Coronary artery calcium to guide treatment in primary prevention—can we afford not to?

This editorial refers to ‘Association between REDUCE-IT criteria, coronary artery disease severity and cardiovascular events: The Western Denmark Heart Registry’, by M.B. Mortensen et al.https://doi.org/10.1093/eurjpc/zwac104. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines shifted the paradigm towards a largely risk-based approach to cholesterol treatment.1 For primary prevention of atherosclerotic cardiovascular disease (ASCVD), rather than relying on cholesterol levels, the 2013 guidelines recommended calculating a 10-year estimate of absolute ASCVD risk using the Pooled Cohort Equation to guide treatment decisions. At the time of the 2013 guidelines, there was evidence supporting use of statin therapy to reduce ASCVD risk but minimal data to support use of other lipid-lowering medications. However, almost a decade later, several other classes of lipid-lowering agents have now been shown to reduce ASCVD risk including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and icosapent ethyl. Given the high cost of several of these agents, how to best allocate them in primary prevention remains a subject of debate and provides a need for effective methods of risk stratification. For further risk assessment beyond estimation of 10-year absolute risk, coronary artery calcium (CAC) has emerged as the most effective risk stratification tool for primary prevention of ASCVD. Coronary artery calcium is associated with a significant increase in the incidence of coronary events with zero CAC being very low risk for ASCVD.2 Coronary artery calcium is an effective risk stratification tool regardless of age, and total plaque burden, as assessed by CAC, is a more powerful predictor of future ischaemic coronary events compared with the degree of coronary stenosis.3 In 2015, further research modelled the utility of CAC in the context of the 2013 ACC/AHA guidelines as tool to guide decision-making for statin therapy.4 Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), Nasir et al. showed that more than 40% of individuals who were statin eligible by the 2013 guidelines had zero CAC and an ASCVD event rate substantially lower than their estimated 10-year ASCVD risk, indicating they were less likely to benefit from statin therapy. This concept of utilizing CAC when decisions about the risks and benefits of statin therapy are unclear was adopted by the 2018 AHA/ACC multi-society cholesterol guidelines.5 Coronary artery calcium can also guide treatment decisions for several other preventive therapies including aspirin and anti-hypertensive agents.6,7 Coronary artery calcium also has potential to refine allocation of preventive medications for those meeting eligibility criteria for randomized controlled trials that showed ASCVD risk reduction. This concept was first described by Blaha et al.8 in MESA participants who met eligibility criteria for JUPITER, a trial testing rosuvastatin for ASCVD prevention in low-to-intermediate risk middle-aged adults. Of the 950 MESA participants who met trial eligibility criteria for JUPITER, 444 (47%) had zero CAC and a subsequent coronary heart disease event rate of 0.8 per 1000 person years. The estimated number-needed-to-treat (NNT) decreased significantly from 549 of CAC score 0–24 for CAC scores >100. In a similar fashion, in this issue of The European Journal of Preventive Cardiology, Mortenson et al.9 describe an analysis of applying eligibility criteria of the REDUCE-IT trial to a sample of individuals undergoing CT coronary angiography included in the Western Denmark Heart Registry. The REDUCE-IT trial demonstrated a significant reduction in ASCVD events with use of icosapent ethyl in a mixed sample of participants with and without established ASCVD. Mortensen et al. hypothesized that use of CAC could efficiently identify those most likely to benefit from use of icosapent ethyl. The population studied included 2146 patients who underwent a CTA between 2008 and 2017 who fulfilled eligibility criteria outlined for enrolment in REDUCE-IT. The patients were classified as having no CAD (0% luminal stenosis and Agatston CAC score of 0), non-obstructive CAD (<50% luminal stenosis), or obstructive CAD (>50% luminal stenosis). Patients were also classified by calcified atherosclerotic plaque burden (CAC = 0, CAC = 1–299, CAC ≥ 300). Atherosclerotic cardiovascular disease events were defined as MI, stroke, revascularization, or all-cause mortality occurring >90 days after CTA testing. Not surprisingly, stratification according to CTA-defined disease severity (none, non-obstructive, obstructive) provided differentiation of ASCVD risk. The same held true in a stepwise fashion for CAC categories. However, CAC was able to further delineate those patients who were at higher or lower risk regardless of CTA-defined disease severity. For instance, the event rate of patients with obstructive CAD and CAC = 0 was 18.5 per 1000 person years, whereas the event rate of patients with obstructive CAD and CAC >300 was 60.7, an over three-fold increase. In REDUCE-IT, the NNT to avoid the primary end point was 21. In this present study, the 5-year estimated NNT with icosapent ethyl was 45. However, when stratified by CAC, the estimations varied significantly with a 5-year NNT of 87 with CAC = 0 and 17 with CAC ≥ 300, suggesting CAC should influence treatment decisions for the use of icosapent ethyl for primary prevention of ASCVD. This study does have limitations. Ultimately, these are estimations based on observational data. In REDUCE-IT, 70% had established ASCVD whereas individuals with prior MI or revascularization were excluded from the current analysis. Treatment of individuals in this cohort almost certainly varied substantially according to the presence of obstructive vs. non-obstructive coronary disease as well as by total plaque burden, which would then influence the reported event rates and estimated NNTs. Therefore, these results should be interpreted with caution. However, the rationale for the conclusions is logical and in line with the growing body of evidence that CAC, as a measure of atherosclerotic plaque burden, is the most effective tool available to guide the allocation of various preventive treatments. This concept is appealing given the high cost of icosapent ethyl and other novel preventive medications. Recently, it was suggested that CAC should be used to identify high-risk patients for inclusion in randomized trials studying interventions for primary prevention of ASCVD.10 The ability of CAC to identify those at the highest ASCVD risk would allow for trials with smaller sample sizes and shorter durations of follow-up, which could substantially reduce the financial burden of these studies. In a similar fashion and supported by the current analysis by Mortensen et al., making treatment decisions about interventions associated with significant cost, such as icosapent ethyl, for primary prevention of ASCVD without first assessing CAC seems financially unwise and suboptimal for the care of our patients.