Incremental prognostic value of coronary artery calcium progression within a large community-benefit calcium score registry

Coronary artery calcium (CAC) scoring is a robust cardiovascular risk marker, yet the prognostic value of serial assessment and the relative importance of incident calcium versus progression from elevated baseline CAC remains incompletely defined. We analyzed 4,166 CLARIFY registry participants (NCT04075162) who underwent ≥2 CAC scans ≥11 months apart (mean interval 4.5 years). Defining CAC progression (ΔCAC>10 Agatston units, AU) identified 1,982 progressors and 2,184 non-progressors. Annualized absolute, square-root, and log-transformed progression were evaluated for association with major adverse cardiovascular events (MACE: myocardial infarction, stroke, mortality, revascularization, and heart failure). Incremental prognostic value was assessed by adding annualized progression to the base MESA-CAC model incorporating baseline CAC, demographics, and traditional risk factors. Over a median 5.9 year follow-up, progressors had higher MACE incidence, though risk gradients differed by baseline CAC. Incident CAC from a baseline zero score was not associated with increased MACE (all p>0.60). However, progression of established CAC was associated with nearly double 5-point MACE (HR 1.96 [1.38–2.80]; p<0.001) which persisted across baseline CAC strata of 1–100, 101–200, and >200 AU (HR 1.74–2.65; all p<0.01). Annualized progression independently predicted events, most strongly using log-transformed metrics (overall cohort HR 1.27 [1.15–1.41]; p<0.0001). Associations persisted across smokers, diabetics and statin-users. Adding annualized progression to the base MESA-CAC model improved net risk reclassification (NRI ∼0.10). Serial CAC imaging may provide incremental prognostic value in individuals with pre-existing atherosclerosis. While incident CAC after a baseline zero score may confer limited short-term risk, it may present a window for preventive intervention.