Saudi Heart Association Position Statement on Early Detection of Subclinical Atherosclerosis in Clinical Practice

Abstract

Background

Atherosclerosis is the leading underlying cause of cardiovascular disease (CVD), which remains the primary cause of mortality in Saudi Arabia. Saudi patients experience CVD events nearly a decade earlier than their Western counterparts. Given the limitations of traditional risk assessment tools, there is a growing need to detect subclinical atherosclerosis to refine risk stratification and improve primary prevention strategies, particularly in younger and asymptomatic individuals.

Methods

The Saudi Heart Association (SHA) developed this position statement through a structured, multistep process that included a comprehensive literature review and two expert panel meetings. Recommendations were formulated based on current evidence, expert consensus, and consideration of population-specific characteristics and healthcare infrastructure in Saudi Arabia. The final recommendations were reviewed by the expert panel to ensure scientific accuracy and relevance to local practice.

Results and conclusions

The SHA recommends systematic screening for subclinical atherosclerosis in individuals aged 35 years or older with borderline or intermediate 10-year ASCVD risk (5–20 %). Subclinical atherosclerosis can be assessed using validated non-invasive imaging modalities: coronary artery calcium (CAC) scoring, coronary computed tomography angiography (CCTA), carotid ultrasound, or ankle-brachial index (ABI). CAC scoring is the most validated modality, especially in individuals aged ≥40 years, while CCTA offers the advantage of detecting both calcified and non-calcified plaques. Carotid ultrasound can be advantageous in younger adults, and ABI is useful in older adults. Management should be tailored to disease burden: lifestyle modification is advised for individuals with minimal disease, while moderate-to high-intensity statin therapy is recommended in those with mild or moderate to severe subclinical disease. These recommendations aim to support evidence-based integration of subclinical atherosclerosis screening into routine clinical practice, facilitating earlier interventions and reducing the burden of cardiovascular disease in Saudi Arabia.

1. Introduction

Cardiovascular disease (CVD) remains the leading global cause of mortality in both men and women [1,2]. Strikingly, approximately 34 % of cardiovascular deaths occur before the age of 70, reflecting a significant opportunity for intervention through screening, early diagnosis, and primary prevention [2].

In Saudi Arabia, the burden of CVD is both severe and distinct from that seen in Western countries. With high age-standardized CVD mortality rates that exceed the global average [3], CVD currently accounts for almost half of all deaths in Saudi Arabia [4–6], positioning it as the most common cause of mortality nationwide. The demographic structure of the Saudi population, characterized by the younger age at CVD onset and over 60 % of the population being under the age of 35, further exacerbates the burden of CVD [7,8]. It has been well-documented by local registries that patients in Saudi Arabia experience CVD events on average 10 years earlier than their Western counterparts and have a high mortality burden [9–15]. Moreover, projections estimate that close to half a million individuals in Saudi Arabia will be affected by CVD by 2035 [8].

The earlier onset of CVD in Saudi Arabia has broad consequences, including reduced quality of life, loss of workforce productivity, and increased healthcare expenditure due to long-term management of chronic disease [4]. Despite this alarming epidemiology, a significant proportion of premature CVD cases are preventable through lifestyle modification and risk factor management [16,17]. A global pooled analysis of 112 cohort studies found that five modifiable risk factors—non-high density lipoprotein cholesterol, smoking, diabetes, elevated systolic blood pressure, and high body mass index—accounted for more than 50 % of incident CVD cases and over 20 % of all-cause mortality [18]. Encouragingly, sustained declines in CVD mortality over the past four decades in developed countries have been attributed to primary prevention, earlier detection, and aggressive risk factor management, including pharmacologic treatment of dyslipidemia and hypertension [19,20].

Early identification of individuals at highest risk for atherosclerotic cardiovascular disease (ASCVD) allows for tailored preventive interventions [21–23]. This has led to growing interest in the detection of subclinical atherosclerosis, particularly in asymptomatic populations. Atherosclerosis, the underlying pathologic process in most forms of CVD, begins silently and can remain clinically undetected for years before the onset of an acute event [24,25]. Assessing subclinical atherosclerosis provides a window of opportunity for risk re-stratification and timely intervention, especially in those who may be misclassified by traditional risk scores alone [21].

This position statement by the Saudi Heart Association (SHA) aims to offer evidence-based recommendations for the appropriate detection of subclinical atherosclerosis and cardiovascular risk assessment among asymptomatic individuals, with a particular focus on applicability in the Saudi Arabian population.

2. Methods

The SHA consensus statement was formulated following a multistep process designed to ensure a comprehensive, evidence-informed approach to adult cardiovascular risk assessment and subclinical atherosclerosis imaging in Saudi Arabia. First, a comprehensive literature review was conducted to evaluate current evidence regarding the use of noninvasive imaging modalities for the detection of subclinical atherosclerosis and their impact on cardiovascular risk stratification and outcomes. This was followed by two structured expert meetings, convening a multidisciplinary panel of experts to critically review the evidence, identify knowledge gaps, and formulate recommendations based on expert insights. Recommendations were developed keeping in mind practical applicability within the Saudi healthcare context. Finally, the final content of the consensus statement was reviewed and approved by all contributing authors prior to submission to ensure scientific accuracy, methodological integrity, and contextual relevance to Saudi Arabia.

3. The silent threat: definition and burden of subclinical atherosclerosis

Atherosclerosis refers to the formation of atheromatous plaques in arterial walls that thicken and narrow the arterial lumen, resulting in restricted blood flow and potential acute thrombotic events. The development of atherosclerosis occurs in stages, starting with the accumulation of extracellular lipids to form lipid pools, commonly referred to as pathologic intimal thickening [26,27]. Other cellular components such as macrophages, smooth muscle cells, and calcification also play a central role in atherosclerosis. Atherosclerosis is not limited to a single vascular territory and is observed in various arteries, such as the lower extremity, carotid, aorta, and coronary arteries.

Subclinical atherosclerosis can be defined as pathological findings and/or lesions with no inducible ischemic signs or symptoms, regardless of their histological morphology [28–30]. The classification of subclinical atherosclerotic lesions usually follows three categories based on imaging findings [29]:

1. Mildly stenotic (<50 % luminal narrowing), non-ruptured plaques that may include various morphologies such as pathological intimal thickening and fibroatheromas.

2. Healed, asymptomatic thrombotic lesions resulting from prior plaque rupture, plaque erosion, or calcified nodules, leading to less than 50 % luminal narrowing.

3. Asymptomatic high-grade stenoses (50 %–99 %) and chronic total occlusions caused by progressive plaque development without clinical symptoms.

Key observational studies have demonstrated that subclinical atherosclerosis poses a significant burden in asymptomatic individuals, even among those considered to be at low risk of CVD by traditional scores (Table 1). In the PESA (Progression of Early Subclinical Atherosclerosis) study, the prevalence of subclinical atherosclerosis in asymptomatic participants aged 40–54 (mean age 45.8 years) was 63 % and this prevalence rose with increased cardiovascular risk to reach 95 % among participants at the highest risk [30]. A subgroup analysis also found that subclinical atherosclerosis can be detected in approximately half of PESA participants who have no cardiovascular risk factors (mean age 45 years), defined as absence of current smoking and untreated, controlled cardiometabolic parameters [31]. The SCAPIS (Swedish CArdioPulmonary bioImage) study (mean age approx. 57 years) reported an overall prevalence of atherosclerosis of 42.1 %in individuals without known coronary heart disease [32]. It also found that atherosclerosis can be increasingly detected with higher coronary artery calcium (CAC) scores, with 5.5 % of participants with zero CAC scores and all participants with CAC>400 having coronary computed tomography angiography (CCTA)-confirmed atherosclerosis [32]. The CARDIA (Coronary Artery Risk Development in Young Adults) is a long-term study that followed adults aged 18–30 and found that by year 15 (mean age 40), 9.6 % of this cohort had any CAC (>0), with a higher prevalence noted among men (15.1 %) [34]. The burden of subclinical atherosclerosis increases with age, as shown in the BioImage study, where nearly 88 % of participants (mean age 68.9 years) had subclinical disease [33]. Notably, 20 % of participants from the BioImage study with zero CAC still had carotid atherosclerosis.

Table 1.

Prevalence of subclinical atherosclerosis in asymptomatic individuals from key international studies.

Study	Country, year of publication	Population, Sample Size	Mean Age (±SD), years	% Female	Prevalence of subclinical atherosclerosis
PESA [30]	Spain, 2015	Asymptomatic individuals aged 40–54 years N = 4184	45.8 (±4.3)	37	% 63 % (71 % in men, 48 % in women); 58 % in low FRS; 84 % in high FRS.
PESA subgroup analysis [31]	Spain, 2017	Asymptomatic individuals with no cardiovascular risk factors N = 1779	45 (±4.1)	50.3 %	49.7 % (60.8 % in men)
SCAPIS [32]	Sweden, 2015	Individuals without known coronary heart disease N = 25,182	57.4 ± 4.3	50.6 %	42.1 %
BioImage [33]	United States, 2024	Asymptomatic individuals N = 5716	68.9	56.7 %	87.7 %
CARDIA, year 15 [34]	United States, 2007	Young adults (18–30 years) N = 3043	40	54.6 %	9.6 % had any CAC (15 % in men, 5.1 % in women)

Abbreviations: CAC: coronary artery calcium; CARDIA: Coronary Artery Risk Development in Young Adults; FRS: Framingham Risk score; PESA: Progression of Early Subclinical Atherosclerosis; SCAPIS: Swedish CArdioPulmonary bioImage Study; SD: standard deviation.

Large-scale, population-based data on the prevalence of subclinical atherosclerosis in Saudi Arabia are limited. That being said, some studies have reported on subclinical atherosclerosis in various settings. In a cross-sectional study of 207 individuals (mean age 57.1 ± 10.4 years; 48 % women) with normal myocardial perfusion imaging, 55 % had any detectable CAC and 12 % had severe coronary atherosclerosis (CAC score >300) [35]. Another retrospective study with a larger sample (n = 2863; mean age) of asymptomatic adult Saudi patients reported that 27.9 % had detectable CAC (score>0), and 2.5 % have extensive CAC (>400) [36]. The study also confirmed that detection of any CAC and the burden of extensive CAC increases with age, male sex and higher CVD risk [36]. Another study focused exclusively on high-risk asymptomatic Saudi women (n = 918; mean age 55 ± 11 years), finding that women younger than 40 years have a mean CAC score of 4, which surpasses 200 by the age of 50 years. It also reported that the 75th and 90th CAC score percentiles in Saudi women were significantly higher compared to their American counterparts [37]. Diabetes was strongly associated with subclinical atherosclerosis in all of these studies, which confirms earlier reports of high subclinical atherosclerosis prevalence (55 %) in asymptomatic Saudi patients with diabetes mellitus [38].

Despite the existing data gap, it is evident that subclinical atherosclerosis is prevalent among asymptomatic adults in Saudi Arabia, and its burden increases with older age, male sex, and cardiovascular risk. Notably, the differences in subclinical atherosclerosis prevalence and severity in Saudi Arabia compared to Western populations underscores the need for population-specific screening and prevention strategies.

4. Implications of subclinical atherosclerosis for cardiovascular risk stratification and prevention

Decades of research have firmly established the principal risk factors for ASCVD, many of which are modifiable through targeted interventions. These include arterial hypertension, smoking, diabetes mellitus, obesity, and dyslipidemia [39–41]. Non-modifiable risk factors such as a family history of premature CVD, familial hypercholesterolemia, male sex, and advancing age should also be considered in individual risk assessments [42]. Additional risk enhancers and modifiers have been proposed, including various biomarkers such as NT-proBNP levels and cardiac troponins which are also recommended by published and forthcoming SHA position statements for cardiovascular risk assessment of asymptomatic patients [43].

Primary prevention of CVD is predicated on the early identification of individuals at increased risk who are most likely to benefit from targeted interventions. Cardiovascular risk assessment, a cornerstone of prevention guidelines, is conventionally performed using standardized risk calculators. Commonly used tools include the 2008 Framingham Risk Score [44], the European Society of Cardiology's Systematic Coronary Risk Evaluation (SCORE2, SCORE2-Diabetes, and SCORE2 Older Person-Older Persons) [45–47], the American College of cardiology/American Heart Association (ACC/AHA) risk calculator [48].

Despite their widespread use, these tools exhibit several limitations. They focus primarily on traditional risk factors, fail to account for all clinically relevant variables, including sex-specific risks, have restricted applicability across diverse ethnic groups and age ranges, and can result in risk misclassification [49–52]. Notably, most do not incorporate CAC or other direct measures of subclinical atherosclerosis.

Recent models such as the MESA (Multi-Ethnic Study of Atherosclerosis) and Astro-CHARM (Atherosclerotic Cardiovascular Disease Risk Tool with Coronary Artery Calcium) risk assessment tools have integrated CAC scores, demonstrating improved discrimination, risk stratification and predictive accuracy for future cardiovascular events [53,54]. Similarly, the national ASCVD risk assessment calculator developed by the National Heart Center in collaboration with the Saudi Health Council incorporates CAC scoring to enhance ASCVD risk estimation in the Saudi population [55].

Enhanced cardiovascular risk detection is critical given the rising global burden of CVD [56] and the limited improvements in clinical outcomes achieved through treatment of end-stage atherosclerosis, even with the use of potent therapies [57–62]. Importantly, the majority of initial cardiovascular events occur in asymptomatic individuals, many of whom were previously classified as being at low risk of CVD according to conventional scoring systems [63,64]. These observations underscore the need for a paradigm shift from a reactive, late-stage therapeutic model (“too much, too late”), to a preventive strategy that identifies and addresses disease in its earliest stages.

In this context, screening and prevention strategies should incorporate reliable predictors of future atherosclerotic disease. A substantial body of pathological, epidemiological and imaging data confirms that atherosclerosis begins early in life, often long before clinical manifestations occur. Subclinical atherosclerosis is frequently present in apparently healthy individuals without overt cardiovascular symptoms or events, including those categorized as being at low risk of developing CVD [63,64]. Accordingly, subclinical atherosclerosis emerges as a critical early indicator of atherosclerotic burden and a valuable target for primary prevention [21].

Atherosclerotic plaque formation is typically followed by a prolonged subclinical phase during which plaque progression occurs [24,25]. This supports the rationale for early lipid-lowering therapy to stabilize and potentially regress plaque development. The involvement of apolipoprotein B-containing lipoproteins (particularly low-density lipoprotein cholesterol [LDL-C]) and pro-inflammatory stimuli in atherogenesis [41,65] highlights the utility of lipid-lowering agents, especially statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, in reducing plaque volume and enhancing plaque stability [57,58,66–73]. These effects have translated into meaningful reductions in adverse cardiovascular outcomes in both randomized trials and observational studies [74]. Notably, a 1 % reduction of atheroma volume has been associated with a 20 % reduction in the risk of major adverse cardiovascular events (MACE) [75].

Current evidence supports the early detection of subclinical atherosclerosis and the prompt initiation of individualized management strategies. This approach serves a dual purpose: attenuating the progression of atherosclerosis, which is prevalent in the general population, and enabling the potential reversal of non-end-stage disease. Naturally, this approach relies on the accurate detection and diagnosis of subclinical atherosclerosis, which are discussed in the following section.

5. Non-invasive imaging of subclinical atherosclerosis: from detection to prediction

Several non-invasive imaging modalities have been employed for the detection and diagnosis of subclinical atherosclerosis. Among these, four have demonstrated sufficient diagnostic accuracy and prognostic utility to warrant incorporation into clinical practice: CAC scoring, CCTA, carotid ultrasound (carotid intima-media thickness [CIMT] or plaque detection), and the ankle-brachial index (ABI).

5.1. CAC scoring

CAC scoring employs non-contrast computed tomography (CT) to quantify the presence and extent of calcified plaque within the coronary arteries. It most commonly follows the Agatston protocol, which accounts for both the total area and maximal density of coronary calcification [76]. Risk stratification based on CAC scores generally follows the following categories: CAC = 0 (absence of calcification, very low risk), CAC 1–99 (mildly increased risk), CAC 100–299 (moderately increased risk), CAC 300–1000 (moderate to severely increased risk), and CAC >1000 (severely increased risk).

The absence or minimal presence of CAC is a powerful negative risk marker, accurately identifying individuals at very low risk of future CVD development [77–80]. This allows clinicians to “de-risk” individuals who may be considered at-risk by conventional tools and to appropriately defer or withhold pharmacologic interventions that may otherwise be indicated [81].

Importantly, the prognostic value of CAC extends beyond its negative predictive capacity. Multiple large-scale studies have demonstrated that CAC scoring is an independent and incremental predictor of cardiovascular events in asymptomatic individuals, with consistent findings across diverse populations, age groups, and levels of baseline risk (Table 2). The St. Francis Heart Study and Budoff et al. study established that CAC predicts coronary events independently of traditional risk factors and biomarkers, and outperforms the Framingham Risk Score in risk discrimination [85,86]. The Cooper Clinic Cohort demonstrated this association even among individuals with no baseline traditional risk factors, and across a wide age spectrum [84]. The MESA study further reinforced CAC's prognostic value across diverse racial and ethnic populations, among whom increasing CAC scores (e.g., >100, >300) significantly elevated the risk of coronary events [87]. The Rotterdam Study confirmed the utility of CAC in the elderly [83], while the CARDIA study extended this evidence to younger adults (aged 32–46 years), where any detectable CAC was associated with a 3- to 5-fold increased risk of coronary and cardiovascular events [88]. The CAC Consortium, the largest cohort study to date, showed that high CAC scores (≥400) predicted increased long-term all-cause and cardiovascular mortality, even in individuals without conventional risk factors (short-term low risk) [89], highlighting the biological relevance of coronary calcification regardless of clinical presentation.

Table 2.

Selected key studies reporting prognostic role of CAC among asymptomatic patients.

Study	Country, Year of Publication	Population, Sample Size	Mean Age± SD (years), % female	Follow-up duration (years)	Main results
PACC Project [82]	United States, 2005	Active-duty Army personnel aged 40–50 years old with no history of CVD N = 2000	42.9 ± 2.8 in males; 42.8 ± 2.7 in females 17.8 % female	3.0 ± 1.4	CAC was associated with an 11.8-fold increase in risk of incident CHD in men ( p = 0.002). Risk increased incrementally across tertiles of coronary calcium severity.
Rotterdam Study [83]	The Netherlands, 2005	Asymptomatic individuals aged 55 years and older N = 1795	71.1 ± 5.7 57.5 % female	3.3 ± 0.8	CAC independently predicts coronary events. Relative risk of coronary events increases with increasing CAC score. CAC predictive value is consistent among the elderly.
Cooper Clinic Cohort [84]	United States, 2005	Asymptomatic individuals aged 22–96 years with no known CVD N = 10,476	53.8 ± 9.9 36 % female	3.5	CAC associated with coronary events, with increasing rates at higher CAC levels. This association was observed in individuals with no baseline risk factors and across younger (<40 years) and older (>65 years) age groups.
St. Francis Heart Study [85]	United States, 2005	Asymptomatic individuals aged 50–70 years N = 4613	59 ± 6 35 % female	4.3	CAC score predicted coronary events independently of standard risk factors and CRP. CAC score ensured superior coronary event prediction and enhanced risk stratification compared to the Framingham risk index.
Budoff et al. [86]	United States, 2007	Asymptomatic individuals N = 25,253	56 ± 11 46 % female	6 ± 3	CAC score independently and incrementally predicts cardiovascular and mortality risk. The addition of CAC to traditional risk factors improved risk prediction.
MESA [87]	United States, 2008	Asymptomatic individuals aged 45–84 years N = 6722	62.2 ± 10.2 52.8 % female	3.8	CAC was a strong predictor of incident coronary heart disease across different racial and ethnic groups. Adjusted risk of a coronary event increased with increasing CAC score (7.73 when CAC 101–300 and 9.67 when CAC >300) regardless of ethnicity.
CARDIA [88]	United States, 2017	Asymptomatic individuals aged 18–30 years N = 3043	40.3 ± 3.6 54.55 % female	12.	In adults 32–46 years, any CAC was associated with a 5-fold increase in CHD events and a 3-fold increase in CVD events. Risk of cardiac events and mortality increased with CAC score.
CAC Consortium [89]	United States, 2020	Individuals without coronary heart disease, N = 66,636	54 ± 11 33 % female	12.5	High CAC scores (≥400) are associated with increased risk of long-term all-cause mortality, CHD- and CVD-related mortality (compared with CAC = 0). A high CAC score (≥400) is predictive of higher mortality rates in participants without risk factors compared with participants with a high burden of risk factors and CAC = 0.

Abbreviations: CAC: coronary artery calcium; CARDIA: Coronary Artery Risk Development in Young Adults; CHD: coronary heart disease; CRP: C-reactive protein; CVD: cardiovascular disease; MESA: Multi-Ethnic Study of Atherosclerosis; PACC: Prospective Army Coronary Calcium; SD: standard deviation.

Collectively, these findings establish CAC scoring as a robust, non-invasive marker of subclinical atherosclerosis, with particular value in primary prevention for individuals at intermediate or uncertain risk. The consistency across cohorts, age groups, and ethnicities supports its integration into modern risk assessment strategies. Meta-analyses support this approach, demonstrating that both the presence and severity of CAC in apparently healthy asymptomatic individuals are strongly associated with adverse cardiovascular events, such as incident stroke, MACE and all-cause mortality [90,91]. Additional meta-analyses have validated its prognostic role in asymptomatic individuals with diabetes [92]. Moreover, even a minimal CAC burden is associated with higher risk than a CAC score of zero, a relationship consistent in both symptomatic and asymptomatic individuals without overt CVD [91,93].

Notably, the predictive power of CAC is preserved in high-risk groups, including those with a family history of premature coronary disease or diabetes mellitus [94–97]. In diabetic individuals, CAC scoring is especially useful for individualizing lipid-lowering therapy, guiding both intensification and de-escalation, and informing LDL-C target setting [98,99]. However, despite a baseline CAC score of zero, individuals with diabetes remain at increased cardiovascular risk, underscoring the potential need for more frequent rescanning in this population [96].

5.2. CCTA

CCTA allows the non-invasive, contrast-enhanced characterization of coronary plaques through the determination of plaque features (qualitative assessment) as well coronary plaque volume and burden (quantitative measurement) [100–103]. Although more commonly used for the evaluation of symptomatic patients, CCTA can be useful for the identification of plaques, be they calcified or non-calcified, and the determination of overall plaque morphology among carefully selected asymptomatic patients of any age. This offers it a clear advantage compared to CAC, whose use for risk stratification generally follows an age cutoff. Both the SCOT-HEART (Scottish Computed Tomography of the Heart) and PARADIGM (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging) trials demonstrated an improvement in clinical outcomes with the incorporation of CCTA-guided management with standard of care. This was evident in the reductions of 5-year mortality and nonfatal myocardial infarction rates, most likely due to the improved use of preventive therapies and increased plaque regression and overall plaque stability [104–106].

Despite this benefit, there are few indications for CCTA-guided screening of asymptomatic individuals in primary prevention guidelines due to its cost, radiation and contrast exposure in addition to the lack of randomized clinical evidence. Ongoing randomized trials, including the SCOT-HEART2 [107] and RESPECT2 [108] studies, are currently exploring the potential role of CCTA for the primary prevention of CVD in asymptomatic individuals. To date, the FACTOR-64 (For Asymptomatic Obstructive Coronary Artery Disease Among High-Risk Diabetic Patients Using CT Angiography, Following Core 64: A Randomized Control Study) trial is the only published study to randomize individuals with diabetes (type 1 or 2) who were asymptomatic for coronary artery disease (CAD) to CCTA-guided care or standard management [109]. There was no significant difference in mortality or major adverse cardiovascular events (MACE) over 4 years, indicating limited short-term clinical benefit of routine CCTA in this population [109]. To note that event curve divergence at 3 years suggests a potential long-term benefit for this approach that warrants further investigation.

By contrast, a more recent meta-analysis of 10 studies including a total of 5012 asymptomatic individuals with diabetes mellitus demonstrated that CCTA-quantified presence and extent of CAD are independently associated with adverse cardiovascular events, with the risk being highest in obstructive CAD compared to non-obstructive or no CAD [110]. Several observational studies have confirmed the prognostic role of CCTA in asymptomatic individuals (Table 3). In the context of diabetes, an evaluation of 400 asymptomatic diabetic individuals without known CAD found that CCTA measures of disease extent and severity significantly improved risk prediction and reclassification for MACE [111]. Similarly, obstructive CAD on CCTA was associated with worse 6-year outcomes among asymptomatic individuals with type 2 diabetes, while non-obstructive or normal findings predicted excellent prognosis [112]. Outside of the context of diabetes, the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) registry showed that CCTA-based detection of any CAD, even nonobstructive plaques, is predictive of increased all-cause mortality and MACE in asymptomatic individuals [113]. An approximately 2-year follow-up of 6531 asymptomatic individuals with a CAC score of 0 revealed that CCTA identified non-calcified plaques in a substantial proportion; these findings were significantly associated with adverse cardiac events, suggesting that a zero CAC score does not equate to negligible risk. The potential role of CCTA for the improvement of risk stratification and prediction for CVD in asymptomatic individuals has also been noted in other asymptomatic populations, particularly those of younger age, the elderly, and at-risk statin candidates [114–116].

Table 3.

Selected key studies reporting prognostic role of CCTA among asymptomatic patients.

Study	Country, Year of Publication	Population, Sample Size	Mean Age± SD (years, % female	Follow-up duration (years)	Main results
CONFIRM [113]	6 countries (United States, Canada, Germany, Switzerland, Italy, and South Korea), 2012	Individuals undergoing CCTA without chest pain syndrome or history of CAD N = 7590	58 ± 12 39 % female	2	CCTA-defined CAD is an independent predictor of mortality and non-fatal myocardial infarction in asymptomatic patients. The incremental prognostic value of CCTA in individuals without chest pain syndrome was low compared to models incorporating CAC score and Framingham risk.
Lee et al. [130]	Korea, 2013	Asymptomatic individuals with CAC score of 0 N = 6531	49.8 ± 8.9 43.6 % female	2.2 ± 1.2	At least one non-calcified plaque identified with CCTA in individuals with CAC = 0 CCTA-detected non-calcified plaque was associated with adverse cardiac events in asymptomatic subjects with CAC = 0
FACTOR-64 [109]	United States, 2014	Individuals with type 1 or type 2 diabetes without symptoms of CAD N = 900	61.6 ± 8.35 in control group, 61.5 ± 7.94 in CCTA group 47.4 % female in control group, 47.2 % female in CCTA group	4 ± 1.7	CCTA-guided treatment was not associated with a reduction in the composite rate of all-cause mortality, nonfatal myocardial infarction, or unstable angina requiring hospitalization at 4 years compared with control.
Min et al. [111]	2014	Asymptomatic individuals without known CAD N = 400	60.4 ± 9.9 35 % female	2.4 ± 1.1	CCTA measures of CAD extent and severity confer incremental prediction, discrimination and reclassification for identification of diabetic individuals at risk of incident major adverse cardiovascular events.
Kang et al. [112]	Korea, 2016	Asymptomatic individuals with type 2 diabetes N = 591	62.2 ± 8.3 40.4 % female	5.3	CCTA-detected obstructive CAD was associated with worse prognosis (lower 6-year event-free survival). Excellent clinical outcomes were observed in non-obstructive CAD and normal coronary arteries.

Abbreviations: CAC: coronary artery calcium; CCTA: coronary computed tomography angiography; CAD: coronary artery disease; CONFIRM: Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry; FACTOR-64: For Asymptomatic Obstructive Coronary Artery Disease Among High-Risk Diabetic Patients Using CT Angiography, Following Core 64: A Randomized Control Study; SD: Standard Deviation.

Collectively, these studies support the role of CCTA in identifying subclinical atherosclerosis and refining cardiovascular risk stratification, especially in high-risk but asymptomatic individuals that may present without CAC.

5.3. Carotid ultrasound

Carotid ultrasound markers, namely CIMT and plaque presence, have been investigated for the non-invasive cardiovascular risk assessment of diverse populations (Table 4). CIMT involves the measurement of the thickness of common carotid arterial wall via ultrasound, specifically the portion separating the intimal and medial layers. Localized focal thickening of the arterial wall on carotid ultrasound indicates plaque presence, which is another common carotid ultrasound marker.

Table 4.

Selected key studies reporting prognostic role of carotid ultrasound measures among asymptomatic patients.

Study	Country, Year of Publication	Population, Sample Size	Mean Age± SD (years), % female	Follow-up duration (years)	Main results
ARIC [117]	United States, 2011	Individuals aged between 45 and 64 years without overt CVD N = 13, 145	54 ± 5.8 56.8 % female	15.1	CIMT and presence of plaque, either alone or combined, improved CHD risk prediction when added to traditional risk factors (reclassification of approx. 23 % to lower risk group).
MESA [120]	United States, 2015	Asymptomatic individuals aged 45–84 years N = 6779	62.2 ± 10.2 52.8 % female	9.5	Mean CIMT≥75th percentile alone did not predict events. Carotid plaque presence improved prediction of stroke/transient ischemic attacks compared with risk factors. Carotid plaque measures were weaker predictors of incident CVD and CHD compared to CAC presence.
MESA [118]	United States, 2017	Asymptomatic individuals aged 45–84 years N = 6500	62.1 ± 10.2 52.6 %	10.2	CIMT based on normative data incrementally improves the prediction of incident CHD in an ethnically diverse cohort when added to Framingham risk factors and positive CAC score.
IMPROVE [119]	5 countries (Finland, France, Italy, Netherlands, Sweden), 2017	Individuals with at least three vascular risk factors but no overt CVD N = 3703	64.2 52.1 % female	3	Maximum CIMT and mean common CIMT measured in plaque-free areas were independent predictors of vascular events, but only maximum CIMT predicted coronary events. Both offer incremental benefit for risk reclassification when combined with Framingham Risk Factors.
SHFS [121]	United States, 2022	Young (<40 years) asymptomatic American Indians N = 1379	26.6 ± 7.8 57 % female	17.8	Atherosclerotic plaque detected by carotid ultrasound was associated with a higher incidence of CVD and all-cause mortality
ACE 1950 subgroup analysis [122]	Norway, 2023	General population N = 3650	63.9 ± 0.64 48.7 % female	6.4	Carotid plaque score predicted ischemic stroke and MACE. Carotid plaque provides incremental prognostic information to SCORE2 A cutoff score of >3 is associated with 75 % increased risk of ischemic stroke and seems to be suitable to discriminate high-risk subjects.
ARCO [123]	Switzerland, 2024	Seemingly healthy individuals aged 40–65 years N = 2842	50 ± 8 years 38 % female	5.9	Total plaque area determined via carotid ultrasound was associated with increased risk of MACE and ASCVD. Addition of total plaque area into SCORE2 provides incremental prognostic information.
Cardiovascular Risk in Young Finns Study [124]	Finland, 2024	Individuals free of ASCVD aged 24–45 years N = 2641	32 55 % female in those who were free of ASCVD at ultrasound examination, 33 % in those who had ASCVD at ultrasound examination	16	Carotid plaque and high CIMT were independently associated with approx. 2-fold higher risk of incident ASCVD.
BioImage [33]	United States, 2024	Asymptomatic individuals N = 5716	68.9 56.7 % female	12.4	Carotid plaque burden at baseline and carotid plaque burden progression were significant predictors of all-cause mortality.

Abbreviations: ACE 1950: Akershus Cardiac Examination 1950; ARCO: ARteris Cardiovascular Outcome; ARIC: Atherosclerosis Risk in Communities; ASCVD: atherosclerotic cardiovascular disease; CAC: coronary artery calcium; CHD: coronary heart disease; CIMT: carotid intima-media thickness; CVD: cardiovascular disease; IMPROVE: IMT-PRo-gression as Predictors of Vascular Events in a high-risk European population; MACE: major adverse cardiovascular events; MESA: Multi-Ethnic Study of Atherosclerosis; SCORE2: European Society of Cardiology's Systematic Coronary Risk Evaluation 2; SD: standard deviation; SHFS: Strong Heart Family Study.

The addition of CIMT and plaque assessment to regular assessments has been shown in the ARIC (Atherosclerosis Risk in Communities) study to offer added value in terms of risk classification compared to the Framingham risk score alone. For the most part, CIMT and plaque assessment more frequently led to the “de-risking” of individuals previously at intermediate risk to the low-risk category [117]. An analysis of the MESA study also showed CIMT based on normative data modestly improved coronary heart disease (CHD) prediction and cardiovascular risk assessment when combined with Framingham risk scores and CAC presence. Its benefit in terms of prediction of future coronary events was both independent and incremental to other risk factors [118]. The IMPROVE (IMT-PRo-gression as Predictors of Vascular Events in a high-risk European population) study also reported the association between maximum CIMT and cardiovascular events [119]. In contrast, another analysis of the MESA study challenged the predictive value of CIMT alone, noting that only carotid plaque presence—rather than elevated CIMT—enhanced stroke prediction [120]. Among younger cohorts, the SHFS (Strong Heart Family Study) highlighted the prognostic relevance of subclinical plaque in American Indian individuals under 40, linking it to elevated CVD and all-cause mortality [121]. Similarly, the 2023 analysis of the ACE 1950 (Akershus Cardiac Examination 1950) study found carotid plaque scores to be strong predictors of ischemic stroke and MACE, with a cutoff >3 indicating a 75 % increased stroke risk [122]. The ARCO (ARteris Cardiovascular Outcome) study corroborated the additive value of total plaque area to SCORE2 in predicting MACE and ASCVD [123]. The 2024 Cardiovascular Risk in Young Finns Study revealed that both carotid plaque and high CIMT independently conferred a twofold increased risk of ASCVD in individuals aged 24–45 [124]. This is in line with findings in older patient groups; one study showed that both carotid plaque and CIMT can improve the predictive performance and cardiovascular risk assessment of SCORE2 in non-diabetic participants aged 46–68 years [125]. A recent analysis of the BioImage study demonstrated a significant association between baseline carotid plaque burden as well as its progression with all-cause mortality among older asymptomatic individuals [33]. However, it is also important to note that several large cohort studies could not establish any significant association between presence of carotid plaque and increased risk of coronary events [126,127].

Collectively, these findings support the role of carotid plaque—more consistently than CIMT—as a valuable adjunct in cardiovascular risk assessment, particularly when incorporated alongside established clinical risk scores [120,128,129]. However, data consistency remains suboptimal, emphasizing the need for harmonization of plaque definition across studies.

5.4. ABI

ABI is a non-invasive measurement of the ratio of systolic blood pressure at the ankle to systolic blood pressure at the upper arm. With its established cutoff values, ABI is a widely accepted measure of atherosclerosis that is simple and inexpensive while also maintaining accuracy [131]. According to the AHA classification, a normal ABI varies between 1 and 1.4 [132]. ABI values that fall outside of the normal range have been shown to be significant indicators of vascular disease [118,132]. While high ABI values (>1.4) generally indicate noncompressible arteries (vessel stiffening), there is evidence to suggest it might also be associated with CVD and mortality [132].

In contrast, low (≤0.90) ABI has been consistently shown to be a reliable predictor of CVD, adverse cardiac outcomes and mortality [118,131–135] (Table 5). The ABI Collaboration published in 2008 was a landmark meta-analysis that demonstrated the association between ABI<0.9 and increased risk of cardiovascular mortality in both males and females with a mean age of 47 years and above [136]. Moreover, ABI integration with risk prediction through the Framingham Risk Score would have led to the reclassification of up to 36 % of patients, thus emphasizing its role in better cardiovascular risk stratification [136]. The meta-analysis include key studies published in earlier years that had examined ABI in asymptomatic populations, such as the Cardiovascular Health [137], Limburg [138], Edinburgh Artery [139] and Strong Heart [140] studies.

Table 5.

Selected key studies reporting prognostic role of ABI among asymptomatic patients.

Study	Country, Year of Publication	Population, Sample Size	Mean Age± SD (years), % female	Follow-up duration (years)	Main results
MESA [141]	United States, 2011	Multiethnic cohort aged 45–84 without overt CVD N = 6647	62.1 52.6 % female	5.3	Low ABI (<1.0) was associated with incident CVD events. The association was independent of traditional risk factors and other measures of subclinical CVD.
ARIC [142]	United States, 2012	Individuals aged 45–64 years without established CVD N = 11,594 (44 %. 53.8 y)	53.8 ± 5.7 and 56.1 % female in the normal ABI (>0.9) group 55.2 ± 5.9 and 70.4 % female in the abnormal ABI (<0.9) group	10	ABI adjusted for Framingham risk variables was independently associated with subsequent hard CVD events. Integration of ABI into Framingham Risk Score had a statistically insignificant modest improvement in prediction performance.
REGICOR [143]	Spain, 2015	Individuals aged 35–74 years without established CVD N = 5248 (45 %, 53.7 y)	53.7 ± 10.9 54.5 % female	5.9	ABI ≤0.9 was associated with increased risk of CHD and CVD. Incorporation of ABI to Framingham-REGICOR risk function led to an improvement of discrimination and reclassification capacity for CVD, but not CHD.
REGICOR [144]	Spain, 2017	Individuals aged 35 years or older without established CVD N = 5679 (54 %, 55.4 y)	55.4 ± 12.1 and 54.5 % in the normal ABI (0.9–1.39) group 60.7 ± 13.4 and 33.3 % in the abnormal ABI (≥1.4) group	6.2	ABI ≥1.4 was independently associated with all-cause mortality and cardiovascular mortality, but not incidence of cardiovascular events.
ARTPER [145]	Spain, 2018	Individuals aged>49 years with no established CVD. N = 2716	62 ± 7 57 % female	9	ABI<0.9 was associated with a 4-fold increase in the incidence of coronary events. Inclusion of ABI in traditional risk assessment tools improved predictive capacity and led to a net reclassification improvement of 7 %

Abbreviations: ABI: ankle-brachial index; ARIC: Atherosclerosis Risk in Communities; ARTPER: Arteriosclerosis Peripheral Study; CHD: coronary heart disease; CVD: cardiovascular disease; MESA: Multi-Ethnic Study of Atherosclerosis; REGICOR: Registre Gironí del Cor; SD: standard deviation; SHFS: Strong Heart Family Study.

Since then, multiple studies have confirmed the prognostic capacity of ABI in apparently healthy middle-aged or elderly individuals without overt CVD. Among these, the MESA study provided compelling evidence that a low ABI (<1.0) was significantly associated with incident cardiovascular events, independent of traditional risk factors and other measures of subclinical atherosclerosis [141]. Importantly, MESA highlighted the relevance of ABI screening in a diverse, asymptomatic population. Similarly, the ARIC study followed 11,594 individuals aged 45–64 years for a decade, reporting that ABI maintained an independent association with subsequent hard CVD events even after adjusting for Framingham risk variables [142]. However, while ABI modestly improved prediction performance, the enhancement in discrimination was not statistically significant, raising questions about its routine incorporation into the Framingham Risk Score in all populations.

The REGICOR (Registre Gironí del Cor) study, conducted in Spain, further reinforced the role of ABI in risk prediction. The study demonstrated that ABI ≤0.9 was associated with increased risk of both coronary heart disease and broader cardiovascular outcomes. Although the addition of ABI to the Framingham-REGICOR function improved discrimination and reclassification for CVD, it did not enhance CHD prediction [143]. A subsequent REGICOR analysis addressed the prognostic value of high ABI values (≥1.4), showing an independent association with all-cause and cardiovascular mortality, though not with incident CVD events [131]. The ARTPER (Arteriosclerosis Peripheral Study) study followed individuals aged >49 years over nine years and found that ABI <0.9 was linked to a four-fold increase in coronary event incidence [145]. Notably, incorporating ABI into traditional risk models improved predictive capacity, yielding a net reclassification improvement of 7 %, reinforcing its value as a risk stratification tool in primary prevention.

Together, these findings strengthen the evidence base for ABI as a practical and effective tool in cardiovascular risk assessment, particularly in asymptomatic individuals. However, evidence is still lacking on the benefit of ABI as a predictor of subclinical atherosclerosis in younger adults [129]. Moreover, it is important to highlight the nuanced interpretation required for borderline (0.91–0.99), which may reflect subclinical atherosclerosis or arterial stiffening and may carry independent prognostic significance [146–149].

6. Subclinical atherosclerosis assessment in practice: Who benefits and when?

As outlined in the previous section, several modalities have demonstrated significant utility in the detection of subclinical atherosclerosis and the stratification of CVD risk in asymptomatic individuals. While these tools offer considerable advantages, they are also subject to important limitations (Table 6). Comparative studies have aimed to define the most appropriate settings and target populations for the use of these modalities as predictors of subclinical atherosclerosis and future cardiovascular events.

Table 6.

Comparative summary of recommended modalities for subclinical atherosclerosis assessment in asymptomatic individuals.

Modality	Advantages	Disadvantages	Practical Considerations	Risk Prediction/Stratification Performance
CAC (via non-contrast CT)	- Reproducible and easy interpretation through a scoring system - Accessible: widely available, fast and fairly inexpensive - Strong predictive value for CVD events - High negative predictive value for atherosclerosis - Incremental value beyond traditional risk scores	- Radiation exposure (approx. 1 mSv) - No information on non-calcified plaque - Limited evidence in young individuals	Most evidence supports CAC being useful in intermediate-risk adults (>40 years) Not widely used for individuals 40 years unless strong family history	Superior to carotid ultrasound measures (CIMT and plaque burden) and ABI for prediction of incident CVD and ASCVD events [120,150,151].
CCTA	- Visualizes calcified and non-calcified plaque - Directly detects obstructive and non-obstructive CAD - High negative predictive value - Reliable and reproducible	- Higher radiation than CAC (approx. 2–5 mSv) - Requires intravenous contrast - High cost and limited availability - Incidental findings - Limited applicability in obese and arrhythmic individuals	Best reserved for symptomatic individuals or those requiring further evaluation in case of uncertainty	CCTA improves discrimination, plaque detection, risk classification and prediction of adverse events compared to CAC (particularly low CAC scores), and carotid ultrasound measures [111,114,153,154] Limited evidence suggests that the incremental prognostic value of CCTA in individuals without chest pain syndrome is low compared to models incorporating CAC score and Framingham risk [113]
CIMT and plaque burden (via ultrasound)	- Non-invasive - No radiation exposure - Visualizes carotid artery structure - Rapid - Detects early arterial changes	- Operator dependent - Variable protocols which complicates interpretation - Limited accessibility and moderate cost	Can be done at any age but is best for middle-aged to elderly adults	Predicts CVD and ASCVD events but is inferior to CAC and CCTA [120,150,151]. Limited evidence that Carotid plaque burden performs better than CAC score for prediction of mortality [33].
ABI	- Simple, rapid, inexpensive, widely available - No radiation exposure - Simple interpretation	- Limited applicability in certain populations (e.g. high calcification burden, hemodialysis) - Less sensitive to subclinical disease	Best for older adults (>50) individuals	ABI <0.9 predicts CVD and mortality with modest improvement in risk classification, but remains inferior to CAC and CCTA [120,150,151].

Abbreviations: ABI: Ankle-Brachial Index; ASCVD: atherosclerotic cardiovascular disease; CAC: Coronary Artery Calcium Score; CAD: Coronary artery disease; CCTA: Coronary Computed Tomography Angiography; CIMT: Carotid Intima-Media Thickness; CT: Computed Tomography; CVD: Cardiovascular Disease.

Among these tools, the strongest body of evidence supports the use of CAC scoring, which offers high prognostic value for identifying subclinical atherosclerosis and provides incremental predictive power when added to traditional risk models. An analysis from the MESA study identified CAC as the most powerful predictor of risk, demonstrating clear superiority over traditional risk factors and other markers of subclinical atherosclerosis, specifically CIMT, plaque burden and ABI [150]. Several other studies have subsequently confirmed CAC's superior predictive ability for incident CVD and ASCVD events in asymptomatic individuals at low to intermediate risk [120,150,151]. However, most CAC data derive from middle-aged and older adults, and accordingly, current guidelines commonly recommend its use in individuals over 40 years of age with intermediate cardiovascular risk [152].

CCTA demonstrates the highest overall prognostic capacity among available modalities [111,114,153,154], but its broader application is restricted by higher costs, radiation exposure, and the need for intravenous contrast. Notably, CCTA enables quantification of disease burden and treatment response and can detect calcified and non-calcified plaques—including in individuals with CAC = 0 [155]. However, it is more technically demanding and involves greater radiation exposure compared to CAC and other modalities.

CIMT and ABI serve as complementary tools that, when combined with traditional risk factors, enhance risk stratification in certain populations, particularly younger adults (<40 years). Carotid ultrasound measures (CIMT and plaque burden) have been reported to perform comparably to CAC in predicting cerebrovascular events such as stroke and transient ischemic attacks [120]. While carotid ultrasound is generally recommended in some primary prevention settings as an alternative to CAC when it is not feasible or available, recommendations for ABI are more variable due to its limited reclassification value [42,156].

7. Subclinical atherosclerosis: implications for treatment decisions

Beyond diagnostic performance, cost-effectiveness is a critical factor in determining the appropriate modality and target population for subclinical atherosclerosis screening. The EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) randomized trial demonstrated that CAC scanning improved risk factor control in asymptomatic individuals without increasing healthcare utilization, primarily by reducing unnecessary downstream testing [157,158]. Similarly, a post hoc analysis from the St. Francis Heart Study revealed that a significant proportion of individuals with CAC >300 were not eligible for statins under traditional criteria, highlighting a missed opportunity for primary prevention [159].

In contrast, the ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular disease) trial suggested that CAC scoring can help prevent overtreatment by reclassifying many individuals into lower risk categories compared to traditional SCORE-based assessments [160]. The Heinz Nixdorf Recall study also demonstrated that CAC led to significant risk reclassification (either upward or downward) in the intermediate risk cohort, with better stratification compared to the Framingham risk score [161].

Overall, these findings support the cost-effectiveness of incorporating reliable markers of subclinical atherosclerosis into clinical practice for identifying candidates for preventive interventions, consistent with the findings of population-based screening studies [162,163]. The DANCAVAS (Danish Cardiovascular Screening Trial) trial showed that population-based screening for CVD, including CAC (but not CCTA), was cost-effective overall, with the greatest benefit likely to be in younger ages groups (<70 years) [164].

Management of subclinical atherosclerosis involves lifestyle changes and, when appropriate, pharmacologic therapy. Statins, along with other lipid-lowering agents, antihypertensives, and antidiabetics form the mainstay of treatment for asymptomatic individuals with imaging-confirmed disease. Several trials have evaluated or are currently investigating early initiation of therapies such as statins for the reduction of adverse clinical outcomes in high-risk pediatric [165–167], and younger adult populations [168,169].

Early, targeted intervention in individuals with imaging-detected subclinical disease may allow for plaque regression with appropriate therapy [21–23]. Recent evidence from the ARCHITECT (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) trial and other studies has shown shrinkage of atherosclerotic plaque burden with early lipid-lowering therapy, such as PCSK9 inhibitors [57,170–175]. The ongoing VICTORION-PLAQUE (A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase IIIb Study Evaluating the Effect of Inclisiran on Atherosclerotic Plaque Progression Assessed by Coronary Computed Tomography Angiography (CCTA) in Participants With a Diagnosis of Non-Obstructive Coronary Artery Disease Without Previous Cardiovascular Events) study (NCT05360446) is currently investigating CCTA-guided intervention using PCSK9 inhibitors in adults aged 18 years and older.

The time-sensitivity of early intervention underscores the importance of timely identification of individuals who would derive the most benefit, which can be achieved through imaging-guided risk assessment using validated modalities. CAC scoring has been shown to enhance precision in treatment selection, supporting the targeted use of preventive therapies such as statins or PCSK9 inhibitors in asymptomatic individuals [176,177]. This is particularly beneficial when treatment cost is high or when it significantly impacts quality of life [176,177]. Importantly, CAC can identify those most likely to benefit from statins for primary prevention, as evidenced with the reduced risk of MACE and CVD among individuals with elevated CAC who received statins—a benefit not observed in those with CAC = 0 [178,179].

Data from a large cohort including over 33 thousand patients demonstrated that statins reduce the risk of myocardial infarction and all-cause mortality in individuals without obstructive CAD on CCTA, with greater benefit proportional to disease burden [180]. The CONFIRM trial further showed that individuals with non-obstructive CAD on CCTA experienced a significant reduction in the risk of mortality with statin therapy, while aspirin was not associated with any benefit, regardless of plaque status [181]. To note that the investigators proposed that the absence of an observed benefit with aspirin was likely attributable to limited statistical power, given the relatively low number of clinical events.

The use of aspirin for primary prevention in asymptomatic populations remains a matter of debate, due to the need to balance its modest cardiovascular benefit with bleeding risk [182–184]. However, some studies suggest that individuals with advanced subclinical atherosclerosis, as indicated by CAC≥ 100 (particularly≥ 400) or carotid plaque score ≥2, might derive benefit from preventive low-dose aspirin, provided they are not at high bleeding risk [185–187]. That said, no benefit could be established with the use of aspirin in individuals with reduced ABI in the POPADAD (prevention of progression of arterial disease and diabetes) and AAA (Aspirin for Asymptomatic Atherosclerosis) trials [188,189]. However, the negative findings of the AAA trial could be due to the lower rate of cardiac events and medication adherence among the studied population.

8. Screening for subclinical atherosclerosis: Saudi Heart Association Recommendations

Based on current evidence and the characteristics of the Saudi population – particularly the earlier onset of CVD – the SHA recommends systematic screening for subclinical atherosclerosis in individuals aged 35 years or older with a borderline or intermediate 10-year ASCVD risk (5–20 %) (Fig. 1).

Fig. 1.

Algorithm for the screening for subclinical atherosclerosis in asymptomatic individuals. * Ezetimibe, PCSK9 inhibitors, inclisiran, bempedoic acid. Abbreviations: ABI: Ankle-Brachial Index; ASCVD: atherosclerotic cardiovascular disease; CAC: Coronary Artery Calcium; CCTA: Coronary Computed Tomography Angiography; CIMT: Carotid Intima-Media Thickness; CVD: cardiovascular disease.

Subclinical atherosclerosis may be assessed using any of the validated non-invasive imaging modalities: CAC scoring, CCTA, carotid ultrasound measures (CIMT or plaque burden), or ABI. As shown in Table 6, the diagnostic performance of these modalities varies by population characteristics; CAC scoring is the most extensively validated tool, offering strong prognostic value, particularly in patients aged 40 years and older at intermediate risk. CCTA provides visualization of both non-calcified and calcified plaque, yielding powerful prognostic insights, although it is associated with higher cost and exposure to contrast and radiation. Carotid ultrasound measuring CIMT and plaque burden is especially useful in younger adults, but plaque burden is generally more predictive than CIMT. ABI is a simple, low-cost tool with reliable event prediction most useful in older adults, though it may offer limited incremental benefit compared to other modalities.

All these modalities enable detection of subclinical atherosclerosis. The choice of screening modality for subclinical atherosclerosis should be guided by the clinical context and available resources and left to the discretion of the treating physician.

Management should be tailored to the extent of subclinical disease: Lifestyle modification is recommended for individuals with minimal or no burden of disease [CAC = 0, no plaque on CCTA or carotid ultrasound, normal ABI (1–1.4)]. Moderate-intensity statin therapy is recommended for individuals with mild disease burden [CAC 1–99, low plaque burden on CCTA or carotid ultrasound, or borderline ABI (0.9–0.99)]. Moderate to severe disease burden [CAC>100, moderate/severe plaque burden on CCTA or carotid ultrasound measures, or abnormal ABI (<0.9 or >1.4)] is an indication for the initiation of moderate-to high-intensity statin therapy. Treatment intensity should be escalated as needed based on follow-up and evolving risk. The use of aspirin may be considered based on individual risk–benefit evaluation and should remain at the physician's discretion.

9. Conclusion

Given the high burden of premature cardiovascular disease in Saudi Arabia, early identification of subclinical atherosclerosis represents a critical opportunity to improve primary prevention. This position statement recommends a systematic, evidence-informed approach to subclinical atherosclerosis screening and risk stratification in asymptomatic individuals, particularly those with borderline or intermediate risk. Non-invasive imaging modalities such as CAC scoring, CCTA, carotid ultrasound, and ABI offer valuable prognostic information that complements traditional risk calculators. By incorporating subclinical disease detection into routine clinical practice, healthcare providers can better individualize treatment strategies, optimize resource utilization, and ultimately reduce the incidence of atherosclerotic cardiovascular events across Saudi Arabia.

Abbreviation list

ABI

Ankle-Brachial Index

ACC

American College of Cardiology

ACE 1950

Akershus Cardiac Examination

AHA

American Heart Association

ASCVD

Atherosclerotic Cardiovascular Disease

CAC

Coronary Artery Calcium

CAD

Coronary Artery Disease

CCTA

Coronary Computed Tomography Angiography

CHD

Coronary Heart Disease

CIMT

Carotid Intima-Media Thickness

CT

Computed Tomography

CVD

Cardiovascular Disease

LDL-C

Low-Density Lipoprotein Cholesterol

MACE

Major Adverse Cardiovascular Events

PCSK9

Proprotein Convertase Subtilisin/Kexin Type 9

SHA

Saudi Heart Association

Funding Statement

There was no financial reward associated with writing the paper. Konoz Retaj (Saudi Arabia) provided editorial assistance for preparing this manuscript based on the Good Publication Practice (GPP 2022) and the ICMJE requirements. This work was funded by Bayer Saudi Arabia LLC. The views and opinions expressed are those of the authors. Bayer Saudi Arabia LLC had no role in the decision to publish, or preparation of the manuscript.