Prognostic Utility of Risk Enhancers and Coronary Artery Calcium Score Recommended in the 2018 ACC/AHA Multisociety Cholesterol Treatment Guidelines Over the Pooled Cohort Equation: Insights From 3 Large Prospective Cohorts

Abstract

Background Limited data exist on the incremental value of the risk enhancers recommended in the 2018 American Heart Association/American College of Cardiology (ACC/AHA) cholesterol treatment guidelines in addition to the pooled cohort equation. Methods and Results Using pooled individual-level data from 3 epidemiological cohorts involving 22 942 participants (56% women, mean age 59 years), we evaluated the predictive ability of the risk enhancers and coronary artery calcium (CAC) score for atherosclerotic cardiovascular disease, and determined their incremental utility using the C statistic, net reclassification index, and integrated discrimination index. A total of 1960 (8.5%) atherosclerotic cardiovascular disease events were accrued over 10 years. Of the 10 risk enhancers evaluated, only 6 predicted atherosclerotic cardiovascular disease independent of the pooled cohort equation. However, the individual enhancers demonstrated little or no incremental benefit. There was more incremental value from combining the 6 enhancers into an aggregate score (hazard ratio [HR], 1.21; 95% CI, 1.08-1.37 for each additional enhancer), and having ≥3 enhancers represents an optimum threshold for incremental prediction (C statistic, 0.766; net reclassification index, 0.041; integrated discrimination index, 0.010; P≤0.007). On the other hand, CAC was superior to individual enhancers (C statistic, 0.774; net reclassification index, 0.073; integrated discrimination index, 0.010; P<0.001), reliably reclassifies intermediate-risk participants with <3 risk enhancers (event rate, 3.5% if no CAC and 9.8% if positive CAC), but offered no reclassification among participants with ≥3 enhancers. Conclusions The individual risk enhancers evaluated in this study provided no or only marginal incremental information added to the pooled cohort equation. However, the presence of ≥3 risk enhancers reliably identified intermediate-risk patients that will benefit from statin therapy, and further CAC testing may be considered among those with <3 risk enhancers.

Keywords: cholesterol; guidelines; pooled cohort equation; risk factors.

Figure 1. Strength of association among 2018 guideline‐recommended risk enhancers after adjusting for the pooled cohort equation.

Coronary artery calcium (CAC) score is provided for comparison. ABI indicates ankle‐brachial index; ApoB, apolipoprotein B; CVD, cardiovascular disease; HR, hazard ratio; hsCRP, high‐sensitivity C‐reactive protein; LDL‐C, low‐density lipoprotein cholesterol; Lp(a), lipoprotein (a); and non‐HDL‐C, non–high‐density lipoprotein cholesterol.

Figure 2. Rate of incident atherosclerotic cardiovascular disease (ASCVD) by number of significant risk enhancers (high‐sensitivity C‐reactive protein ≥2 mg/L, apolipoprotein B ≥130 mg/dL, chronic kidney disease, family history of premature cardiovascular disease, lipoprotein (a) ≥50 mg/dL, and ankle‐ brachial index <0.9) and coronary artery calcium (CAC) score.

A, Irrespective of risk category. B, Among participants with intermediate risk.

Figure 3. Interaction between coronary artery calcium (CAC) score and risk enhancer for rate of incident atherosclerotic cardiovascular disease (ASCVD) among participants with intermediate risk.