Review: Should we screen for asymptomatic coronary artery disease in the community?
Introduction: Coronary artery disease (CAD) is the accumulation of atherosclerotic plaque in the coronary arteries; resulting in limited myocardial perfusion. CAD has high levels of global morbidity and mortality and is well researched. Asymptomatic coronary artery disease (ACAD) is the precursor subclinical state and is inadequately detected and researched. The aim of this article was to cross-examine the current research on ACAD. Emphasis was placed on methods of assessment and screening of ACAD.
Materials and Methods: A review of the literature was completed following a structured protocol; search engines, inclusion and exclusion criteria were defined a priori.
Results: Forty-eight articles met all inclusion criteria and were retrieved for detailed analysis. Outcome-based evidence suggested that cardiovascular disease risk stratification followed by imaging based assessments in low-to-moderate risk candidates were shown to be of clinical value in ACAD. A ‘treat all’ primary preventative approach was shown to be of most benefit; however the social and financial implications of this remain unclear.
Conclusions: Effective management of ACAD is essential to lower the worldwide incidence, morbidity and mortality of CAD. Further outcome-based evidence highlighting the benefits of identification, screening and early primary prevention of ACAD is urgently needed.
Keywords: Asymptomatic coronary artery disease, asymptomatic coronary atherosclerosis, subclinical coronary artery disease, subclinical coronary atherosclerosis, asymptomatic coronary artery disease screening, asymptomatic coronary artery disease investigations, asymptomatic coronary artery disease management
Coronary heart disease is an important health problem
Coronary artery disease (CAD) is well described in the literature [1-3]. CAD and stroke are important health problems, continuing to be the leading causes of morbidity and mortality in the Western World . Indeed, CAD accounts for nearly one-third of all deaths worldwide and is projected to exceed 25 million in 2020 .
Overt CAD is a complex disease , being the result of atherosclerosis occurring within the coronary arteries. As illustrated in Figure 1, atherosclerosis involves a chronic inflammatory response to endothelial injury, whereby lipoproteins and lipids accumulate, monocytes and platelets adhere to the vessel wall, and eventually smooth muscle cell proliferation occurs. Fatty streaks and intermediate lesions are usually asymptomatic and occur in the second and third decades of life, Figure 1i. With time, these lesions can increase in size and can progressively obstruct the coronary arteries; reducing the oxygen-rich blood supply to the active contracting myocardium during periods of increased exertion [7,8], Figure 1ii. The reduced oxygen supply can cause the myocardium to become ischaemic during exertion, resulting in reversible symptomatic CAD, termed ‘stable angina’. From the fourth decade onwards, these lesions can become fibrotic and can acutely rupture, even at rest, resulting in haematoma formation. Acute vessel obstruction can lead to hypoxia-induced myocardial cell death. This can be characterised as partial obstruction termed ‘unstable angina’ or as complete obstruction termed ‘myocardial infarction’ (MI) [9, 10], Figure 1iii.
It is emphasised that atherosclerosis of the coronary arteries is a gradual process and, until the transition phase, the process is clinically silent. This phase of the disease has been termed ‘asymptomatic coronary artery disease’ (ACAD). ACAD always precedes CAD when the underlying pathological process is atherosclerosis.
Approaches to lowering CAD-related morbidity and mortality
The longstanding Framingham Study and the INTERHEART study [11, 12] demonstrated that 90-95% of population-attributable risk of overt cardiovascular disease (CVD) is related to just nine modifiable risk factors; smoking status , apolipoprotein B/apolipoprotein A1 ratio , hypertension, diabetes mellitus status , abdominal obesity , psychosocial factors , daily consumption of fruit and vegetables , regular alcohol intake , and regular physical activity . These factors are widely accepted as the main drivers of CAD [21, 22], and are the likely drivers of subclinical ACAD .
Plaque rupture resulting in thrombosis and acute vessel obstruction in symptomatic CAD has been a topic of research for decades , despite this 40-60% of major obstructive atherosclerotic cardiovascular events (MI, sudden death) occur as de novo events in asymptomatic, clinically well patients . Between 4% and 10% of acute MI’s are seen in patients below the age of 45 years old . Furthermore Chan et al, 2006 posited that up to 96% of young patients (≤45 years old) have at least one antecedent CVD risk factor (most frequently hypertension or hyperlipidaemia), often unidentified and untreated at the time of their first premature CVD event .
Current interventions to lowering CAD-related morbidity and mortality in otherwise asymptomatic individuals are primarily focused on risk factor reduction strategies. This does not involve screening for the disease process itself that may be occurring in asymptomatic individuals. The objective of this review was to evaluate whether implementing a national screening program to detect and manage ACAD would be effective in reducing disease burden and be feasible.
Materials and Methods
A comprehensive literature review was undertaken following a structured protocol . Searches were made using two key search engines; The Cochrane Library and PubMed. Inclusion and exclusion criteria were established in advance of the searches and articles which satisfied the criteria were analysed further.
Articles must be:
1. Published by one or more of the specified search engines when the following medical subject headings (MeSH) terms were entered:
a. ‘Asymptomatic coronary artery disease’
b. ‘Asymptomatic coronary atherosclerosis’
c. ‘Subclinical coronary artery disease’
d. ‘Subclinical coronary atherosclerosis’
e. ‘Asymptomatic coronary artery disease screening’
f. ‘Asymptomatic coronary artery disease investigations’
g. ‘Asymptomatic coronary artery disease management’
2. Relevant to the proposed question
3. Of reasonable standing in the hierarchy of evidence – including:
a. Case report
b. Clinical trial
c. Comparative study
f. Journal article
h. Multicentre study
i. Practice guideline
j. Randomized controlled trial
l. Systematic review
4. Written in English
5. Published between 2000 and 2012
6. Human studies only
1. Articles which did not meet all of the above inclusion criteria were excluded from further analysis.
The search method described above yielded 3381 potentially relevant primary articles from electronic databases. The reference list of each primary article was assessed and a further 10 articles were added to the search results. Following peer review, an additional 2 articles were also included. As a result, the titles and abstracts of 3393 articles were reviewed and 3041 articles were excluded (3034 of the original 3381 primary articles, and 7 of the 12 additional articles). The remaining 352 articles were retrieved for full text screening, of which, 48 articles were selected (43 of the original 3381 primary articles, 3 of the 10 further articles, and both of the articles as recommended by the reviewers).
As such, 48 articles met all of the inclusion criteria and were highlighted (e.g. in bold font) in this review as they provided the best evidence to address the proposed question, Figure 2. Additional citations (n=39) which are relevant to this article but not returned from the literature review are included in the text but are not highlighted in bold font.
((((asymptomatic coronary artery disease) OR subclinical coronary artery disease) OR asymptomatic coronary artery disease screening) OR asymptomatic coronary artery disease investigations) OR asymptomatic coronary artery disease management AND (("2000/01/01"[PDat]: "2012/12/31"[PDat]) AND Humans[Mesh] AND English[lang])
Identification of asymptomatic coronary artery disease
Subclinical ACAD is seldom purposefully identified in the community . Often individuals with possible ACAD are deemed ‘too young’ or ‘too well’ (non-diabetic) and do not exhibit any associated symptoms of CAD . Resultantly these individuals are not routinely candidates for 10-year CVD predicted risk analysis  or pharmacotherapy [31, 32].
However, identification of ACAD does occasionally result as an ‘incidental finding’ of investigations completed for ‘other’ indications (such as during angiography prior to, for example, major non-cardiac or valvular surgery , or during computed tomography, for example, to investigate a pulmonary embolus . Moreover, further investigation of this subset (using imaging based assessments), often demonstrates that significant atherosclerotic burden does exist .
Coronary calcium scoring (CCS) is a popular technique to locate and quantitatively assess coronary artery calcium levels; providing accurate prognostic information and CAD risk scores . Evidence continues to emerge demonstrating the prognostic value of this mode of assessment [22, 37, 38]. In 2008, Raggi et al, theorised that CCS is directly linked to all-cause mortality with increased CCS being associated with decreasing survival across all age deciles . In addition the use of CCS allowed more than 40% of the patients ≥70 years old to be reclassified, by excluding risk (i.e., CCS <400) in those with >3 risk factors. However for the majority who are ‘low-to-moderate-risk’ asymptomatic individuals this technique is not infrequently used to investigate for subclinical CAD.
A second method used in the detection of atherosclerosis in the carotid vessels is B-mode ultrasonography (B-mode USS) . B-mode USS is by comparison quicker, safer and cheaper than CCS . It functions by measuring the intima-media (carotid artery intima-media thickness [CIMT]; the site at which atheroma accumulates in carotid artery stenosis). In 2008, key proponents including Stein et al., presented that the presence of atherosclerotic plaque on B-mode ultrasonography (CIMT >1.5mm or a thickening 50% greater than that of the surrounding wall) in asymptomatic subjects is associated with increased risk of a future cardiovascular event .
Additional modalities which may be of diagnostic and prognostic value in assessing patients for coronary artery disease include computed tomography (CT) , magnetic resonance imaging (MRI)  and CT angiography . However, these modalities are rarely used to identify ACAD in the community, unless the patient presents with symptoms or overt risk factors (such as diabetes).
According to current evidence, CCS does appear to be the modality of choice and has been shown to be superior over B-mode USS/CT angiography/MRI by various studies [7, 37]. Conversely, and of note, CCS does involve high doses of radiation exposure (median 2.3 mSv ) and thus may pose a cancer risk in vulnerable individuals. The frequency and timing of CCS assessment would therefore need to be considered carefully to avoid excess exposure. The prognostic value of B-mode USS (since it is safe and radiation free) must therefore be highlighted [47, 48], especially as a potential first line assessment (of carotid artery calcification) and thus provide insight into the likelihood of coronary artery calcification .
The National Cholesterol Education Program (NCEP) and Adult Treatment Panel III (ATPIII) proposed that the degree of treatment should reflect the extent of clinical disease  and that early treatment of subclinical disease may reduce morbidity and mortality . Evidence suggests that young and old patients have different risk factor profiles, presentations of atherosclerotic disease and prognoses . Cole et al, 2003 postulated that whilst younger patients have a better short-term outcome, the long term prognosis is generally poor and mortality at fifteen years is similar to that of older patients following their first event . Whilst the translatability of evidence based outcomes from symptomatic to asymptomatic disease is not well proven, Rubin et al. argued that the burden of ACAD on the population is significant and that it can be measured by comparison to symptomatic CAD .
Recent outcome-based evidence would suggest that widespread primary prevention (by means of education, lifestyle modifications [including smoking cessation, weight loss and increased activity levels], and ‘treat all’ statin therapies) is of most benefit [1, 55, 56, 57, 58]. However, the paradigm of ‘treat all primary prevention’ has yet to be realised, due to several difficulties in implementation. Treating everyone with medicines to reduce risk (such as widespread statin use , liberal use of anti-hypertensive or anti-coagulant therapies  or the ‘polypill’)  or encouraging lifestyle modifications would be near on impossible to enforce [61, 62].
As outlined by the JUPITER Trial  lipid lowering agents are expensive, would need to be taken life-long, would produce side effects and adverse reactions and would require compliance . A further barrier is the perception that individuals without signs or symptoms of CAD may still need treatment to avoid the disease developing in later life . Most young and healthy individuals would not consider that they are at future risk and that their current activities and lifestyle may lead to symptomatic CAD in later life. Consequently lifestyle, dietary and prescription modification may not be socially, culturally, or economically acceptable for everyone [62, 65].
Viability of a screening program for ACAD
The use of global risk factor assessment estimation tools for CVD, such as the Framingham risk score and the QRISK2 score, provide a valuable tool when assessing those patients who are at high risk of CVD in the future. Whilst global risk factor assessment estimation tools for CVD are highly predictive for risk and are adjusted for a contemporary UK population by factoring in additional variables (social deprivation, current treatment with anti-hypertensive therapies) , they also use assumed values for missing variables, and therefore do not apply specifically to individuals. It would seem that this mismatch in risk stratification and actual risk could be addressed by imaging based modalities – and those demonstrated to be at future CVD risk, could then be investigated further [57, 67, 68]. The level of risk that should trigger imaging based assessments would need to be based on age, gender and degree of risk. CVD risk score analysis can be used to risk stratify patients and direct the selection of the highest-risk patients for treatment to maximise the benefit/cost ratio.
Via the techniques discussed, a national coronary artery screening program could be implemented. This program could be delivered in a non-invasive, acceptable, safe way, at reasonable cost, and provide personalised identification of subclinical disease in the community . The information from these simple investigations could direct the intensity of management and subsequent therapies required for each individual . Such an approach could spare those at very low risk unnecessary treatment, free up resources and finances to treat those with developing risk stratified disease, and reduce the need to “pull out all the stops”, airlifting patients to coronary catheter labs during an acute coronary event .
Several key proponents [21, 71, 72] have reported that subjects with an elevated CCS strongly adhere to statin and aspirin therapy. In fact, just the knowledge of having a positive CCS alone motivated most subjects to partake in risk-reduction behaviours in all domains of lifestyle and medications, adding a secondary benefit to screening asymptomatic individuals with CCS.
In 2008, Karim et al, showed that in a sample of 312 patients considered to be ‘low risk’ (<10% risk of a CAD event in 10 years), 69% had subclinical disease in ≥1 of the 3 vascular beds (coronary, aortic, carotid) . In 2003, Akosah et al, documented similar limitations of the Framingham risk score showing that in a cohort of 222 patients presenting with a premature CAD event, 75% did not qualify for statin therapy under current guidelines. A significant number (60-70%) of primary events occur in ‘low’ or ‘intermediate’ risk categories . A further inherent flaw in the Framingham risk score is that a large proportion of women are categorised as being low risk at a young age (<65 years) despite a high lifetime risk. Thus these women with time go on to develop ACAD and then symptomatic CAD without triggering further global risk factor risk assessment or imaging based assessment.
The SHAPE (Screening for Heart Attack Prevention and Education) Task Force advocated and set out guidelines for the use of imaging to enhance CAD risk assessment . The SHAPE Task Force recommended that all asymptomatic men aged 45-75 years old and women aged 55-75 years old should be screened using a non-invasive imaging modality. As shown in the Dallas Heart Study Cohort, SHAPE guidelines resulted in re-classification of 35-48% of the cohort into the ‘high risk’ stratum . These results again call into question the accuracy and prognostic value of solely using global risk factor assessment estimation tools when investigating CAD.
To assess the cost-effectiveness of such a strategy, in 2009, Diamond and Kaul analysed the cost effectiveness of the NCEP/ATPIII guidelines compared to the SHAPE Task Force guidelines. They showed that the SHAPE algorithm was more cost-effective than the NCEP/ATPIII strategy, but did suggest that unconditional treatment ‘for all’ was the most financially effective method reducing costs associated with emergency care and in-patient stays. It was noted that because the SHAPE strategy increased adherence to preventative therapies, this promoted its cost-effectiveness as a modality for screening, but also as a primary preventative strategy. Cost-benefit analysis of CAD screening programmes has been calculated by various groups [77, 78] and has consistently demonstrated total savings do exist and that that imaging based screening is an affordable option in identifying ‘at risk’ candidates. Such studies recommend further larger trials to calculate the total financial impact of national coronary screening.
Whilst most of the emerging evidence advocates imaging based assessments as a diagnostic and prognostic approach it must be highlighted that CCS and B-mode USS do not provide information on the composition, phenotype, or index of vulnerability of the plaques when they are identified [79, 80]. Questions over the plaques vascularity, remodelling, circulating biomarkers, and risk of rupture would all provide clearer prognostic information if available. The modalities to answer such questions are currently underway in the High Risk Plaque Initiative (The HRP Initiative: http://www.hrpinitiative.com), with much awaited results.
Randomized controlled trial data is limited in demonstrating the efficacy and cost-effectiveness of imaging-based risk assessment in asymptomatic patients with subclinical ACAD. The SHAPE Task Force advocated imaging-based risk assessment  and other recent studies [71, 72] suggested that imaging may improve adherence to and compliance with risk-modifying interventions in a primary preventative setting.
Despite the evidence, global risk factor assessment estimation tools for CVD, such as the Framingham risk score and the QRISK2 score are still inadequately used in the community and therefore those at low-to-moderate risk remain unidentified . Far too routinely, patients are deemed ‘too young’ or ‘too well’ in primary care and do not have a comprehensive CVD 10-year risk score calculated or recorded . It is counterintuitive to prioritise the ‘high risk’ individuals and not assess those at ‘low to moderate’ risk, as on 10-year risk score analysis, 40-60% of those at risk of a major CAD event have been shown to be at low to moderate risk [21, 82].
Collectively, the current evidence recommends the implementation of pragmatic and effective CVD risk stratification and screening strategies in a primary preventative setting in individuals at low-to-moderate risk to reduce the future burden of ACAD on society.
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