Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate-Risk Individuals

Study Questions:

What is the relative improvement in prediction of incident coronary heart disease (CHD) and cardiovascular disease events (CVEs) by the Framingham Risk Score (FRC) with the addition of other risk markers including coronary artery calcium (CAC), carotid intima–media thickness (CIMT), ankle-brachial index (ABI), brachial flow–mediated dilation, high-sensitivity C-reactive protein (CRP), and family history of CHD within intermediate-risk participants (FRS <5%-<20%) in the MESA (Multi-Ethnic Study of Atherosclerosis) study?


Of 6,814 MESA participants recruited from six US field centers, 1,330 were intermediate risk, without diabetes mellitus, and had complete data on all six markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Probability-weighted Cox proportional hazard models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement were used to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity.


Mean age was 63.8 years, 33% were women, and 36% were white. Approximately 43% had a family history of CHD, median CAC score was 7.0 (interquartile range [IQ], 0-112), median CRP was 1.62 mg/dl (IQ 0.79-3.68 mg/dl), and FRS was 8.8 (IQ 6.5-12.2). After a 7.6-year median follow-up, 94 CHD events (7.1%) and 123 CVEs (9.2%) occurred. CAC, ABI, CRP, and family history were independently associated with incident CHD in multivariable analyses (HR, 2.60; 95% confidence interval [CI], 1.94-3.50; HR, 0.79; 95% CI, 0.66-0.95; HR, 1.28; 95% CI, 1.00-1.64; and HR, 2.18; 95% CI, 1.38-3.42, respectively). CIMT and brachial flow–mediated dilation were not associated with incident CHD in multivariable analyses (HR, 1.17; 95% CI, 0.95-1.45 and HR, 0.95; 95% CI, 0.78-1.14). Although addition of the markers individually to the FRS plus race/ethnicity improved AUC, CAC afforded the highest increment (0.623 vs. 0.784), whereas brachial flow–mediated dilation had the least (0.623 vs. 0.639). For incident CHD, the net reclassification improvement with CAC was 0.659, brachial flow–mediated dilation was 0.024, ABI 0.036, CIMT 0.102, family history 0.160, and CRP was 0.079. Similar results were obtained for incident CV disease (CVD).


CAC, ABI, high-sensitivity CRP, and family history were independent predictors of incident CHD/CVD in intermediate-risk individuals. CAC provided superior discrimination and risk reclassification compared with other risk markers.


Importantly, the approximate 8% total CVE rate in the 7.6-year MESA follow-up supports the use of the FRS in the modern era. The added predictive strength of the CAC score when intermediate risk includes the range of 6-19% is very impressive, as is the relative strength of the CAC score compared to family history, CIMT, and CRP. While there is good reason for a clinical trial to determine the value of CAC independent of classic risk factors, the present evidence supports clinical use in the intermediate risk as defined herein, and particularly if the cost is moderate.

Keywords: Ethnic Groups, Coronary Artery Disease, Bariatric Surgery, Atherosclerosis, Carotid Intima-Media Thickness, Ankle Brachial Index, Coronary Disease, Calcinosis, Risk Factors, C-Reactive Protein, Cardiology, Cardiovascular Diseases, Confidence Intervals, Diabetes Mellitus

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