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Refining Coronary Heart Disease Event Prediction in Young and Old Individuals by Coronary Artery Calcification Imaging With Computed Tomography

Published:September 14, 2014DOI:https://doi.org/10.1016/j.mayocp.2014.08.008
      The important discussion about how to refine the prediction of the risk of cardiovascular (CV) events in individuals without known CV disease continues in the October 2014 issue of Mayo Clinic Proceedings.
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      In the September 2014 issue of the Proceedings, an editorial and 2 articles
      • Kullo I.J.
      • Trejo-Gutierrez J.F.
      • Lopez-Jimenez F.
      • et al.
      A perspective on the new American College of Cardiology/American Heart Association guidelines for cardiovascular risk assessment.
      • Lopez-Jimenez F.
      • Simha V.
      • Thomas R.J.
      • et al.
      A summary and critical assessment of the 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: filling the gaps.
      • Robinson J.G.
      Contemporary evidence-based guidelines: practice based on the strongest evidence.
      presented a variety of perspectives on the updated 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines for Cardiovascular Risk Assessment
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • et al.
      2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      and for the Treatment of Blood Cholesterol to Reduce Atherosclerotic Disease Risk in Adults.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      The current article by Nasir et al
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      adds to the pertinent body of knowledge by addressing how to refine risk assessment, at both ends of the age spectrum that commonly used CV risk prediction models cover, by using computed tomography of coronary artery calcification (CAC).
      There is general agreement that 90% of patients with coronary heart disease (CHD) have at least 1 CV risk factor and that known CV risk factors account for 90% of the population-attributable risk of myocardial infarction.
      • Greenland P.
      • Alpert J.S.
      • Beller G.A.
      • et al.
      2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      Imaging for subclinical CHD in the form of CAC by computed tomography
      • Greenland P.
      • Bonow R.O.
      • Brundage B.H.
      • et al.
      ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography.
      is one of the approaches meant to close the remaining “detection gap” by identifying subclinical atherosclerosis as an anatomical marker of otherwise unrecognized CHD event risk.
      Current CV risk prediction models, such as the Framingham Risk Score (FRS)

      Risk Assessment Tool for Estimating Your 10-Year Risk of Having a Heart Attack. http://cvdrisk.nhlbi.nih.gov/. Accessed August 1, 2014.

      or the new ACC/AHA ASCVD (Atherosclerotic Cardiovascular Disease) Risk Estimator,

      ASCVD Risk Estimator. http://tools.cardiosource.org/ASCVD-Risk-Estimator. Accessed August 1, 2014.

      are profoundly affected by patient age. The Table indicates how the 10-year CV risk estimates for individuals without conventional CV risk factors vary by age alone. Like any other form of medical testing, CAC imaging with computed tomography is most meaningful and justifiable if the results can be expected to change management or outcome. Because most young people are at low risk for CV events and many elderly people are at high risk, one might argue empirically that CAC imaging will not meaningfully advance our assessment of risk in most of these individuals. Nasir et al
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      set out to address whether this is true or false.
      TableThe 10-Year Risk Estimates for Cardiovascular Events
      ASCVD = Atherosclerotic Cardiovascular Disease.
      ,
      The 10-year risk of myocardial infarction (Framingham Risk Score) or myocardial infarction and stroke (ASCVD Risk Estimator) for individuals without conventional risk factors aged 40, 60, and 79 years. Neither risk prediction model provides estimates for patients older than 79 years. The risk estimates in this table reflect the following values for cardiovascular risk factors: total cholesterol, 180 mg/dL (to convert to mmol/L, multiply by 0.0259); high-density lipoprotein cholesterol, 60 mg/dL (to convert to mmol/L, multiply by 0.0259); systolic blood pressure, 120 mm Hg; no treatment for hypertension; no diabetes mellitus; and no smoking.
      Age (y)Framingham Risk Score

      Risk Assessment Tool for Estimating Your 10-Year Risk of Having a Heart Attack. http://cvdrisk.nhlbi.nih.gov/. Accessed August 1, 2014.

      ASCVD Risk Estimator

      ASCVD Risk Estimator. http://tools.cardiosource.org/ASCVD-Risk-Estimator. Accessed August 1, 2014.

      Male (%)Female (%)Male (%)Female (%)
      401.0<10.60.3
      606.01.06.22.5
      7915.05.026.622.0
      a ASCVD = Atherosclerotic Cardiovascular Disease.
      b The 10-year risk of myocardial infarction (Framingham Risk Score) or myocardial infarction and stroke (ASCVD Risk Estimator) for individuals without conventional risk factors aged 40, 60, and 79 years. Neither risk prediction model provides estimates for patients older than 79 years. The risk estimates in this table reflect the following values for cardiovascular risk factors: total cholesterol, 180 mg/dL (to convert to mmol/L, multiply by 0.0259); high-density lipoprotein cholesterol, 60 mg/dL (to convert to mmol/L, multiply by 0.0259); systolic blood pressure, 120 mm Hg; no treatment for hypertension; no diabetes mellitus; and no smoking.

      Summary of the Current Study

      To evaluate the association of CAC with CHD events in young (45-55 years old) and elderly (75-85 years old) individuals, the authors retrospectively analyzed CAC data from a prospective, population-based cohort study that was originally designed to examine the characteristics and risk factors of subclinical CV disease.
      • Bild D.E.
      • Bluemke D.A.
      • Burke G.L.
      • et al.
      Multi-ethnic study of atherosclerosis: objectives and design.
      This Multi-Ethnic Study of Atherosclerosis enrolled 6809 persons aged 45 to 84 years without known CV disease, representing 4 prespecified ethnicities from 6 US communities, and followed them up for a median of 8.5 years.
      The authors of the current study
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      found that, as expected and previously reported, prevalence and quantity of CAC increased with age, but were lower for women than for men in each age group. Across all ages and within age groups stratified by decades, participants with higher CAC scores also had higher FRSs. All CHD event (angina, revascularization, myocardial infarction, and cardiac death) rates, hard CHD event (nonfatal myocardial infarction and cardiac death) rates, and risk of CHD events after adjustment for CV risk factors increased with increasing age and increasing CAC scores.
      Among participants 45 to 54 years of age, 83% had no CAC (ie, a CAC score of 0), 14% had CAC scores of 1 through 100, and 3% had CAC scores greater than 100 (Figure 1 in the article by Nasir et al
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      ). All CHD event rates and hard CHD event rates per 1000 patient-years were 0.9% and 0.6% for participants with CAC scores of 0, 3.8% and 2.4% for participants with CAC scores of 1 through 100, and 21.1% and 12.5% with CAC scores greater than 100 (Figure 3 in the article by Nasir et al
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      ). After multivariable adjustment for CV risk factors, young participants with CAC scores greater than 100 had a significantly increased risk of hard CHD events with a hazard ratio of 7.8 when compared with young participants with CAC scores of 0.
      Among participants 75 to 84 years of age, 14% had CAC scores of 0, 32% had CAC scores of 1 through 100, and 54% had CAC scores greater than 100 (Figure 1 in the article by Nasir et al
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      ). All CHD event rates and hard CHD event rates per 1000 patient-years were 1.5% and 0.7% for participants with CAC scores of 0, 9.1% and 8.6% for participants with CAC scores of 1 through 100, and 23.3% and 15.6% with CAC scores greater than 100 (Figure 3 in the article by Nasir et al
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      ), respectively. After multivariable adjustment for CV risk factors, elderly participants with CAC had a significantly increased risk of hard CHD events compared with elderly participants with CAC scores of 0, with a hazard ratio of 11.6 for CAC scores of 1 through 100 and a hazard ratio of 20.3 for CAC scores greater than 100.

      Incremental Value of CAC in Young Individuals

      People between 45 and 54 years of age represent approximately 21% of the US population in the age range (20-79 years)

      US Census Bureau. 2010 Census Briefs: Age and Sex Composition: 2010. http://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf Accessed August 7, 2014.

      that the FRS prediction model covers.

      Risk Assessment Tool for Estimating Your 10-Year Risk of Having a Heart Attack. http://cvdrisk.nhlbi.nih.gov/. Accessed August 1, 2014.

      Although the incidence of CHD reaches its peak after 55 years of age, the annual number of adults per 1000 who are diagnosed as having myocardial infarction or fatal CHD in this age group is 25 in men and 10 in women.
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      Heart disease and stroke statistics—2014 update: a report from the American Heart Association.
      The indirect cost of heart disease that results from lost productivity attributable to mortality (estimated at $97.2 billion for 2010)
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      Heart disease and stroke statistics—2014 update: a report from the American Heart Association.
      and morbidity is notoriously difficult to estimate but must, to a large extent, occur in the younger segment of the population who have the longest productive careers yet ahead of them.
      Among young patients with incident CHD, the prevalence of family history of CHD is high, but a family history of CHD is not currently part of the FRS or the new ACC/AHA ASCVD Risk Estimator. Some studies suggest that CAC could serve as a marker of genetically determined propensity for CHD events in individuals with a family history of CHD, particularly in young individuals who otherwise have little by the way of other conventional risk factors and low FRSs.
      • Gidding S.S.
      • McMahan C.
      • McGill H.C.
      • et al.
      Prediction of coronary artery calcium in young adults using the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) risk score: the CARDIA study.
      What does the current study tell us about discordance between FRS and CAC as predictors of CHD event risk in young individuals without known CHD?
      In the current study, among the participants 45 to 54 years of age, 91% had low (≤10%) FRSs, 8% had an intermediate (10%-20%) FRS, and less than 2% had a high (>20%) FRS (Khurram Nasir, MD, and T.C.G., written communication, August 8, 2014), with a mean (SD) FRS of 3.6% (4.1%). If we consider participants with low FRSs but CAC scores greater than 100 and participants with high FRSs but CAC scores of 0 to be risk reclassifications (not to be confused with the net reclassification rate, which could not be determined from the data available), CAC scores indicated higher CHD event risk than predicted by the FRS in approximately 89 of 1947 young participants (4.6%) and lower CHD event risk than predicted by the FRS in 12 of 1947 young participants (0.6%).

      Incremental Value of CAC in Elderly Individuals

      People between 75 and 79 years of age represent approximately 3% of the US population in the age range (20-79 years)

      US Census Bureau. 2010 Census Briefs: Age and Sex Composition: 2010. http://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf Accessed August 7, 2014.

      that the FRS prediction model covers.

      Risk Assessment Tool for Estimating Your 10-Year Risk of Having a Heart Attack. http://cvdrisk.nhlbi.nih.gov/. Accessed August 1, 2014.

      Of note, neither the FRS

      Risk Assessment Tool for Estimating Your 10-Year Risk of Having a Heart Attack. http://cvdrisk.nhlbi.nih.gov/. Accessed August 1, 2014.

      nor the new ASCVD Risk Estimator

      ASCVD Risk Estimator. http://tools.cardiosource.org/ASCVD-Risk-Estimator. Accessed August 1, 2014.

      makes prediction adjustments for age older than 80 years. The annual number of adults aged 75 to 84 years per 1000 who are diagnosed as having myocardial infarction or fatal CHD is 120 in men and 105 in women.
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      Heart disease and stroke statistics—2014 update: a report from the American Heart Association.
      The increasing direct and indirect costs of CV disease are projected to increase most steeply through 2030 in the age groups of 56 to 79 years and older than 80 years.
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      Heart disease and stroke statistics—2014 update: a report from the American Heart Association.
      Could refined risk prediction clear a path to decreased use of expensive treatments, such as coronary care units, implantable cardioverter defibrillators, or left ventricular assist devices, in a sizable number of individuals?
      Among participants 75 to 84 years of age in the current study,
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      36% had high (>20%) FRSs, 42% had intermediate (110%-20%) FRSs, and only 22% had low (≤10%) FRSs (Khurram Nasir, MD, and T.C.G., written communication, August 8, 2014), with a mean (SD) FRS of 15.8% (7.4%). This distribution is not surprising given the age dependence of the FRS. CAC scores greater than 100 indicated a higher than anticipated CHD event risk in 76 of 965 participants (7.9%) with low FRSs, and CAC scores of 0 indicated lower than anticipated CHD event risk in 42 of 965 elderly participants (4.3%) with high FRSs.

      Implications for Patient Management and Future Directions

      Of course, predicting a patient’s 10-year risk of CHD events, no matter how precise, without being able to change the outcome is much like watching from a distance a freight train speed toward a school bus sitting disabled on the tracks. Can we use the CHD event risk prediction refinement that is provided by CAC to improve patient outcomes?
      Many of the components of risk prediction models, such as the FRS and the AHA/ACC ASCVD Risk Estimator, are modifiable risk factors. Although the specifics are currently moving targets, it is well established that CV risk in general can be reduced by managing these modifiable risk factors, ideally by lifestyle modifications, such as diet, exercise, and weight management, and supplemented by pharmacologic intervention where needed.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Eckel R.H.
      • Jakicic J.M.
      • Ard J.D.
      • et al.
      2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      By comparison, CAC represents atherosclerosis, and CAC itself is not a manageable risk factor. Although CAC can predict CHD event risk independent of and incremental to conventional risk factors,
      • Greenland P.
      • Bonow R.O.
      • Brundage B.H.
      • et al.
      ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography.
      it is typically not independent of FRS, just like it was not in the current study.
      • Tota-Maharaj R.
      • Blaha M.
      • Nasir K.
      • et al.
      Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
      Yet, it is tempting to speculate how knowledge about CAC could inform risk factor management in an individual patient.
      One of the most frustrating experiences for preventive cardiologists is the counseling of young patients who have a prominent family history of CHD but whose conventional risk factors are well controlled already. Can we reduce these patients’ CHD event risk by implementing stricter risk factor modification goals or simply prescribing statins if they have CAC? One post hoc analysis of an overall negative trial of the effects of statin on outcomes in patients with CAC seems to suggest that this may be the case,
      • Mulders T.A.
      • Sivapalaratnam S.
      • Stroes E.S.G.
      • Kastelein J.J.P.
      • Guerci A.D.
      • Pinto-Sietsma S.-J.
      Asymptomatic individuals with a positive family history for premature coronary artery disease and elevated coronary calcium scores benefit from statin treatment: a post hoc analysis from the St. Francis Heart Study.
      but the strength of this evidence will not convince everyone.
      Conversely, could we possibly relax or abandon risk factor modification in elderly patients who have no CAC, for example, in those who are unwilling or unable to take statin medications, arguing that they have not developed even subclinical atherosclerosis despite prolonged exposure to risk factors? First, the data on primary prevention in individuals older than 75 years are limited because few were included in the randomized controlled trials available. Second, no data indicate that relaxing risk factor modification in individuals without CAC is safe in any age group, and no such data will be forthcoming any time soon. Given the well-established efficacy of risk factor modification in patients with increased FRSs,
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Eckel R.H.
      • Jakicic J.M.
      • Ard J.D.
      • et al.
      2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      trials that compare placebo and effective pharmacologic therapy in patients with CHD risk factors but a CAC score of 0 would face considerable ethical hurdles.
      We will continue to see steady refinements in CHD risk prediction. We next need studies that overcome ethical and funding obstacles to convincingly show us how to use this incremental information to improve patient outcomes.

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