The document outlines the 6 steps of evaluating a novel biomarker for cardiovascular risk from early studies establishing a correlation between the biomarker and disease, to prospective validation in cohort studies, determining incremental predictive value over existing measures, evaluating if the marker changes risk enough to alter treatment, clinical outcomes trials, and finally cost-effectiveness analysis. It specifically discusses the evaluation of coronary artery calcium scoring, which is currently in the planning stages for a large clinical outcomes trial over 6-8 years to complete all 6 steps from initial studies to determining if measuring it improves health outcomes.

1. Coronary calcium and other CVD risk biomarkers: From epidemiology to comparative effectiveness research Philip Greenland, MD

2. Coronary Artery Calcium Score as a model of translational research: From “Basic Science” to “Clinical Utility”

3. Criteria for evaluation of novel markers of cardiovascular risk Hlatky MA, Greenland P, et al. Circulation 2009;119: 2408-16.

7. Rumberger J A et al. Circulation 1995; 92: 2157-2162. Copyright © American Heart Association

8. Step 1C: Proof of Concept for Prediction in Asymptomatic People

9. Step 1C: Proof of Concept for Prediction in Asymptomatic People

10. Step 1C: Proof of Concept for Prediction in Asymptomatic People

11. Step 2: Prospective Validation in a Cohort Study Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. JAMA. 2004 Jan 14;291(2):210-5.

12. Step 3: Incremental Value for Prediction Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. JAMA. 2004 Jan 14;291(2):210-5.

13. Step 3: Incremental Value for Prediction (2008)

14. Step 3: Incremental Value for Prediction (2008)

15. Step 3: Incremental Value for Prediction (2008)

16. Step 3: Incremental Value for Prediction (2008)

17. Step 3: Incremental Value for Prediction (2008)

18. Step 4: Clinical Utility (2010): Does the Marker Change Predicted Risk Enough to Change Rx? Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, Burke GL, Guerci AD, Greenland P. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA. 2010 Apr 28;303(16):1610-6.

21. Step 6: Cost Effectiveness?

22. VIEW Your Heart Trial: A proposed NHLBI-endorsed clinical trial

27. From the Website of The Society for Heart Attack Prevention and Eradication (SHAPE): The Society for Heart Attack Prevention and Eradication was formed to redefine preventive heart health. We are the only non-profit organization that is dedicated to ending the threat of heart attack. To accomplish our immediate objectives we are focused on promoting the SHAPE Guideline, a screening protocol that builds on the old paradigm in cardiology, risk factor detection and treatment.

29. “ There should be no double standard. Biomedical researchers have performed large-scale randomized trials on a variety of screening tests, and screening tests for coronary artery disease should be subject to the same level of rigor. It is not at all clear that the risk stratification paradigm is the best way to reduce substantially the burden of clinically active coronary artery disease in our population. “

30. “ Our next step is to have the humility to admit that we do not know which approach or combination of approaches is best, but that, in the public interest, we will join forces to design and implement the definitive large-scale randomized trials that our patients and the public should rightly demand.”

32. Criteria for evaluation of novel markers of cardiovascular risk Hlatky MA, Greenland P, et al. Circulation 2009;119: 2408-16. More than 50 years from Phase 1 to Phase 5!