.jpg)
.png)
Evaluation of a patient’s risk for cardiovascular disease (CVD) is the basis of deciding whether to institute statin therapy. The 2013 ACC/AHA Guidelines on the Assessment of Cardiovascular Risk recommend using the Pooled Cohort Equation to predict the 10-year risk of having an atherosclerotic cardiovascular disease (ASCVD) event in non-Hispanic Whites and African Americans, 40 to 79 years of age. This calculation includes all forms of cardiovascular disease, including stroke and coronary heart disease (CHD). Several other risk calculators have been developed to assess an individual’s CVD risk, however, all have limitations. Risk calculators provide a bio-statistical approach that estimates risk for a specific patient population but not necessarily for an individual. This approach can identify those patients at high risk based on traditional risk factors, but frequently does not address those with low or intermediate risk who contribute most of the population-attributable risk.
Coronary artery calcium (CAC) is a disease score that integrates the effect of genetics, environment, traditional risk factors, biomarkers, and the unknown. It correlates with the degree of atherosclerosis and the risk of developing symptomatic cardiovascular disease.2 The Multi-Ethnic Study of Atherosclerosis (MESA) score is a new coronary heart disease (CHD) risk calculator (https://www.mesa-nhlbi.org/calcium/input.aspx) that incorporates CAC score in addition to the traditional risk factors of demographics, cholesterol, systolic blood pressure, diabetes, smoking, family history of CHD, and the use of hypertension or cholesterol medications..png)
The following cases will illustrate the added clinical utility of the CAC and MESA scores.
LS is a 57-year-old white female whose father had a myocardial infarction (MI) in his 40s. She stopped smoking in her 30s and has no history of hypertension or diabetes. Her calculated 10-year risk of ASCVD using the ACC/AHA Pooled Cohort Equations is 1.5 percent and her lifetime risk is 27 percent. She had a chest computed tomographic angiography in 2009 because of chest pain, which showed no evidence of “any significant obstruction,” but did demonstrate calcification in the proximal left anterior descending artery. A follow-up CAC score was 247 Agatston units, placing her in the 97th percentile for her age. Her MESA 10-year CHD risk score was 2.5 percent without her CAC score and 6.7 percent with the score. A standard lipid profile showed cholesterol 158 mg/dL, triglycerides 128 mg/dL, HDL-C 58 mg/dL, and LDL-C 74 mg/dL. She had a normal NMR LipoProfile, lipoprotein-associated phospholipase A2 (Lp-PLA2), lipoprotein(a) [Lp(a)], and flow-mediated dilatation. Because of her absolute CAC score, she was placed on a high-intensity statin and aspirin. Of note, her older sister also had a similar lipid profile and a significantly elevated CAC score.
LE is a 68-year-old white female referred by her primary care physician after the patient developed myalgias on numerous statins. Her cholesterol was 249 mg/dL, triglycerides 119 mg/dL, HDL-C 57 mg/ dL, and LDL-C was 168mg/dL. She had no history of hypertension, smoking, or diabetes mellitus. Her father had a MI in his 50s. Her calculated 10-year ASCVD risk was 8.5 percent using the ACC/AHA calculator. Her MESA risk score was 6.4 percent without her CAC score and 2.6 percent with her CAC score of zero. After reviewing the information with the patient, it was decided not to pursue statin therapy or start aspirin. She was instead referred for weight management.
These cases help to demonstrate that incorporating the CAC score into risk calculations can alter patient management. The ACC/AHA 2013 Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recognize the effectiveness of statins in reducing cardiovascular risk in four clinical scenarios: patients ≤75 years of age with clinical ASCVD, patients ≥21 years of age with LDL-C ≥190mg/ dL, patients 40–75 years of age with diabetes mellitus, and patients 40–75 years of age with an estimated 10-year ASCVD risk ≥7.5 percent, based on the ACC/AHA Pooled Cohort Equations. CAC score can be used for cardiovascular risk stratification in patients who do not fall into one of these four categories when there is uncertainty regarding statin therapy. The 2013 guidelines state that CAC score may be considered (Class IIb recommendation) to inform treatment decision-making in patients when such a decision is unclear after conventional risk assessment.3 The authors of the guidelines should be commended for supporting the use of “non-traditional” risk factors to aid in clinical decision-making.
INTERHEART: A Global Case-Control Study of Risk Factors for Acute Myocardial Infarction evaluated 15,152 cases of acute myocardial infarction in 52 countries. There were nine risk factors that accounted for 93 percent of the population-attributable risk. The individual risk factors that had the largest impact were apolipoprotein B/apolipoprotein A-1 (58.9 percent), psychosocial factors (43.5 percent), and smoking (40.7 percent). Abdominal obesity had a greater impact than hypertension and diabetes. In 6 percent of the study population, no conventional risk factor was identified. It has been reported that only 60 to 70 percent of patients who present with early atherosclerosis will have traditional risk factors.4 There are 64 genomic loci associated with CAD. Only one-third are related to traditional risk factors, while two-thirds are related to endothelial function, inflammation, and smooth muscle cells.4 CAC score provides insight into the effect that these pathophysiological processes have on an individual’s risk of CVD.
The CAC score is most likely to affect the management of patients deemed at intermediate or low risk for CVD based on traditional risk factors.5 A zero CAC score in the MESA trial was the strongest negative predictor with a diagnostic likelihood ratio (DLR) of 0.41 for CHD and 0.54 for CVD. DLR quantifies the change in risk obtained with knowledge of a test result and a value less than one indicates that the test result is less likely to be seen in those with disease and may be used to downgrade risk. However, a zero calcium score does not mean there is no CAD. Gottlieb, et al. reported that a zero CAC score had a negative predictive value of 68 percent in finding a greater than 50 percent stenosis in patients referred to cardiac catheterization for symptoms.6 Defining the 10-year risk category by using an absolute calcium score — such as <100 being low risk and >400 being high risk — is more predictive than indexing the score for age.7 Based on the results of the Heinz Nixdorf Recall, MESA, and Rotterdam studies, the ACC/ AHA supported revising an individual’s risk assessment upward if a patient has a CAC score of greater than 300 Agatston units or 75th percentile for their age. Interestingly, statins may actually increase CAC score through “de-lipidation” of soft, cholesterol-laden plaques leading to a rise in calcium density. Therefore, serial CAC scores should not be used to determine the efficacy of statin therapy.
In the Cardia Study, there were 2,831 people between the ages of 33 and 45 who had coronary calcium imaging. In Figure 1, the CAC prevalence is compared to the Framingham Risk Score (FRS).8 This figure demonstrates the presence of CAC, even in those individuals deemed low risk.
In the MESA study, CAC varied by age (Figure 2). Even at the extremes of age 45–50 versus 75–80, CAC was predictive of risk (Figure 3).9
Area under the curve (AUC)/c-statistic evaluates the ability to discriminate between patients who will and will not develop the defined event. A review of various calculators shows that most generally have an AUC of 0.7510 (1 is perfect and 0.5 is random). Inclusion of CAC in the MESA risk score significantly improves the prediction for 10-year CHD risk compared to using traditional risk factors alone. The AUC increased from 0.75 to 0.8. External validation in both the Dallas Heart Study and Heinz Nixdorf Recall studies showed very good discrimination and calibration.11
In assessing a patient’s cardiovascular risk, CAC score provides additional information when added to traditional risk factors. The MESA score is a new clinical tool that incorporates CAC score into CHD risk assessment. Ultimately, there is no perfect risk calculator that can substitute for clinical decision-making. A healthcare provider must integrate all of the available information to arrive at a joint decision with the patient regarding management.
Disclosure statement: Dr. Goldenberg has no disclosures to report. Dr. Meng has no disclosures to report.
References are listed on page 46 of the PDF.
Article By:
Clinical Professor of Medicine Thomas Jefferson University
Medical Director of Cardiovascular Prevention
Christiana Care Health System
Newark, DE
Diplomate, American Board of Clinical Lipidology
Cardiovascular Fellow
Christiana Health Care System
Newark, DE