Cardiovascular (CV) risk prediction has evolved in recent decades, with some developments, such as the use of coronary artery calcium (CAC) scoring, receiving more significant attention than an optimal CV history and physical examination. Other high-yield strategies for personalizing preventive pharmacotherapies, such as assessment for risk-enhancing factors (REFs), remain underexplored.

Clinicians initially focused primarily on traditional risk factors for vascular events identified in the Framingham Heart Study (hypercholesterolemia, smoking, hypertension, and diabetes mellitus [DM]).¹ The ever-expanding literature in the field of preventive cardiology, including the growing recognition and prevalence of CV-kidney-metabolic syndrome has prompted clinicians to incorporate additional risk factors in estimating lifetime risk of cardiovascular disease (CVD).² This change is reflected in the PREVENT (AHA Predicting Risk of CVD Events) risk score, which is based on much larger datasets than previous risk estimators and allow for 10-year and 30-year risk prediction of CVD. The PREVENT risk score can estimate risk of atherosclerotic cardiovascular disease (ASCVD) and heart failure separately. Additionally, the PREVENT risk score incorporates biomarkers such as hemoglobin A1c concentration and urine albumin-to-creatinine ratio.³

Although clinical understanding of CVD has deepened, uncertainty in risk-prediction models remains an issue for clinicians. Whereas the most up-to-date equations allow for more longitudinal and nuanced estimates of risk, many patients fall somewhere in between low-risk and high-risk categories. Thus, decision-making regarding statin initiation must acknowledge gray areas and allow for patient preference.

CV risk estimators are designed to operate at a population level and often overestimate or underestimate an individual patient's risk. This discrepancy is especially important for patients at intermediate risk of ASCVD, defined as 7.5-19.9% over 10 years using the Pooled Cohort Equations (PCE), given that the PCE may overestimate risk in healthier populations. In this risk range, American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend a risk-benefit discussion between the patient and clinician to inform statin initiation.⁴

For this group of patients, there are two key toolsets available to augment decision-making. For patients at intermediate risk and when a risk decision is uncertain, coronary computed tomography imaging—specifically a CAC scan—is a well-validated tool for improving risk stratification. However, for all patients at borderline or intermediate risk, clinicians should assess for presence of REFs before measuring CAC.⁵

REFs are clinical conditions or markers that can help guide clinician decision-making and refine estimates of both short-term and long-term CV risk.⁶ Going beyond traditional risk factors used in the PCE, the presence of multiple REFs favors statin therapy for patients at intermediate or borderline risk. In 2013, when REFs were first introduced into the ACC/AHA guidelines, they included family history of premature ASCVD, high-sensitivity C-reactive protein level ≥2 mg/L, CAC score >300, and ankle-brachial index <0.9.⁴ In 2018, the multisociety Guideline on the Management of Blood Cholesterol added the following REFs: elevated lipoprotein(a) (Lp[a]) levels, elevated apolipoprotein(b) (Apo[b]) levels, metabolic syndrome, chronic kidney disease, conditions specific to people with the capacity for pregnancy such as pre-eclampsia or premature menopause (age <40 years), ethnicities with higher risk of adverse CV outcomes (e.g., South Asian ethnicities), inflammatory conditions (e.g., rheumatoid arthritis, HIV, psoriasis, or systemic lupus erythematosus), and persistently elevated low-density lipoprotein cholesterol levels ≥160 mg/dL or non–high-density lipoprotein cholesterol (HDL-C) levels ≥190 mg/dL and elevated triglyceride levels.⁵

Importantly, there are insufficient data to demonstrate that these REFs statistically modify risk on a population level. Unlike the treatable risk-modifying factors used in the PCE, including smoking status, blood pressure, DM status, total cholesterol levels, and HDL-C levels, REFs have associations of variable strength with ASCVD risk. Indeed, the presence or absence of REFs does not markedly change 10-year risk estimates using the PCE.⁷ A 2021 analysis of >22,000 patients in National Heart, Lung, and Blood Institute (NHLBI) cohorts demonstrated that the 10 REFs cited by the 2018 multisociety guideline on cholesterol individually provided no, or only marginal, 10-year risk information. However, 6 of the 10 REFs predicted ASCVD risk independently of the PCE.⁸

Whereas the presence of a single REF was not sufficient to adjust risk prediction, this same analysis demonstrated that the presence of three or more REFs was sufficient to identify which patients at intermediate ASCVD risk would likely benefit from statin initiation, independent of CAC scoring. This finding suggests that, in patients at intermediate risk, the presence of multiple REFs should tip the balance toward statin initiation. This consideration might be useful for patients who are reluctant to pursue CAC scanning due to cost or concerns about radiation exposure, although costs are often under $100 and the radiation dose is small (~1 mSv). However, CAC scoring remains the best tool to reclassify ASCVD risk and, for most patients, a cost-effective way to determine statin eligibility, particularly given that, among patients with intermediate ASCVD risk found to have a CAC score of 0, the presence of even three or more REFs is not associated with elevated ASCVD risk at which statin therapy would be recommended.^9-11

The 2018 multisociety guideline on cholesterol allows for clinician flexibility and shared decision-making (SDM) for patients at intermediate risk.⁵ The 10-year risk estimate should be calculated to determine where the risk discussion begins, not where it ends. The absence or presence of any number of REFs can help personalize decision-making for these patients, independent of a CAC scan. Even if the patient proceeds to a CAC scan, which is recommended if a risk decision is uncertain, REFs can help patients and clinicians appreciate the patients' holistic risk profiles. As further studies around REFs and ASCVD risk prediction develop, future iterations of cholesterol treatment guidelines may highlight the prognostic importance of the presence of multiple REFs in patients at intermediate risk using the PREVENT risk score.

Assessment of REFs is a high-yield approach to refine CV risk estimation and preventive therapies, especially for patients at intermediate CV risk. Family history, ethnicity, comorbidities, obstetric-gynecologic history, and biomarkers including Lp(a) and Apo(b) levels can provide vital data at low cost to arrive at patient-centric solutions. Moreover, REF assessment supports the vision of SDM for patients at borderline or intermediate risk based on a comprehensive assessment of ASCVD risk. The more that clinicians and patients see the whole picture, the greater the impact on CV risk reduction.

References

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