Nontraditional Risk Factors Among Patients Ineligible for Statins

Study Questions:

Does the use of additional clinical information beyond that included in the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score identify adults with a risk score <7.5% who may benefit from statin therapy?


Data from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort were used for the present study. Adults free of clinical CVD at baseline were included. Calibrated Pooled Cohort Equations (cPCEs) were created for each participant using the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline for treatment of cholesterol with statin therapy and the risk score tool. ASCVD was defined as myocardial infarction, coronary heart disease death, and fatal or nonfatal stroke. For participants who had a cPCE <7.5%, additional risk markers were examined; these included a low-density lipoprotein (LDL) ≥160 mg/dl, family history of ASCVD (FH), high-sensitivity C-reactive protein (hs-CRP) ≥2 mg/dl, and a coronary artery calcium (CAC) score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity, and an ankle-brachial index (ABI) <0.9. Absolute and relative risk were examined for those with and without abnormal risk markers. The number needed to screen to identify one person with abnormal test (NNSI) for each risk marker, defined as the number of participants with baseline cPCE risk <7.5% divided by number with abnormal test reclassified as statin eligible, was examined for each additional risk factor.


The MESA cohort includes 6,814 adults; after excluding those with missing data or who were on statins, 5,185 participants remained. A total of 4,185 participants had a cPCE risk <7.5%. Over 10 years of follow-up, 57 of the ASCVD events occurred among those who has a risk <7.5%. After excluding those with diabetes, CAC information reclassified 6.8% of those participants to a higher risk (event rate of 13.3%, with a NNSI of 14.7. Other markers also identify participants at increased risk, although to a lesser degree, including FH (event rate 4.6% and NNSI 21.8), hs-CRP (event rate 2.6% and NNSR 39.2), ABI (event rate 0.6% and NNSI 176.5%) and LDL >160 mg/dl (event rate 0.5% and NNSI 193.2). An estimated 11.1% of these participants would be reclassified to higher 10-year ASCVD risk and be considered eligible for statin therapy.


The authors concluded that among generally low-risk US adults, a large proportion of ASCVD events occur even when the 10-year calculated PCE is <7.5%. Using CAC, hs-CRP, FH, and ABI, the authors observed higher than expected event rates. They concluded that such subgroups may benefit from statin therapy even when a 10-year ASCVD risk is calculated to be <7.5%.


This thoughtful analysis of a multiethnic population estimated risk for additional factors not included in current risk tool, yet may be useful to identify those with a low 10-year risk, but who may benefit from statin therapy. Prospective evidence is an important next step in refining the use of such tests in conjunction with the ASCVD risk tool and the 2013 ACC/AHA cholesterol guideline.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Ankle Brachial Index, Atherosclerosis, C-Reactive Protein, Cholesterol, Coronary Artery Disease, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, LDL, Myocardial Infarction, Primary Prevention, Risk Factors, Stroke

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