Negative Risk Markers for Cardiovascular Events in the Elderly

Background: Cardiovascular risk increases dramatically with age, leading to nearly universal risk-based statin eligibility in the elderly population. To limit overtreatment, elderly individuals at truly low risk need to be identified. Objectives: Discovering “negative” risk markers able to identify elderly individuals at low short-term risk for coronary heart disease and cardiovascular disease. Methods: In 5,805 BioImage participants (mean age 69 years; median follow-up 2.7 years), the authors evaluated 13 candidate markers: coronary artery calcium (CAC) = 0, CAC ≤10, no carotid plaque, no family history, normal ankle-brachial index, test result <25th percentile (carotid intima-media thickness, apolipoprotein B, galectin-3, high-sensitivity C-reactive protein, lipoprotein(a), N-terminal pro–B-type natriuretic peptide, and transferrin), and apolipoprotein A1 >75th percentile. Negative risk marker performance was compared using patient-specific diagnostic likelihood ratio (DLR) and binary net reclassification index (NRI). Results: CAC = 0 and CAC ≤10 were the strongest negative risk markers with mean DLRs of 0.20 and 0.20 for coronary heart disease (i.e., ≈80% lower risk than expected from traditional risk factor assessment) and 0.41 and 0.48 for cardiovascular disease, respectively, followed by galectin-3 <25th percentile (DLR 0.44 and 0.43, respectively) and absence of carotid plaque (DLR 0.39 and 0.65, respectively). Results obtained by other candidate markers were less impressive. Accurate downward risk reclassification across the Class I statin-eligibility threshold defined by the American College of Cardiology/American Heart Association was largest for CAC = 0 (NRI 0.23) and CAC ≤10 (NRI 0.28), followed by galectin-3 <25th percentile (NRI 0.14) and absence of carotid plaque (NRI 0.08). Conclusions: Elderly individuals with CAC = 0, CAC ≤10, low galectin-3, or no carotid plaque had remarkable low cardiovascular risk, calling into question the appropriateness of a treat-all approach in the elderly population.