Screening for Atherosclerotic Cardiovascular Disease in Asymptomatic Individuals

Distinction Between Traditional Screening and Individualized Risk Assessment

Traditional screening is defined as the routine evaluation of a general population with the goal of detection of disease among people without signs or symptoms of the disease, not exclusion of disease. In 1968, Wilson and Jungner outlined 10 criteria for a valid screening program for the World Health Organization (WHO) ( Box 29.1 ) that still hold true today. Briefly, a screening program should be targeted at a disease that is an important health problem, a disease that has a long latent phase where early detection is possible, where treating in an early stage is more beneficial than treating at a later stage, and where potential benefits of screening outweigh the costs.

Thus, screening for ASCVD meets all of these WHO criteria and has great appeal due to the long disease latency, emerging technologies for early detection, and existence of proven therapies that slow its natural history. Nonetheless, various experts have pointed to potential problems with ASCVD screening due to false-positive test results, inappropriate downstream testing, and creation of “pseudodisease.” Pseudodisease means that some individuals with subclinical atherosclerosis may not be destined to have an ASCVD event and there is a risk of overtreatment with medications.

One of the WHO criteria is that costs should be balanced against potential benefits. For ASCVD screening, costs include not only the direct cost of the screening test itself but downstream costs from additional testing, specialty referrals, and treatments; sometimes screening can even lead to more invasive procedures such as coronary angiography and revascularization, which have their own associated risks and expense. In addition, there might be psychological harm from anxiety or being labeled as “diseased” because of subclinical atherosclerosis or mild left ventricular dysfunction.

Several organizations have issued guidelines on ASCVD screening, including the United States Preventive Service Task Force (USPSTF), the American College of Cardiology (ACC)/American Heart Association (AHA), and the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS). Interestingly, these guidelines often reach different conclusions, owing in large part to different interpretations of the role of screening in routine clinical care. Table 29.2 outlines potential screening or risk assessment tools and the recommendations for or against their use in asymptomatic individuals by these major guideline bodies.

The USPSTF has consistently advised against routine screening for ASCVD beyond measurement of traditional ASCVD risk factors such as total cholesterol and blood pressure. The recommendations from the USPSTF are best understood in the context of our definition of traditional screening. Because most current tests for the diagnosis of CHD are limited by a low positive predictive value for future CHD events (thus, there is concern for false-positive tests and overtreatment), these tests fail as broad-based population-wide screening tests per the USPSTF criteria.

The ACC/AHA guidelines and the ESC guidelines take a different approach to screening, targeting their recommendations at the individual patient rather than the larger population. This approach is commonly referred to as clinical risk assessment. The goal of individual risk assessment is to inform therapy decisions, particularly in intermediate-risk patients or in patients in whom treatment decisions are otherwise uncertain. As opposed to traditional screening, which focuses exclusively on disease detection, when conducting individual risk assessment, the identification of low ASCVD risk (and, therefore, persons not in need of the aggressive pharmacologic prevention treatment) is equally important. The hallmark of individual risk assessment is that patients may move both up and down the risk spectrum after testing (i.e., risk reclassification). Clinical risk assessment offers the opportunity to rule out high-risk states (and the potential to reduce the intensity of preventive interventions and avoid or withdraw pharmacologic therapy) in a patient who would otherwise have qualified for aggressive treatment based purely on risk factor--based ASCVD screening.

Population-Based Prevention: Is Screening Needed?

Several strategies for ASCVD prevention do not require any type of screening. Foremost among these are purely population-based strategies, which seek to modify risk for everyone across an entire population and are a primary tool for primordial ASCVD prevention. Examples of successful population-based prevention strategies include public smoking bans, trans-fat bans, and salt reduction in packaged and prepared foods.

Some experts have advocated for dismissal of formal screening and adoption of a simple “treat-all” approach to ASCVD prevention. For example, some cost-effectiveness analyses have suggested that treating all adults aged 55 years and over with a low-cost statin may be more cost-effective than any currently available screening strategy. A related strategy adapted to populations with less healthcare resources is the polypill, where all older patients are treated with a combination pill including a statin, aspirin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and thiazide diuretic. Interestingly, the 2013 ACC/AHA Cholesterol Guidelines, which lowered the threshold for recommending statin therapy, have inched closer toward a modified age-based treat-all approach with statin therapy for men over the age of 60 and women over the age of 65. As a general rule, when treatment thresholds are lowered, the importance of traditional population-based screening decreases (because most people will already have qualified for pharmacologic treatment) and the importance of individual risk assessment increases (to determine which individuals might avoid pharmacologic treatment at that point in time and for the next few years).

As a result, in most industrialized countries with greater healthcare budgets, there is an increasing push for greater personalization of preventive therapy. A fundamental goal of individual risk assessment is to limit overtreatment by matching the intensity of preventive therapy to the absolute risk of the patient, thereby maximizing potential benefit while minimizing the potential for harm ( Fig. 29.2 ).

Individualized Screening Starts with Global Risk Assessment

The typical initial approach to screening is ascertainment of traditional ASCVD risk factors, and for specific age-groups (generally excluding the young and the elderly), to estimate one’s 10-year global risk for ASCVD. Multiple risk prediction models have been developed ( Table 29.3 ). Most models include age, sex, smoking status, systolic blood pressure (as well as antihypertensive treatment), total cholesterol, high-density lipoprotein cholesterol, and diabetes mellitus. Some additionally consider family history of ASCVD (Reynolds risk score, QRISK, ASSIGN, PROCAM ) or markers of inflammation (Reynolds risk score), and some of the European risk scoring models (QRISK, ASSIGN) are unique by including measures of social deprivation.

The ESC/EAS guidelines recommend using the SCORE system, which estimates 10-year risk of fatal ASCVD, with separate risk estimations for high- and low-risk regions in Europe. In the ESC/EAS guidelines, recommendations for drug treatment of dyslipidemia (vs lifestyle alone) are based on both one’s estimated 10-year risk of fatal ASCVD using SCORE (with < 1% being low risk, 1–4% moderate risk, 5–10% high risk, and ≥ 10% very high risk) and one’s low-density lipoprotein cholesterol (LDL-C) level. In general, individuals at higher predicted fatal ASCVD risk are recommended for drug treatment at much lower LDL-C levels.

In the United States, the 2013 ACC/AHA guideline on the assessment of cardiovascular risk endorses risk factor screening every 4 to 6 years for those aged 20 to 79 years and application of the pooled cohort equations in asymptomatic adults aged 40 to 79 years to estimate 10-year risk for a first “hard” ASCVD event (myocardial infarction [MI] or stroke). The ACC/AHA risk estimator was not designed to be used in those already on statin therapy. In contrast to previous cardiovascular risk scores, there are now separate models by race (e.g., non-Hispanic whites and blacks) and by sex for more refined risk prediction. These guidelines are linked to the ACC/AHA cholesterol guidelines, which state that higher-risk individuals (10-year predicted risk of ASCVD ≥ 7.5%) are recommended for statin treatment, after a clinician-patient discussion. Moreover, those persons with a 5% to 7.4% risk over the next decade can also be considered for moderate-intensity statin therapy after a clinician-patient discussion. In addition, the ACC/AHA guidelines support estimating a 30-year or lifetime ASCVD risk based on traditional risk factors for adults aged 20 to 59 who are not at high short-term (i.e., 10-year) risk.

The USPSTF also recently posed draft recommendations on statin use for the primary prevention of ASCVD in adults on its website. They recommended that the people who benefit most from statin use are 40 to 75 years of age with at least one other risk factor for ASCVD and have a 10-year ASCVD risk estimate of 10% or greater (grade B recommendation). They advise that those with a 7.5% to 10% estimated 10-year risk are less likely to benefit and should talk to their doctor (grade C recommendation).

Risk Uncertainty Often Remains After Global Risk Assessment

In contrast to the ASCVD risk estimation tools developed for the United States and Europe, there are many areas of the world such as the BRICS countries (Brazil, Russia, India, China, and South Africa) where accurate tools have not been developed; yet these countries have a large burden of cardiovascular disease. Current risk estimation calculators may over- or underestimate risk in these populations. Caution should be used when applying the ACC/AHA pooled cohort equations to groups outside the United States and to groups that are neither white nor black within the United States. This may result in overestimation of ASCVD risk among those of Chinese/East Asian descent and underestimation in American Indians and those of South Asian descent.

In addition, in the context of epidemiologic trends pointing toward continually decreasing ASCVD rates in the United States and in many developed countries, there remains a concern that risk scores such as the ACC/AHA pooled cohort equations that are based on historic data may systematically overestimate ASCVD risk in modern populations.

Furthermore, with all risk calculators, applying the results from population-based estimators to clinical decision-making at the individual level can be problematic. Specifically, these calculators estimate the average risk in a group of individuals who have similar risk factor profiles; however, a given risk score is far more accurate for this group than it is for any individual within the group. Indeed, with respect to the individual, each estimate has a theoretical confidence interval that is unknown and that may overlap personalized treatment thresholds.

A critical feature of the 2013 ACC/AHA guidelines is the acknowledgment that in many cases after initial 10-year risk estimation, the treatment decision about statin therapy will still remain uncertain to either the patient or the clinician. The guidelines allow for revising one’s risk status upward if one of the following is present: elevated lifetime risk, family history of premature ASCVD, high-sensitivity C-reactive protein (hs-CRP) ≥ 2.0 mg/L, LDL-C ≥ 160 mg/dL, abnormal coronary artery calcium (CAC) score (Agatston score ≥ 300 or ≥ 75th percentile for one’s age and sex), or ankle-brachial index (ABI) < 0.9.

The ESC/EAS guidelines, which endorsed the SCORE estimator as a starting point, also acknowledged uncertainty by including many important “qualifiers” in their document where risk estimation may need to be adjusted upward or downward based on an individual’s pretest probability. These guidelines state that (1) risk will be overestimated in countries with falling ASCVD mortality rates and underestimated in countries where mortality is increasing; (2) at a given age, women will have a lower predicted 10-year ASCVD risk than men, but this may be misleading because eventually similar numbers of women will die of ASCVD compared to men; (3) risk will be higher in individuals with social deprivation; (4) risk will be higher among those who are sedentary and have central obesity; (5) risk will be higher among those with low high-density lipoprotein (HDL)-C, increased triglycerides, increased apolipoprotein B, or increased hs-CRP; (6) risk will be higher among asymptomatic individuals with evidence of subclinical atherosclerosis; (7) risk will be higher among those with impaired renal function; (8) risk will be higher among those with a family history of premature ASCVD; and (9) risk will be lower among those with high HDL-C or a family history of longevity.

Despite these limitations, global risk estimation tools are helpful in initiating a risk-based discussion of preventive pharmacologic therapy, and we strongly endorse their routine use as a starting point. But, given these caveats of risk underestimation among certain patient subgroups (i.e., potential for undertreatment) alongside concerns for risk overestimation in other populations combined with much lower treatment thresholds (i.e., potential for overtreatment), the need for further individualized risk assessment has become increasingly important.

With their extensive safety data and the availability of low-cost generic statins, combined with much lower treatment thresholds, many more patients are now eligible for statin therapy under the 2013 ACC/AHA guidelines. The group previously recommended for risk reclassification (the “intermediate-risk” group) has become much more narrow and with lower absolute risk; however, uncertainty of risk often remains among a broad range of estimated risk scores (5–15% 10-year risk). We discuss later in this chapter how selective use of additional tools may help refine personalization of risk assessment. Select tests are discussed in detail hereafter, with a particular emphasis on exercise stress testing (to assess cardiorespiratory fitness or exercise capacity) and noncontrast cardiac computed tomography (CT) (to measure the presence of or the amount of CAC), which appear to be the best predictors of long-term survival.

Additional Medical and Social Factors for Revising Risk Estimation Upward

Before one considers ordering additional testing to refine risk, there are additional elements that can be obtained from a detailed medical and social history that help guide risk assessment. For example, there are many risk factors for ASCVD that are not included in the pooled cohort equations including a family history of premature or later-onset ASCVD, former cigarette smoking, secondhand exposure to smoke, history of erectile dysfunction (ED), history of adverse pregnancy outcomes (i.e., preeclampsia or gestational diabetes), insulin resistance/prediabetes/metabolic syndrome, sedentary behavior, autoimmune disease, human immunodeficiency virus infection, chronic kidney disease, obstructive sleep apnea, and hepatosteatosis. Several of these are discussed herafter.

It would be cumbersome and impractical to add these and other unique risk factors to a universal risk prediction model. However, physicians require further direction on how best to categorize individuals with unique risk factors. It is especially in this setting that further risk stratification with tests that inherently individualize risk, such as measuring subclinical atherosclerosis, may better delineate those who would most likely benefit from preventive therapies.