Coronary calcium and other CVD risk biomarkers: From

epidemiology to comparative effectiveness research

Philip Greenland, MD

Coronary Artery Calcium Score as a model of translational research: From

“Basic Science” to “Clinical Utility”

Criteria for evaluation of novel markers of cardiovascular risk

Hlatky MA, Greenland P, et al.

Circulation 2009;119: 2408-16.

Step 1A: Proof of Concept

Earliest studies suggesting that coronary calcium correlated with coronary atherosclerosis by autopsy and coronary angiography.

– Blankenhorn DH, Stern D. Calcification of the coronary arteries. Am J Roentgenol. 1959;81:772-777.

– Rifkin RD, Parisi AF, Folland E. Coronary calcification in the diagnosis of coronary artery disease. Am J Cardiol. 1979;44:141-147.

Step 1B: Proof of Concept of Cardiac CT

for CAC Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827-832.

Rumberger JA, Schwartz RS, Simons DB, Sheedy PF, Edwards WD, Fitzpatrick LA. Relation of coronary calcium determined by electron-beam computed tomography and lumen narrowing determined at autopsy. Am J Cardiol. 1994;73:1169-1173.

Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation. 1995 Oct 15;92(8):2157-62.

Step 1B: Proof of Concept of Cardiac CT

for CAC Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz

RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation. 1995 Oct 15;92(8):2157-62.

– Thirty-eight coronary arteries from 13 autopsy hearts were dissected, straightened, and scanned with EBCT in 3-mm contiguous increments.

– Coronary calcium area was defined as one or more pixels with a density > 130 Hounsfield units (0.18 mm2/pixel).

– Each artery was divided into corresponding 3-mm segments, representative histological sections were stained, and atherosclerotic plaque area per segment (mm2) was quantified.

– Coronary artery calcium and coronary artery plaque areas were correlated for the hearts as a whole, for individual coronary arteries, and for individual coronary artery segments.

– The sums of histological plaque areas versus the sums of calcium areas were highly correlated for each heart and for each coronary artery.

Rumberger J A et al. Circulation 1995; 92: 2157-2162.

Copyright © American Heart Association

Step 1C: Proof of Concept for Prediction in Asymptomatic

People

Step 1C: Proof of Concept for Prediction in Asymptomatic

People

Step 1C: Proof of Concept for Prediction in Asymptomatic

People

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.

Step 3: Incremental Value for Prediction

Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. JAMA. 2004 Jan 14;291(2):210-5.

Step 3: Incremental Value for Prediction (2008)

Step 3: Incremental Value for Prediction (2008)

Step 3: Incremental Value for Prediction (2008)

Step 3: Incremental Value for Prediction (2008)

Step 3: Incremental Value for Prediction (2008)

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.

Step 5: Clinical Outcomes

Clinical Trial is in the planning stages and may be completed within the next 6-8 years!

This question is one of the Institute of Medicine “Top 100” comparative effectiveness topics.

Step 6: Cost Effectiveness?

VIEW Your Heart Trial: A proposed NHLBI-endorsed

clinical trial

Background

More than 50% of CHD events occur in people with estimated CHD risk in the “intermediate” and “low risk” categories.

Many of these people would not qualify for statins under current guidelines

Methods that extend beyond traditional risk factors are needed to identify who is at risk for a CHD event and could potentially benefit from statin therapy

Potential advantages of CAC Testing

Easily obtained, highly reproducible May help identify additional patients who

would benefit from statin therapy May improve adherence May also identify who is at very low risk and

doesn’t need a statin May improve cost-effectiveness of prevention

Potential disadvantages of CAC

Cost Downstream testing Radiation exposure

Differing Views Regarding Non-Invasive Testing for Detection of CHD Risk

• “Get noninvasive studies in most patients” • Society for Heart Attack Prevention and Eradication (SHAPE):

a private organization that has convinced the State of Texas to require insurance companies to fund non-invasive screening

• Shah PK. Atherosclerosis Research Center, Division of Cardiology and Cedars Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles (Expert Cardiologist)

• “Get more data first – need a trial”• Lauer MS. Director, Division of Cardiovascular Sciences,

National Heart, Lung, and Blood Institute, Bethesda (representing NHLBI)

• US Preventive Services Task Force, Agency for Healthcare Research and Quality, Bethesda.

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.

  

“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. “

“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.”

Value of Imaging in Enhancing the Wellness of Your Heart Trial

30,000 people Multi-center --- Primary Care Patients EHR screening FRS >5% and <10% 10-year risk >$80 million in direct costs Accepted for review at NHLBI If funded, could begin in 2012

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!

2010 ACCF/AHA Guideline

RECOMMENDATIONS FOR CALCIUM SCORING METHODS

CLASS IIa1. Measurement of CAC is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (10% to 20% 10-year risk). (Level of Evidence: B)

CLASS IIb1.Measurement of CAC may be reasonable for cardiovascular risk assessment in persons at low to intermediate risk (6% to 10% 10-year risk). (Level of Evidence: B)

CLASS III: NO BENEFIT1.Persons at low risk (<6% 10-year risk) should not undergo CAC measurement for cardiovascular risk assessment. (Level of Evidence: B)

EVIDENCE FOR IMPROVED NET HEALTH OUTCOMES?“Evidence is not available to show that risk assessment using CAC scoring improves clinical outcomes by reducing mortality or morbidity from CAD.”