Should We Focus on Novel Risk Markers and Screening Tests to Better Predict and Prevent Cardiovascular Disease? Or Are We Putting the Cart Before the Horse?


Nathan D. Wong, PhD, MPH, President, American Society for Preventive Cardiology, Heart Disease Prevention Program, Sprague Hall 112, University of California, Irvine, CA 92697

Our American Society for Preventive Cardiology–sponsored debate at the recent March 2010 meeting of the American Heart Association Council on Epidemiology and Prevention and Council on Nutrition, Physical Activity and Metabolism was titled “Should We Focus on Novel Risk Markers and Screening Tests to Better Predict and Prevent Cardiovascular Disease?” Dr James DeLemos took the pro side, titled “Novel Risk Markers and Screening Tests Will Improve the Prediction and Prevention of Cardiovascular Disease,” and Dr. Donald Lloyd-Jones took the con side, titled “Better Implementation of Existing Knowledge Will Save More Lives Than All of the Novel Biomarkers in the World.”

Since the development of the original Framingham Risk Scores approximately 20 years ago, there has been increasing interest in the concept of assessing total coronary heart disease (CHD) risk on the basis of simple-to-use and inexpensive office-based measures including total and high-density lipoprotein cholesterol, systolic blood pressure, and knowledge of the patient’s smoking and diabetes status, age, and sex.1,2 More recently, versions of this concept have incorporated newer novel biomarkers such as high-sensitivity C-reactive protein (hs-CRP)3 and also prediction of cardiovascular disease risk,3,4 which is presumably of more interest to most clinicians than CHD risk alone.

While proponents of global risk assessment argue that some 90% of persons experiencing CHD events have at least one major CHD risk factor,5 others have demonstrated that the majority of persons with CHD events would not be identified as being at high risk for CHD by global risk assessment algorithms and thus would not be targeted for aggressive risk factor modification.6 One study also reported that three-fourths of persons experiencing a CHD event would not have been candidates for statin therapy on the basis of current National Cholesterol Education Program guidelines that focus on the global risk assessment approach for identifying threshold levels at which low-density lipoprotein cholesterol should be treated.7

The potentially exciting role for newer biomarkers was ushered into existence by the work of Ridker8 and others more than a decade ago, demonstrating the important role hs-CRP may play in enhancing prediction of CHD risk over global risk assessment and traditional risk factors. The JUPITER trial in persons with elevated hs-CRP has also given us perspective into how such a biomarker can be used clinically to identify persons who might benefit from aggressive statin therapy.9 Moreover, the American Heart Association and Centers for Disease Control have recommended that persons at intermediate risk for CHD may be appropriate for hs-CRP screening.10 Nevertheless, studies have shown that the incremental prediction of CHD offered by hs-CRP over traditional risk factor assessment is minimal at best.11,12

Since the evolution of hs-CRP, the potential role of other biomarkers such as B-type natriuretic peptide and troponin levels, and especially multimarker approaches in the assessment of CHD risk in asymptomatic persons, has become of great interest. However, there are mixed reports regarding the clinical utility of such multimarker approaches for improving risk prediction over traditional risk factors.13–15 Moreover, we know less about therapies that could reduce some of these other biomarkers should we find elevated levels than we know about hs-CRP; thus, the clinical utility of these other markers is less clear.

Probably the most promising approaches for enhancing risk prediction over global risk assessment thus far involves the use of subclinical atherosclerosis measures, such as coronary artery calcium or carotid intimal medial thickness and plaque assessments. Recent reports have demonstrated their clinical utility in terms of reclassifying a significant proportion of individuals for the purpose of stratification of treatment intensity.16–18 However, unlike certain biomarkers, these imaging technologies require investments in specialized equipment and personnel, and while certain national groups have suggested their utility in screening intermediate risk persons,19,20 most insurance groups have yet to cover such screening even in these recommended populations.

While the office-based risk assessment can be done easily in the primary care setting with personnel and other resources typically available, this has yet to be a widespread practice among most clinicians, few of whom even calculate Framingham or other global risk scores. Clearly, one could argue that we need to increase efforts to get clinicians to routinely do global risk assessment before we can begin promoting more advanced risk assessment approaches such as measurement of biomarkers or screening for subclinical atherosclerosis. Often the individual clinician becomes intrigued by new biomarkers or screening tests, perhaps at the expense of the more basic measures and ensuring that key risk factors such as blood pressure, lipids, and glucose are adequately controlled. For instance, recently published data demonstrate that only one-tenth of persons with both hypertension and dyslipidemia have their blood pressure and low-density lipoprotein cholesterol at goal levels,21 and among diabetics, only one-tenth are simultaneously at goal for hemoglobin A1c, low-density lipoprotein cholesterol, and blood pressure.22 While the potential utility of newer biomarkers and screening tests for subclinical atherosclerosis needs to be considered in cases in which they might best provide information that may affect clinical decision making on recommended treatments, it is clear that we have to do a better job in ensuring that standard risk factor evaluations are preformed and that we are making all efforts to control the risk factors for which we have the evidence base of cardiovascular benefit.

The manuscripts provided by Drs Enriquez and DeLemos,23 promoting a forward-thinking view of measurement of novel biomarkers and screening tests, and those by Drs Wilkins and Lloyd-Jones,24 supporting more traditional risk factor evaluation with a more critical view of the using biomarkers for risk assessment, provide important insight into this ongoing debate that is likely to continue for the foreseeable future.