Introduction

In the United States and Europe, atherosclerotic cardiovascular disease (ASCVD) risk management is based on recommendations from the 2018 American Heart Association (AHA)/American College of Cardiology (ACC)/Multisociety (MS) guideline on the Management of Blood Cholesterol¹ and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) Dyslipidemia guideline,² respectively. Both guidelines aim to reduce ASCVD risk with aggressive lifestyle modifications and by lowering low-density lipoprotein cholesterol (LDL-C) levels with statin and non-statin add-on therapies when indicated. There are, however, clinically meaningful differences in their approach.

While the AHA/ACC/MS guideline emphasizes primary and secondary prevention based on the presence of a prior ASCVD event to guide the percent LDL-C reduction achieved with lipid-lowering therapies, the ESC/EAS guideline prioritizes LDL-C goals using subgroups based on individual estimated risk and the presence of high-risk clinical conditions, including subclinical coronary artery disease (CAD) on imaging tests. Despite these differences, the goal of both guidelines is to match ASCVD risk with the appropriate level of preventive efforts.³

CCTA in the Evaluation and Management of ASCVD in Symptomatic Individuals

Coronary computed tomography angiography (CCTA) has emerged as an important tool in the evaluation of CAD in symptomatic individuals without high risk features in the United States and Europe.⁴ The PROMISE trial first demonstrated that in a real-world, low-to-intermediate risk patient population referred for noninvasive testing for CAD, both CCTA and functional testing (i.e. exercise electrocardiogram, exercise imaging, pharmacologic imaging) have similar economic, safety, and clinical-based outcomes.⁵ However, since CCTA is better able to detect nonobstructive CAD, the discriminatory ability of CCTA in predicting future mid-term ASCVD events bests functional testing. In this context, CCTA and functional testing can both be considered for the noninvasive evaluation of CAD.

It was not until 2018, when SCOT-HEART Investigators demonstrated that CCTA for evaluation of individuals with stable chest pain was associated with a lower rate of death from coronary heart disease or nonfatal myocardial infarction compared to standard of care, that the use of CCTA was routinely adopted for outpatient evaluation in individuals with stable chest pain and no known CAD.⁶ After identifying both obstructive and nonobstructive CAD in symptomatic patients on CCTA, the early implementation of aggressive preventive strategies including lipid-lowering, anti-hypertensive, and anti-anginal therapies resulted in improvement in clinical outcomes.

More recently, in the ISCHEMIA trial, CCTA was also used to detect significant left main CAD, to identify possible surgical candidates who were excluded from randomization to invasive (angiography and revascularization) versus medical treatment.⁷ This further reinforced the notion first arising from emergency department trials of CCTA, including ROMICAT⁸ and ACRIN PA,⁹ then with PROMISE and SCOT-HEART, that CCTA could also serve as an important tool for potentially directing invasive versus noninvasive management of ASCVD.

Coronary Artery Disease Severity as a Treatment Guide

In the recent issue of JACC: Cardiovascular Imaging, Mortensen et al. studied the risk prediction of CAD severity, as measured by diagnostic CCTA, and then modeled the potential influence of this information on the benefit of lipid-lowering therapies.¹⁰ Among 20,241 symptomatic patients from the Western Denmark Heart Registry, the authors concluded that treatment decisions based on objective measures of CAD burden can achieve a more personalized and effective approach to ASCVD risk reduction after initial CCTA evaluation.

Of the 20,241 patients, 4,240 (21%) had obstructive CAD (≥50% luminal stenosis). Those with obstructive CAD tended to be older (62 vs. 56 years of age) and on statin therapy prior to CCTA (50% vs. 34%) with a higher prevalence of hypertension (57% vs. 43%) and diabetes mellitus (12% vs. 7%). Those with obstructive CAD also had higher baseline coronary artery calcium (CAC) scores (117 vs. 0) and ASCVD risk according to the Pooled Cohort Equation (PCE) (13% vs. 6%).

The cumulative incidence of ASCVD events was greatest among 3 vessel CAD with a graded decrease as the number of obstructed vessels or CAC score in nonobstructive CAD decreased. The prevalence of events >90 days after CCTA over a 6-year period was highest in 3 vessel CAD (13.6%) followed by 2 vessel CAD (9.6%), 1 vessel CAD (7.3%), nonobstructive CAD with CAC >400 (7.2%), nonobstructive CAD with CAC ≤400 (2.4%), and no CAD (1.7%).

In a number needed to treat (NNT) analysis, each CAD subgroup was stratified by ESC/EAS and AHA/ACC guideline treatment targets, specifically LDL-C goals and percent LDL-C reduction, respectively. The NNT to prevent one ASCVD event in 6 years had a graded decrease as CAD burden increased using both guideline treatment targets, with NNT <50 in individuals with nonobstructive CAD plus CAC >400 and obstructive CAD (1-3 vessels).

In these subgroups, the proportion of ASCVD events prevented in 6 years ranged from 25 – 36% independent of guideline treatment targets. In all subgroups regardless of CAD severity, the NNT was largely dependent on pre-CCTA LDL-C levels since patients starting with higher baseline LDL-C will tend to have larger absolute reductions in LDL-C for any given lipid-lowering therapy.

To highlight the clinical significance of using CCTA data to guide treatment decisions, Mortensen et al. estimated the impact of achieving guideline-determined LDL-C levels in individuals stratified by CAD severity. The percentage of individuals on statin therapy significantly increased among all subgroups, including no CAD; however, the increase was greatest in individuals with higher CAD burden. This resulted in a significant change in LDL-C levels among all individuals with nonobstructive CAD plus CAC>400 and obstructive CAD subgroups achieving the lowest levels of LDL-C.

Following CCTA, once statin therapy was initiated or intensified, only 10-18% of patients with CAD achieved ESC/EAS treatment targets. To further determine the role of achieving ESC/EAS guideline treatment targets, an analysis determining the NNT to prevent one ASCVD event by intensifying treatment to achieve LDL-C targets was also completed.

NNT was <50 in individuals with obstructive CAD (NNT 19-31), and individuals with nonobstructive CAD plus CAC >400 had a NNT of 59. As a result of treatment intensification in individuals with obstructive CAD where NNT was <50, the proportion of additional ASCVD events prevented in 6 years was approximately 14-17%.

Discussion

In their recent manuscript, Mortensen et al. highlight how further incorporating cardiovascular imaging data, specifically the extent of CAD burden on CCTA in patients with an initial symptomatic presentation, into the ASCVD risk assessment may help individualize the approach to ASCVD risk reduction and could potentially improve outcomes. Using the treatment strategies recommended by the recent American and European cholesterol guidelines, the authors demonstrate the benefits of initiating lipid-lowering therapy based on the burden of CAD to reduce ASCVD events over a 6-year period. Building off of SCOT-HEART, this paper provides additional real-world data and modeling estimates on the beneficial effects of aggressively treating symptomatic patients with moderate and advanced CAD on CCTA.

Currently, the AHA/ACC/MS guideline, which does not discuss ASCVD risk assessment in symptomatic individuals, limits any imaging for guiding treatment decisions to a CAC score for only asymptomatic individuals if the treatment decision is still uncertain after considering estimated ASCVD risk and risk enhancing factors in individuals with borderline (5 – 7.5%) or intermediate (7.5 – 19%) estimated 10-year ASCVD risk. If the CAC score is 1-99 or ≥100, statin therapy is favored and indicated, respectively.¹ The ESC/EAS guideline also includes a CAC score (and carotid and femoral plaque) to inform risk assessment of asymptomatic individuals at low to moderate ASCVD risk.²

The AHA/ACC/MS guideline has a limited framework for the aggressive treatment of symptomatic patients with CCTA evidence of obstructive or nonobstructive CAD, which included almost 80% of the study population. In contrast, the ESC/EAS guideline considers unequivocal ASCVD on imaging (defined as significant plaque on coronary angiography, multivessel CAD with two major epicardial arteries having >50% stenosis on CCTA or carotid ultrasound) as a very high-risk subgroup where an LDL-C goal of <55 mg/dl along with ≥50% reduction from baseline should be sought. While the challenge remains determining if CCTA is cost-effective for ASCVD risk assessment and management, the current recommendations from the ESC/EAS guideline make use of valuable CCTA data when available for guiding treatment decisions.

The United States guideline strongly endorses a CAC score in the primary prevention setting for its ability to stratify ASCVD risk (or "de-risk" when CAC = 0) in asymptomatic individuals beyond our typical risk assessment tools. The ESC/EAS guideline also broadly incorporates imaging evidence of ASCVD to guide aggressive management. Without clear recommendations on the management of symptomatic individuals with CAD on CCTA, regardless of whether the extent of CAD explains the present symptoms, the AHA/ACC/MS guideline leaves the decision to implement aggressive prevention to the discretion of clinicians. This is an area where harmony between future prevention and chest pain/CAD evaluation guidelines can be improved. Currently, while the guidelines differ in their approach to aggressive LDL-C reductions for imaging evidence of ASCVD only, randomized controlled trials like SCOT-HEART and this recent study by Mortensen et al. demonstrate the potentially important role imaging can play in helping to initiate preventive therapies earlier for long-term benefits in ASCVD outcomes.

This paper also illustrates how cardiovascular imaging is uniquely positioned to identify individuals at risk for ASCVD, which may not be evident using risk calculators like the PCEs, and allow for treatment according to CCTA findings in symptomatic patients when available and ASCVD risk. The median 10-year ASCVD risk according to the PCEs was 13% (IQR 6.6-21.4) in individuals with obstructive CAD on CCTA. Therefore, the majority of patients with obstructive CAD would have likely qualified for at least a moderate intensity statin with an anticipated ≥30% LDL-C reduction.

In those with nonobstructive CAD, the median estimated 10-year ASCVD risk was 5.7% (IQR 2.5 – 12), which means that many would not have qualified for statin therapy by estimated ASCVD risk alone. This is of particular importance as a large benefit for LDL-C lowering was seen not only in the obstructive CAD subgroups, but also the nonobstructive CAD plus CAC >400 subgroups, where baseline ASCVD risk estimates according to the PCEs were lower.

Given its cost-effectiveness, low risk profile and clinical utility, a CAC score has historically helped re-stratify asymptomatic individuals based on objective evidence of subclinical atherosclerosis. Once subclinical atherosclerosis is identified, a clinician-patient risk discussion often leads to intensification of preventive treatments.¹ Based on the results of this study, CCTA data may be considered to guide preventive therapies for ASCVD risk reduction in symptomatic individuals when available. According to this framework, a low-to-intermediate risk individual (based on the 10-year ASCVD risk score) with symptoms and moderate stenosis on CCTA can be included in a high-risk subgroup where aggressive preventive therapies are considered.

Until cost-effectiveness data is available, it is not clinically and economically feasible to image all symptomatic low-to-intermediate risk individuals with CCTA to determine CAD severity and personalize ASCVD risk. However, the availability of CCTA data is increasing given its important role as a noninvasive modality for the evaluation of CAD.^11-13 Therefore, as CCTA becomes more ubiquitous and the extent of CAD burden according to CCTA becomes available to clinicians, there may be a role for leveraging this data to further inform an individual's ASCVD risk and allocate aggressive preventive therapies more appropriately. Until then, the most cost-effective alternative is to avoid routinely using CCTA for ASCVD risk assessment in individuals with stable angina and known atherosclerosis and instead simply start a high-intensity statin to achieve a ≥50% reduction in LDL-C or an LDL-C level <55 mg/dL with a low threshold to add ezetimibe if needed.

Conclusion

The noninvasive evaluation of CAD via CCTA is a rapidly expanding field with numerous emerging clinical applications. The SCOT-HEART trial paved the way by demonstrating the value of using CCTA to determine the extent of CAD burden in symptomatic patients and help direct personalized, aggressive preventive therapies for improved ASCVD outcomes. The most recent work by Mortensen et al. provides additional evidence for using CCTA to evaluate CAD burden in symptomatic individuals and guide the implementation of more aggressive lipid-lowering therapies for ASCVD risk reduction and improved outcomes.

While the approach to primary and secondary prevention of ASCVD may differ between guidelines, there is a clear agreement of LDL-C lowering and optimization of lifestyle habits leading to significant improvement in ASCVD outcomes for symptomatic patients with obstructive and nonobstructive CAD on CCTA. Ultimately, if individuals with obstructive CAD and nonobstructive CAD plus CAC >400 adhered to statin therapy and non-statin add-on therapy when needed in order to achieve an expected ≥50% reduction in LDL-C, roughly one out of every three individuals may potentially avoid an ASCVD event. Working towards these goals will be paramount in reducing future preventable ASCVD events.

References

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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging, Chronic Angina

Keywords: Dyslipidemias, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cholesterol, LDL, Cholesterol, Atherosclerosis, Antihypertensive Agents, American Heart Association, Prevalence, Secondary Prevention, Coronary Angiography, Outpatients, Constriction, Pathologic, Calcium, Cardiovascular Diseases, Random Allocation, Angina, Stable, Chest Pain, Risk Factors, Risk Assessment, Cost-Benefit Analysis

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