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Requests for reprints should be addressed to Andrew M. Freeman, MD, FACC, Department of Medicine, Cardiovascular Prevention and Wellness, National Jewish Health, 1400 Jackson St. J317, Denver, CO 80206.
Although atherosclerosis represents the primary driver of coronary artery disease, evaluation and treatment approaches have historically relied upon indirect markers of atherosclerosis that include surrogates (cholesterol), signs (angina), and sequelae (ischemia) of atherosclerosis. Direct quantification and characterization of atherosclerosis may encourage a precision heart care paradigm that improves diagnosis, risk stratification, therapeutic decision-making, and longitudinal disease tracking in a personalized fashion.
Observations
The American College of Cardiology Innovations in Prevention Working Group introduce the Atherosclerosis Treatment Algorithms that personalize medical interventions based upon atherosclerosis findings from coronary computed tomography angiography (CTA) and cardiovascular risk factors. Through integration of coronary CTA-based atherosclerosis evaluation, clinical practice guidelines, and contemporary randomized controlled trial evidence, the Atherosclerosis Treatment Algorithms leverage patient-specific atherosclerosis burden and progression as primary targets for therapeutic intervention. After defining stages of atherosclerosis severity by coronary CTA, Atherosclerosis Treatment Algorithms are described for worsening stages of atherosclerosis for patients with lipid disorders, diabetes, hypertension, obesity, and tobacco use. The authors anticipate a rapid pace of research in the field, and conclude by providing perspectives on future needs that may improve efforts to optimize precision prevention of coronary artery disease. Importantly, the Atherosclerosis Treatment Algorithms are not endorsed by the American College of Cardiology, and should not be interpreted as a statement of American College of Cardiology policy.
Conclusions and Relevance
We describe a precision heart care approach that emphasizes atherosclerosis as the primary disease target for evaluation and treatment. To our knowledge, this is the first proposal to use coronary atherosclerosis burden and progression to personalize therapy selection and therapy changes, respectively.
Disclosure
The American College of Cardiology Foundation has made an investment in Cleerly, Inc., makers of a software solution that utilizes coronary CT angiography findings to evaluate coronary artery disease.
Since the identification of atherogenic lipids, elevated blood pressure, diabetes, tobacco use, obesity, and physical inactivity as factors associated with cardiovascular risk in population-based studies, these conditions have served as the cornerstone for treatment targets for coronary artery disease prevention in American College of Cardiology/American Heart Association clinical practice guidelines.
2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
In daily practice, the contribution of risk factors to atherosclerotic cardiovascular disease risk can be assessed through calculators offered by the American College of Cardiology,
2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Despite these findings, coronary artery disease remains the leading cause of mortality and morbidity in the world, with rates of major adverse cardiovascular events now increasing.
Several factors may contribute to the imperfection of a risk factor-based strategy, and include:
•
A Population-Based Approach Misses the Majority of Individuals Who Will Develop Coronary Artery Disease. While risk factors are associated with coronary artery disease in large populations, they possess significantly less diagnostic and prognostic precision when applied to individual patients. As an example, in the Get with the Guidelines database of 136,905 individuals hospitalized for coronary artery disease, >50% had low-density lipoprotein <100 mg/dL, the level considered ideal at the time of publication.
These findings are consistent with the Framingham Heart Study, wherein >80% overlap of cholesterol levels was observed for patients with and without coronary artery disease in a 26-year follow-up.
Risk Factor-Guided Approaches Perform Differently in Different Populations. Atherosclerotic cardiovascular disease risk estimation is known to perform better in certain populations than others. In the Women's Health Initiative of a multiethnic population of 19,995 women, observed risks of atherosclerotic cardiovascular disease events were significantly lower than that estimated by risk calculators.
Risk Factor Presence Does Not Ensure Presence of Coronary Artery Disease, Even in High-Risk Individuals. While diabetes is widely considered a “coronary artery disease equivalent,”
population-based cohorts of diabetic individuals undergoing coronary computed tomography angiography have revealed that one-third have no or minimal coronary artery disease, a finding associated with low rates of major adverse cardiovascular events.
Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clinical trial.
Population-based definitions do not ideally classify individuals with diabetes who may actually be at low clinical risk.
•
Risk Factor Control Fails the Majority of Individuals Who Retain High Residual Risk. Risk factor control does not reliably pinpoint individuals who are successfully treated for risk factors but who retain significant residual risk for major adverse cardiovascular events. As an example, Libby
has espoused the concept of the “forgotten majority” to the 62%-75% of individuals with dyslipidemia who are treated with statin therapy but still go on to experience major adverse cardiovascular events.
•
Atherosclerotic Cardiovascular Disease Risk Scoring Does Not Account for Other Well-Known Factors That Predispose an Individual to Major Adverse Cardiovascular Events. Hundreds of conditions have been identified that predispose an individual to major adverse cardiovascular events, and are unaccounted for in atherosclerotic cardiovascular disease scoring.
These include: cardiometabolic disorders such as non-alcoholic steatohepatitis; renal disorders such as chronic kidney disease; pulmonary disorders such as chronic obstructive pulmonary disease and exposure to air pollution; and many others.
•
Atherosclerotic Cardiovascular Disease Risk Scoring Does Not Account for As-Yet Unknown Factors That Predispose an Individual to Major Adverse Cardiovascular Events. It remains likely that there is an array of contributors to atherosclerotic cardiovascular disease risk that have not yet been identified.
Further, beyond risk factor presence, it is likely that its severity, duration, and treatment efficacy contribute to major adverse cardiovascular events risk, and are not accounted for by atherosclerotic cardiovascular disease risk scoring. Precision prevention to reduce atherosclerotic cardiovascular disease risk will ideally integrate the totality of clinical, psychosocial, environmental, and genetic determinants into actionable metrics that can improve personalized evaluation and treatment and can be tracked over time.
Coronary Computed Tomography Angiography
Coronary computed tomography angiography (CTA) allows for evaluation of the full spectrum of coronary health and disease. Coronary CTA allows for quantitative measurement of atherosclerotic burden, its secondary anatomic consequences on the coronary lumen (stenosis), and its tertiary late-stage physiologic consequences on flow (ischemia).
Large-scale randomized trials applying coronary CTA in individuals with suspected coronary artery disease—such as the Scottish COmputed Tomography of the HEART trial (SCOT-HEART) and the PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE)—have demonstrated superior or equivalent clinical outcomes when compared with ischemia-guided approaches.
These trials have established the necessary evidence to advance coronary CTA to Level IA in guidance documents, most recently in the 2021 American Heart Association/American College of Cardiology Chest Pain Guidelines.
for invasive angiography wherein the majority of individuals who will suffer MI have only mild stenosis. Together, these findings suggest a need for definitions of coronary artery disease severity wherein the burden of atherosclerosis may offer independent insights into MI risk.
Coronary CTA for Atherosclerosis Burden and Type
Coronary CTA performs robustly compared with intravascular ultrasound for atherosclerosis, with sensitivity and specificity of 93% and 92%, respectively.
Coronary computed tomographyangiography versus intravascular ultrasound for estimation of coronary stenosis and atherosclerotic plaque burden: a meta-analysis.
Coronary CTA offers advantages over intravascular ultrasound by enabling whole-heart atherosclerosis quantification rather than limiting evaluation to proximal portions of single arteries. Reporting of plaque burden by coronary CTA is similar to intravascular ultrasound, employing total plaque volume or percent atheroma volume. Atherosclerosis by coronary CTA has been commonly categorized by composition: low-density non-calcified plaque (<30 Hounsfield units [HU]), non-calcified plaque (30-350 HU), and calcified plaque (351+ HU).
Automatic quantification and characterization of coronary atherosclerosis with computed tomography coronary angiography: cross-correlation with intravascular ultrasound virtual histology.
Coronary CTA atherosclerosis informs prognosis. In the CONFIRM study, presence of atherosclerosis in proximal segments conferred greater predictive value for future major adverse cardiovascular events than stenosis, with both features additive for prognostication of major adverse cardiovascular events.
Optimized prognostic score for coronary computed tomographic angiography: results from the CONFIRM registry (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter Registry).
Similarly, by quantitative coronary CTA in the 3V FFR-FRIENDS study, outcomes were worse for non-ischemic vessels exhibiting high-risk atherosclerosis, including increasing total plaque volume and percent atheroma volume.
These findings demonstrate that atherosclerosis improves identification of risk of major adverse cardiovascular events in a manner independent to risk factor scoring, stenosis, and ischemia.
Coronary CTA also allows for quantification of advanced coronary artery disease features, including low-density non-calcified plaque and positive remodeling. Together, low-density non-calcified plaque and positive remodeling in a single lesion has been termed “high-risk plaque.” In the Incident COroNary syndromes Identified by Computed tomography (ICONIC) study of 25,251 patients, low-density non-calcified plaque volume was the strongest discriminator of future MI.
Use of high-risk coronary atherosclerotic plaque detection for risk stratification of patients with stable chest pain: a secondary analysis of the PROMISE randomized clinical trial.
Low-attenuation noncalcified plaque on coronary computed tomography angiography predicts myocardial infarction: results from the multicenter SCOT-HEART trial (Scottish Computed Tomography of the HEART).
Similarly, in PROMISE, high-risk plaque was associated with major adverse cardiovascular events independent of conventional markers such as stenosis, with predictive value of high-risk plaque generalizable to individuals without severe stenosis.
Mechanistically, high-risk plaques may offer inflammatory and anatomic insights into plaque biology. High-risk plaques by coronary CTA are associated with features considered prototypic of the “vulnerable plaque,” such as thin fibrous caps, macrophage infiltration, and necrotic intraplaque cores.
On the opposite end of the spectrum from dark low-density non-calcified plaques are bright calcified plaques. Calcified plaques include 1K plaques (with HU >1000), which were found in ICONIC to be associated with a lower risk of future acute coronary syndrome. Indeed, a continuum of risk of acute coronary syndrome from high to low is observed for plaques with compositions between low-density non-calcified plaque (dark) and 1K plaques (bright) (Figure 1
Figure 1Plaque composition assessment demonstrates lower-density non-calcified plaques to be associated with higher risk of future acute coronary syndrome, and higher-density calcified plaques to be associated with lower risk of future acute coronary syndrome. Adapted from: van Rosendael AR, Narula J, Lin FY, et al. Association of high-density calcified 1K plaque with risk of acute coronary syndrome; JAMA Cardiol. 2020;5:282-290.
showed that plaque progression in individuals was the strongest predictor of future major adverse cardiovascular events over stenosis and risk factors. Coronary CTA may be used for direct assessment of coronary artery disease changes over time to personalize determination of the efficacy of medical therapy.
In the Progression of AtheRosclerotic plAque DetermIned by computed tomoGraphic angiography iMaging (PARADIGM) study, statins were associated with 21% reduction in annualized percent atheroma volume progression and 35% reduction in high-risk plaque at a 3.4-year follow-up serial coronary CTA.
While statins were associated with slower progression, the overall reduction was modest, as statins slowed non-calcified plaque formation while accelerating calcified plaque formation. Independent of statin use, rate of plaque progression was independently associated with major adverse cardiovascular events, indicating that atherosclerosis changes over time may be an essential tool to identify individuals who are not responding optimally to medical therapy.
Results similar to PARADIGM have been observed for icosapent ethyl, PCSK9 inhibitors, colchicine, Dietary Approaches to Stop Hypertension diet, and physical activity, wherein these therapies transformed plaque composition from non-calcified plaque to calcified plaque, findings associated with improvement in outcomes
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results.
• Statins associated with lower rate of plaque progression • Statins associated with higher rate of calcified plaque formation, lower rate of non-calcified plaque formation
Icosapent ethyl
• RCT
• 18 mo
• LD-NCP volume
• Icosapent ethyl reduced LD-NCP volume compared with placebo
Evolocumab
• Single center, retrospective
• 6 mo
• Stability and size of plaques at 6 months
• Evolocumab increased CT density of plaques • Evolocumab decreased % stenosis
Colchicine
• Single center, prospective
• 12.6 mo
• LD-NCP volume
• Colchicine reduced LD-NCP
DASH diet + physical activity
• RCT
• 15.4 mo
• △ in percent atheroma volume and plaque composition
• Diet + activity slowed the progression of atherosclerosis • Diet + activity reduced non-calcified plaque
Rationale and Aim of the Atherosclerosis Treatment Algorithms
The Atherosclerosis Treatment Algorithms were developed as an evidence-based disease-focused approach to more accurately personalized coronary artery disease risk assessment and treatment efficacy. Whole-heart atherosclerosis phenotyping allows for a non-invasive approach for personalized, quantitative disease tracking, and integrates into a single metric an individual's exposure to all coronary artery disease risk factors—whether known or unknown—over the course of their lifetime.
Advanced non-invasive imaging—including mammography, colonoscopy, and lung CT—for direct visualization of disease has proven effective in reducing cancer mortality.
Staging by presence (tumor), extent (lymph nodes), and severity (metastasis);
3.
Classification of type of cancer;
4.
Personalization of treatment to an individual's actual disease characteristics, and;
5.
Repeat advanced imaging to assess therapeutic response.
Importantly, the Atherosclerosis Treatment Algorithms are not intended to serve as a replacement to practice guidelines or consensus statements, nor are they expected to be divorced from risk factor scoring.
Defining Severity of Coronary Atherosclerosis by Coronary CTA
To quantify atherosclerosis burden, we used total plaque volume and percent atheroma volume, defined as (plaque volume/vessel volume) × 100%, as these approaches are least influenced by a patient's body size and surface area.
To stage atherosclerosis, we contemplated several definitions, including 1) population-based ranges of age, sex, and ethnicity; 2) plaque volumes for stable individuals who experience future acute coronary syndrome; and 3) plaque volumes according to stenosis severity by QCA. We chose the latter, given the widespread familiarity of these cut points in clinical care for angiographically non-obstructive and obstructive 1-vessel, 2-vessel, or 3-vessel/left main >50% diameter stenosis. Given significant overlap of atheroma volume in patients with non-obstructive and 1-vessel angiographic coronary artery disease, we combined these groups in a single stage.
Stress myocardial perfusion imaging vs coronary computed tomographic angiography for diagnosis of invasive vessel-specific coronary physiology: predictive modeling results from the computed tomographic evaluation of atherosclerotic determinants of myocardial ischemia (CREDENCE) trial.
The coronary atherosclerosis stages were derived from a multinational trial wherein patients underwent coronary CTA and quantitative coronary angiography
Stress myocardial perfusion imaging vs coronary computed tomographic angiography for diagnosis of invasive vessel-specific coronary physiology: predictive modeling results from the computed tomographic evaluation of atherosclerotic determinants of myocardial ischemia (CREDENCE) trial.
Figure 2Examples of patients with Stage 0, Stage 1, Stage 2 and Stage 3 atherosclerosis. Staging of coronary atherosclerosis should say total Cleerly Labs and Cleerly Coronary (Cleerly Inc., Denver, Colo). PAV = percent atheroma volume; TPV = total plaque volume. Adapted from J Cardiovasc Comput Tomogr. 2022 16(5):415–422.
Stress myocardial perfusion imaging vs coronary computed tomographic angiography for diagnosis of invasive vessel-specific coronary physiology: predictive modeling results from the computed tomographic evaluation of atherosclerotic determinants of myocardial ischemia (CREDENCE) trial.
Increases in atherosclerosis >1.0% percent atheroma volume/year are associated with worsened prognosis, and higher baseline atherosclerosis is the strongest driver of coronary artery disease progression.
In the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients with Elevated Triglycerides on Statin Therapy (EVAPORATE) and PARADIGM trials, significant atherosclerosis changes were noted within 9 months and 2 years, respectively.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results.
The EVAPORATE trial provides important mechanistic data on plaque characteristics that have relevance to the REDUCE-IT results and clinical use of icosapent ethyl.
It follows that an earlier follow-up coronary CTA to determine therapeutic success may be more valuable for those with higher baseline coronary artery disease burden. Our proposal is that serial coronary CTA may be beneficial for patients with Stage 0, 1, 2, and 3 atherosclerosis at 4, 3, 2, and 1 years, respectively. In the event of significant atherosclerosis progression, therapeutic decision-making can then be informed by changes in an individual's actual disease process.
Treating Atherosclerosis Burden and Progression
Less than 5 years ago, the “toolbox” of primary prevention for coronary artery disease was limited, with statins, ezetimibe, aspirin, and antihypertensive agents largely the only agents available. Today, there are myriad of Food and Drug Administration-approved therapies (with several others anticipated shortly) that have a beneficial impact on risk factors or reducing major adverse cardiovascular events (Supplementary Table
The EVAPORATE trial provides important mechanistic data on plaque characteristics that have relevance to the REDUCE-IT results and clinical use of icosapent ethyl.
The “toolbox” now enables >10 classes of medications to treat atherosclerosis, with newer agents—such as those targeting Lp(a) and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists—expected shortly. Notably, the Atherosclerosis Treatment Algorithms emphasize therapies with the most robust outcomes data at the time of writing. This does not preclude other medications as having utility and, as evidence develops, the Atherosclerosis Treatment Algorithms will be adjusted accordingly.
2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision making to ensure patient literacy of elevated bleeding risk.
For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision making to ensure patient literacy of elevated bleeding risk.
• Other lipid-lowering medications: PCSK-9 inhibitors, icosapent ethyl, inclisiran, bempedoic acid • Colchicine 0.6 mg QD • Cardiac rehabilitation or other supervised exercise program (if covered) If diabetic: GLP-1 receptor agonist and SGLT2 inhibitor
1 year
ASA = acetylsalicylic acid; BID = twice a day; CCTA = coronary CT angiography; GDMT = guideline-directed medical therapy; GLP-1 = glucagon-like peptide 1; QD = once a day; SGLT2 = sodium-glucose transport protein 2.
For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision making to ensure patient literacy of elevated bleeding risk.
Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease.
The EVAPORATE trial provides important mechanistic data on plaque characteristics that have relevance to the REDUCE-IT results and clinical use of icosapent ethyl.
Supplementary Figure 1“Treat Disease” algorithms for patients with dyslipidemia. (B)1PCSK9 inhibitors include: alirocumab (starting 75 mg/2 weeks or 300 mg/4 weeks, maintenance 150 mg/2 weeks or 300 mg/4 weeks); evolocumab (140 mg/mL SQ 2 weeks or 420 mg SQ month); Inclisiran administered at 284 mg at baseline, 3 months and then every 6 months. (C)1For all patients with PAV >10.0%, suggest check Lp(a) >50 mg/dL or >125 nmol/L, consider PCSK9 inhibitors as first-line lipid-lowering agent. 2PCSK9 inhibitors include: alirocumab (starting 75 mg/2 weeks or 300 mg/4 weeks, maintenance 150 mg/2 weeks or 300 mg/4 weeks); evolocumab (140 mg/2 weeks or 420 mg/month). *For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision-making to ensure patient literacy of elevated bleeding risk. (D)1For all patients with PAV >10.0%, suggest check Lp(a) >50 mg/dL or >125 nmol/L, consider PCSK9 inhibitors as first-line lipid-lowering agent. 2PCSK9 inhibitors include: alirocumab (starting 75 mg/2 weeks or 300 mg/4 weeks, maintenance 150 mg/2 weeks or 300 mg/4 weeks); evolocumab (140 mg/2 weeks or 420 mg/month). 3See dosing table. 4Pending Food and Drug Administration approval, availability, and safety profile. *For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision-making to ensure patient literacy of elevated bleeding risk. LDL = low-density lipoprotein; PAV = percent atheroma volume; QD = once a day; SQ = subcutaneous.
Supplementary Figure 1“Treat Disease” algorithms for patients with dyslipidemia. (B)1PCSK9 inhibitors include: alirocumab (starting 75 mg/2 weeks or 300 mg/4 weeks, maintenance 150 mg/2 weeks or 300 mg/4 weeks); evolocumab (140 mg/mL SQ 2 weeks or 420 mg SQ month); Inclisiran administered at 284 mg at baseline, 3 months and then every 6 months. (C)1For all patients with PAV >10.0%, suggest check Lp(a) >50 mg/dL or >125 nmol/L, consider PCSK9 inhibitors as first-line lipid-lowering agent. 2PCSK9 inhibitors include: alirocumab (starting 75 mg/2 weeks or 300 mg/4 weeks, maintenance 150 mg/2 weeks or 300 mg/4 weeks); evolocumab (140 mg/2 weeks or 420 mg/month). *For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision-making to ensure patient literacy of elevated bleeding risk. (D)1For all patients with PAV >10.0%, suggest check Lp(a) >50 mg/dL or >125 nmol/L, consider PCSK9 inhibitors as first-line lipid-lowering agent. 2PCSK9 inhibitors include: alirocumab (starting 75 mg/2 weeks or 300 mg/4 weeks, maintenance 150 mg/2 weeks or 300 mg/4 weeks); evolocumab (140 mg/2 weeks or 420 mg/month). 3See dosing table. 4Pending Food and Drug Administration approval, availability, and safety profile. *For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision-making to ensure patient literacy of elevated bleeding risk. LDL = low-density lipoprotein; PAV = percent atheroma volume; QD = once a day; SQ = subcutaneous.
Supplementary Figure 2“Treat Disease” algorithms for patients with diabetes. (A) If patient LDL >70 mg/dL, please refer to Lipid algorithm; standard lipid guidelines apply. (B)1If patient LDL >70 mg/dL, please refer to Lipid algorithm; standard lipid guidelines apply. 2See dosing table. (C)1If patient LDL >70 mg/dL, please refer to Lipid algorithm; standard lipid guidelines apply. 2See dosing table. *For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision-making to ensure patient literacy of elevated bleeding risk. (D)1If patient LDL >70 mg/dL, please refer to Lipid algorithm; standard lipid guidelines apply. 2See dosing table. 3Pending Food and Drug Administration approval, availability, and safety profile. *For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision-making to ensure patient literacy of elevated bleeding risk. GLP = glucagon-like peptide; HgbA1c = glycosylated hemoglobin; LDL = low-density lipoprotein; SGLT2 = sodium-glucose transport protein 2.
Supplementary Figure 2“Treat Disease” algorithms for patients with diabetes. (A) If patient LDL >70 mg/dL, please refer to Lipid algorithm; standard lipid guidelines apply. (B)1If patient LDL >70 mg/dL, please refer to Lipid algorithm; standard lipid guidelines apply. 2See dosing table. (C)1If patient LDL >70 mg/dL, please refer to Lipid algorithm; standard lipid guidelines apply. 2See dosing table. *For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision-making to ensure patient literacy of elevated bleeding risk. (D)1If patient LDL >70 mg/dL, please refer to Lipid algorithm; standard lipid guidelines apply. 2See dosing table. 3Pending Food and Drug Administration approval, availability, and safety profile. *For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision-making to ensure patient literacy of elevated bleeding risk. GLP = glucagon-like peptide; HgbA1c = glycosylated hemoglobin; LDL = low-density lipoprotein; SGLT2 = sodium-glucose transport protein 2.
Supplementary Figure 3“Treat Disease” algorithms for patients with obesity or tobacco use. 1WildingJP, Batterham RL, Calanna S et al. N Engl J Med 2021; 384-989-1002. 2Poirier P, Comier MA, Mazzone T et al. Circulation 2011.
Supplementary Figure 4“Treat Disease” algorithms for patients with hypertension. ACC = American College of Cardiology; AHA = American Heart Association. 1Welton PK, Carey RM, Aronow WS et al. Hypertension 2018; 71:e13-115.
Several important issues should be considered when applying the Atherosclerosis Treatment Algorithms into daily clinical practice:
•
Atherosclerosis Treatment Algorithms emphasize patient-based, rather than lesion-based, measures of atherosclerosis burden and progression. We advocate the concept of assessing the “vulnerable patient” over that of the “vulnerable plaque.” In part, this may be due to the dynamism of atherosclerosis and morphologic changes over time that contribute to the likelihood of any given plaque to become culprit in future acute coronary syndrome.
The authors' current thinking is that morphologic quantitative assessment of plaques alone is inadequate to precisely pinpoint lesions at risk of becoming culprit, and that significant contributors to major adverse cardiovascular events risk beyond atherosclerosis itself—such as inflammation and thrombosis—will improve predictive precision.
•
Atherosclerosis Treatment Algorithms highlight total atherosclerosis burden rather than focusing on a specific plaque composition. The preponderance of prognostic data has emphasized overall atherosclerotic burden for risk stratification.
Use of high-risk coronary atherosclerotic plaque detection for risk stratification of patients with stable chest pain: a secondary analysis of the PROMISE randomized clinical trial.
Low-attenuation noncalcified plaque on coronary computed tomography angiography predicts myocardial infarction: results from the multicenter SCOT-HEART trial (Scottish Computed Tomography of the HEART).
As future studies are performed examining the differential prognostic utility of atherosclerotic plaques by compositional phenotype, the Atherosclerosis Treatment Algorithms may be updated accordingly to account for not only atherosclerosis stage, but also classification of phenotypic disease type.
•
Atherosclerosis Treatment Algorithms do not incorporate advanced atherosclerosis markers of risk by coronary CTA (eg, high-risk plaques). Several high-risk features have been observed by coronary CTA to be predictive of future major adverse cardiovascular events, including low-density non-calcified plaque, positive remodeling, and others.
We elected not to include these Atherosclerosis Treatment Algorithms for reasons of simplicity, and to offer a single integrated metric (percent atheroma volume) that represents a patient's total atherosclerotic burden.
Atherosclerosis Treatment Algorithms propose longitudinal coronary CTA-based evaluation commensurate to the burden of disease. Given that baseline plaque burden is the strongest predictor of plaque progression, we reasoned that those with higher atherosclerotic burden should undergo re-evaluation after therapeutic initiation at a shorter inter-scan interval than individuals with lesser amounts of disease. A 4-3-2-1-year inter-scan interval for repeat coronary CTA was considered reasonable for patients with Stage 0, 1, 2, and 3 atherosclerosis, respectively.
Future Outlook
As additional evidence is developed, we expect the Atherosclerosis Treatment Algorithms to evolve to include other features; for example:
•
Atherosclerotic Plaque Composition. Given the continuum of prognosis that has been observed across the continuum of Hounsfield unit gray scale (ie, lower-density = greater risk, higher density = lower risk), incorporating continuous measures of plaque compositions may improve understanding of patient- and plaque-level risk.
Additional Atherosclerosis Features. In addition to measures of high-risk plaque—such as low-density non-calcified plaque and positive remodeling—several other atherosclerosis and vascular morphology features have been demonstrated to impart prognostic importance.
These include plaque location, diffuseness, geometry, vessel and lumen volume; and may accentuate evaluation of those undergoing coronary CTA .
As prior treatment trials have emphasized surrogate markers of coronary artery disease in lieu of coronary artery disease itself, our proposed approach to targeting atherosclerosis as the primary disease target is intuitive but unproven. Validation of the Atherosclerosis Treatment Algorithms will require randomized trials and observational cohort studies, which are ongoing. Given the multitude of available treatments for coronary artery disease, it is likely that real-world strategy trials that enable comparison of an approach to atherosclerosis treatment will be most informative.
Economic Implications of a Personalized Approach to Coronary Artery Disease Diagnosis
The Atherosclerosis Treatment Algorithms incorporate an array of novel, highly effective medications, some of which are costly.
There are ∼40 million in the United States alone who may qualify for these therapies based upon risk factors.
Prescribing paradigm shift? Applying the 2019 European Society of Cardiology-led guidelines on diabetes, prediabetes, and cardiovascular disease to assess eligibility for sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists as first-line monotherapy (or add-on to metformin monotherapy) in type 2 diabetes in Scotland.
However, in both symptomatic and population-based cohorts, the majority of individuals with coronary artery disease risk factors do not, in fact, possess significant coronary artery disease.
Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clinical trial.
Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease.
In this regard, a precision diagnostics approach to serve as a judicious referral management tool that espouses the “right treatment for the right patient at the right time” based upon quantitative disease burden may allow for a more rationale and individualized approach to guide therapy. This approach may reduce the economic burden for the physician and Pharmacy Benefit Manager. At present, more than $80,000 per physician per annum is spent on prior authorizations.
A personalized approach with objective measures of disease may be effective at curbing prior authorization costs while ensuring that the patients receive the most appropriate medications. These cost savings should be balanced by the cost of coronary CTA, which may in some instances be performed serially. At present, the approximate Medicare reimbursement for coronary CTA is ∼$180 USD.
Conclusion
The authors describe a precision heart care approach that emphasizes atherosclerosis as the primary disease target for evaluation and treatment. By integrating visualized coronary atherosclerosis with risk factors to personalize therapy, Atherosclerosis Treatment Algorithms are, to our knowledge, the first to propose using coronary atherosclerosis burden and progression to personalize therapy selection and therapy changes, respectively.
2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clinical trial.
Coronary computed tomographyangiography versus intravascular ultrasound for estimation of coronary stenosis and atherosclerotic plaque burden: a meta-analysis.
Automatic quantification and characterization of coronary atherosclerosis with computed tomography coronary angiography: cross-correlation with intravascular ultrasound virtual histology.
Optimized prognostic score for coronary computed tomographic angiography: results from the CONFIRM registry (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter Registry).
Use of high-risk coronary atherosclerotic plaque detection for risk stratification of patients with stable chest pain: a secondary analysis of the PROMISE randomized clinical trial.
Low-attenuation noncalcified plaque on coronary computed tomography angiography predicts myocardial infarction: results from the multicenter SCOT-HEART trial (Scottish Computed Tomography of the HEART).
Stress myocardial perfusion imaging vs coronary computed tomographic angiography for diagnosis of invasive vessel-specific coronary physiology: predictive modeling results from the computed tomographic evaluation of atherosclerotic determinants of myocardial ischemia (CREDENCE) trial.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results.
Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease.
The EVAPORATE trial provides important mechanistic data on plaque characteristics that have relevance to the REDUCE-IT results and clinical use of icosapent ethyl.
Prescribing paradigm shift? Applying the 2019 European Society of Cardiology-led guidelines on diabetes, prediabetes, and cardiovascular disease to assess eligibility for sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists as first-line monotherapy (or add-on to metformin monotherapy) in type 2 diabetes in Scotland.
Conflicts of Interest: DLB discloses the following relationships—Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences; Boston VA Research Institute: Bristol Myers Squibb, Board of Directors, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi: Cleerly, Research Funding, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Takeda.
JKM discloses the following relationships: Cleerly (employment and equity interest); Arineta (advisory board); National Institutes of Health (grant funding).
AMF discloses the following relationships: Non-promotional speaking for Boehringer-Ingelheim, Consulting for Medtronic.
MA discloses: She receives honoraria for speaking and royalties from books. She conducts research with Flourish, Inc and through this, she is the primary investigator for a study with IQVIA.
JPE discloses: Employed by Cleerly; Equity Holding in Cleerly.
Authorship: All authors contributed through data collection, collation, manuscript writing, manuscript editing, and figure creation.
For patients at bleeding risk, use of rivaroxaban and aspirin is suggested only after shared decision making to ensure patient literacy of elevated bleeding risk.
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