Determinants of Incident Atherosclerotic Cardiovascular Disease Events Among Those With Absent Coronary Artery Calcium: Multi-Ethnic Study of Atherosclerosis

Background: The 2018 American Heart Association/ American College of Cardiology Multisociety (AHA/ACC/MS) cholesterol guideline states that statin therapy may be withheld or delayed among intermediate risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up. Methods: We included participants with CAC=0 at baseline from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors [cigarette smoking, diabetes mellitus, hypertension, preventive medication use (aspirin and statin), family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers] and adjudicated incident ASCVD outcomes. Results: We studied 3,416 individuals (mean (SD) age 58 (9) years; 63% were female, 33% White, 31% Black, 12% Chinese-American, and 24% Hispanic. Over a median follow-up of 16 years, there were 189 ASCVD events (composite of CHD and stroke) of which 91 were CHD, 88 were stroke, and 10 were both CHD and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000-person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes mellitus (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable-adjustment, risk factors that were significantly associated with ASCVD: hazard ratio (HR) 95% confidence interval (CI) included current cigarette smoking: 2.12 (1.32,3.42), diabetes mellitus: 1.68 (1.01,2.80), and hypertension: 1.57 (1.06,2.33). Conclusions: Current cigarette smoking, diabetes mellitus, and hypertension are independently associated with incident ASCVD over 16-year follow-up among those with CAC=0. Family history of premature ASCVD may be associated with ASCVD risk among women only.