Novel Risk Factors Improve Prediction of Cardiovascular Disease in Intermediate-Risk Persons

February 12, 2013

It has been predicted that costs for cardiovascular disease will increase to more than $1 trillion dollars annually in the US by 2030. If statins are effective in preventing heart disease, why are costs still rising?

Many years ago (the cohort was assembled from 1949-1951 and followed thereafter) in Framingham, Massachusetts, cardiovascular risk prognostication was born by way of the Framingham Risk Score.1 (FRS calculation tool can be accessed here.) The study itself has exceeded 5 decades.

The FRS uses “traditional” risk factors-including age, sex, elevated cholesterol level, family history, decreased HDL level, smoking, hypertension, diabetes, obesity, and a sedentary lifestyle. It continues to be used today and classifies individuals as high, intermediate, or low risk for cardiovascular events. There has been one lingering problem with the FRS, however: the intermediate-risk group is heterogeneous. That is, individuals at intermediate risk include high-risk folks who may benefit from more aggressive risk reduction (with 1 or more medications for lower lipid targets).2 Conversely, other people in this group are at lower risk and need only lifestyle measures.2

Decades have passed since the FRS became a tool, and novel risk factors have been subsequently validated. These include carotid intima-media thickness (CIMT), coronary artery calcium scores on CT (CACs), brachial-mediated flow dilatation (FMD, a new one for this author), ankle-brachial index (ABI), C-reactive protein (CRP) level, and a family history of heart disease.2

Can these novel predictors better separate intermediate-risk people into lower- and higher-risk categories after scoring by the FRS? Another cohort (N = 6814; mean follow-up, 7.6 years)-people enrolled in the MESA Study (Multi-Ethnic Study of Atherosclerosis)3-was used to answer that question. If individuals incurred a myocardial infarction, stroke (CVD), or cardiovascular heart death (CHD); were resuscitated for a cardiac arrest; or experienced angina followed by revascularization during study follow-up, they were classified as incident CHD and CVD. This subset was the outcome group. The results will add precision to cardiac risk prognostication in intermediate-risk individuals.

After multivariable analysis, CAC provided the highest improvement in discrimination compared with the FRS alone (hazard ratio = 2.60; 95% confidence interval, 1.94-3.50; P < .001). Framed in another manner, adding CAC to the FRS correctly reclassified 66% of intermediate-risk persons compared with adding more parameters to family history (16%), CIMT (10.2%), CRP (7.9%), and ABI (3.6%). To emphasize the significance of CAC as a predictor, the Rotterdam and Eisner Studies also found that the test improves predictive value.4,5 Although CAC was a superior discriminator, with univariable analysis, some of the other tests-FMD, ABI, CIMT, and family history-may become significant additions as well.6 

Is the greater precision worth the radiation, expense, and effort?

The answer is yes-but must be justified. It has been predicted that costs for cardiovascular disease will increase to more than $1 trillion annually in the US by 2030.7,8 If statins are effective in preventing heart disease, why are costs still rising? Despite the proven efficacy of statins, many individuals are left with significant residual risk. Risk is the topic of my next 2 reports.          


1. Kannel WB. The Framingham Study: historical insight on the impact of cardiovascular risk factors in men versus women. J Gend Specif Med. 2002;5:27-37.
2. Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA. 2012;308:788-795.
3. Criqui MH, McClelland R, McDermott MM, et al. The ankle-brachial index and incident cardiovascular disease events in the MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2010;56:1506-1512.
5. Kavousi M, Elias-Smale S, Rutten JH, et al. Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study. Ann Intern Med. 2012;156:438-444.
6. Rozanski A, Gransar H, Shaw LJ, et al. Impact of coronary artery calcium scanning on coronary risk factors and downstream testing. The Eisner (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) Prospective Randomized Trial. J Am Coll Cardiol. 2011;57:1622-1632.
7. Steinberg DI. Clinical Prediction Guide. ACP Journal Club. Ann Intern Med. 2012;157:IC6-IC13.
8. Mohamad TN, Subhi Y. Primary and secondary prevention of coronary artery disease.