areas) with
prevalence of clinical cardiovascular disease was high (Odds Ratio of upper to lower
TPA quintile: 8.38; 95% CI 2.57 to 27.32). TPA greater than 42 mm2 (cut-point
derived from ROC curve analysis) identified 266 (34.9%) of the population that
contained 87/113 (76.9%) of the clinical events (sensitivity: 77%; specificity: 73%;
positive predictive value: 33%; negative predictive value: 94%). Thus, the presence
and size of preclinical plaques in both carotid and both common femoral arteries is
emerging as having a strong association with coronary heart disease and stroke.
Advantages of screening with ultrasound are that it is relatively inexpensive and
devoid of radiation. High resolution portable equipment is now available. A scan can
be performed in 20 minutes. In addition, it can be repeated at 6-monthly intervals or
annually providing information on plaque progression or regression. The availability
of atherosclerotic plaque images provides an incentive to individuals to persevere
with prophylactic therapy. An added benefit of ultrasound is that with the addition of
an extra five minutes, individuals over the age of 65 can be screened for the presence
of abdominal aortic aneurysm as recently recommended by NICE.
A Rational Screening and Prophylactic Practice
a). Individuals with low FRS: should be screened with ultrasound. Absence of plaques
found in 50% of individuals in this low risk group will confirm the low risk and
further follow-up with ultrasound will not be necessary for 3 to 4 years. However, the
presence of plaques found in the other 50% will result in reclassification to a higher
risk and will prompt the clinician to advise not only on risk factor modification if any
modifiable risk factors are present, but also to look for non conventional risk factors
such as elevated homocysteine. Two recent prospective randomised controlled trials
in individuals with known cardiovascular disease have demonstrated that lowering
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homocysteine with vitamin supplements has reduced the risk of ischemic stroke by
25% (12, 13).
b). Individuals with an intermediate FRS: should be initially screened with
ultrasound. Those with plaques are advised to have aggressive risk factor
modification. They are told that plaques should not be allowed to progress and that
regression, which with treatment to target can occur in 28%, is associated with a 50%
reduction in risk (10). They are also advised to have an annual ECG stress test. If
plaques are absent then CACS may be performed. The latter will allow
reclassification to a lower or higher risk group with confidence.
c). Individuals with a high FRS: are advised to have aggressive risk factor
modification according to the current guidelines. Screening with ultrasound in order
to follow plaque progression or regression is optional. This and the associated plaque
images provide a strong incentive to persevere with prophylactic therapy as
compliance can be challenging.
The strategy outlined above uses a combination of conventional risk factors with
ultrasound which is in the forefront of noninvasive, inexpensive imaging modalities
for screening asymptomatic individuals. It should go a long way towards achieving
the government target of reducing heart attacks and strokes by 40% (14) because it
identifies many individuals at increased risk that would be missed by FRS. Setting up
cardiovascular screening services or centres throughout the country should be
seriously considered. The major investment would not be in the equipment, which is
now relatively inexpensive and portable, but in trained staff. Asymptomatic
individuals should be referred to such centres by their doctor or consultant. This will
prevent inappropriate use of the services. The referring doctor will be responsible in
making the decisions on the preventive management after considering the report and
recommendations from the screening centre.
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