The CAC Consortium: Highlights from Four Years of Research

Quick Takes

  • The CAC Consortium is the largest CAC cohort to date and has contributed a great deal to the literature, helping to make CAC scoring the valuable and widely used tool that it is today.
  • Research from the Consortium has expanded the uses of CAC scoring, demonstrating its value for risk predication and prognostication in a variety of patient populations and clinical scenarios.
  • Assessment of plaque location and features, such as density, volume, and area, can yield valuable information and is a focus of ongoing research.

The Coronary Artery Calcium (CAC) Consortium is a multicenter observational cohort of patients enrolled between 1991-2010 free of known coronary artery disease (CAD) who underwent CAC testing.1 It is the largest CAC cohort to date. A review in Radiology: Cardiothoracic Imaging provides a summary of seminal studies from CAC consortium data.2

Refining Risk-prediction with CAC and Traditional Risk Factors:

  1. Borderline to Intermediate Risk Patients: Current guidelines recommend selective use of CAC scoring for adults age 40-75 with LDL-C ≥70mg/dl who are at intermediate and select borderline 10-year atherosclerotic cardiovascular disease (ASCVD) risk by the pooled-cohort equation (PCE).3 The addition of CAC scoring more accurately defines risk. The Principal Investigator of the CAC Consortium, Dr. Michael Blaha, and colleagues found that CAC added to the PCE, as well as CAC added to the Multi-Ethnic Study of Atherosclerosis (MESA) Risk Score, were the best predictors of cardiovascular disease (CVD) and coronary heart disease (CHD) outcomes, respectively.4 Added risk prediction with CAC was most notable in borderline to intermediate risk patients.
  2. Hypertension: Trials examining optimal blood pressure targets have yielded mixed results regarding the benefit of intensive control;5,6 this may be due to differences in baseline risk among the populations studied. Current guidelines recommend using the PCE to determine ASCVD risk for patients with Stage 1 hypertension (BP 130-139/80-89) when deciding whether to implement BP-lowering medication.7 Uddin et al. showed that CAC scoring could better define high-risk populations, who may be more likely to benefit from intensive blood pressure control.8 A CAC score of approximately 220 corresponds to elevated baseline risk approximately equivalent to participants enrolled in SPRINT.
  3. Race/Ethnicity and Asian-Americans: The PCE generally overestimates or underestimates risk in certain ethnic groups.9 Accurate risk assessment is important, particularly among groups with disproportionately high CVD mortality rates.10 CAC has been the best predictor of CVD mortality, irrespective of ethnic group,11 and this has been confirmed in the CAC Consortium.12

    The presence of CAC portends a higher risk of mortality among Blacks and Hispanics compared to Whites.12 Across all CAC categories, after controlling for other risk factors, Blacks and Hispanics have higher CVD mortality compared to Whites.

    There is an increased prevalence of premature CVD and higher mortality from myocardial infarction (MI) in the South Asian population. There is a difference in the progression of CAC burden in South Asian men as compared to women; additionally, there is increased CAC progression in South Asian men as compared to other ethnic groups. Hence, CAC burden and change in CAC score for this at-risk group may be an important prognosticating factor.13 The CAC Consortium showed excellent risk prediction with CAC in a general Asian-American population.14
  4. CAC in Women versus Men: High CAC scores and multivessel CAC have greater prognostic implications in women.2 CVD mortality was similar among men and women with a CAC of 0, but women had disproportionately higher CVD risk when CAC was present, especially if calcified lesions were large in size or number.15
  5. CAC in the Young and Elderly: Young patients represent another group in whom the CAC may have important implications. A study of patients age 30-49 years found individuals with CAC >100 to have a 10 times increased risk of CHD mortality compared to those of the same age with CAC of 0.16 Another study examined the role of CAC in even younger patients (<30 years) with multiple ASCVD risk factors and found that the percent of patients with CAC increased with the number of risk factors present.17 Using CAC scoring in select young patients provides an opportunity to identify truly high-risk patients earlier.

Extremes of the Spectrum

Mounting interest has developed surrounding CAC and the "power of zero," i.e., the ability of a CAC score of 0 to substantially downgrade risk. Blaha et al. found 45% of patients to have a CAC of 0 and very low rates of mortality.18 This was highlighted in the 2019 ACC/AHA Primary Prevention Guideline that individuals with CAC 0 are at low risk ≥10 years period and could safely defer statin therapy.19

However, patients with CAC ≥1000 were more likely to have multivessel CAC and more dispersed calcifications. Compared to those with CAC 0, patients in this group had a 5-fold higher risk of CVD mortality after adjusting for age, sex, hypertension, dyslipidemia, smoking, diabetes, and family history of CHD.20 CAC ≥1000 should lead to aggressive risk factor control and possibly newer lipid lowering and glycemic controlling agents.

Calcium Distribution in the Coronary Bed: Beyond the Agatston Score

The distribution of CAC has important prognostic significance. While patients in the Consortium with left main CAC tended to have higher Agatston scores, even after adjusting for total CAC and baseline risk factors, those with left main lesions had 20-30% higher CVD mortality.21

An increased number of vessels with calcified plaque is a high-risk feature. A new scoring system has been proposed: the CAC Data and Reporting System (CAC-DRS) expresses scores as Ax/Ny with "A" for Agatston score and "N" indicating the number (0-4) of the major coronary arteries affected.22 The new system was validated using data from the CAC Consortium with certain categories associated with significantly higher mortality rates. These recommendations call for the reporting of CAC on all non-gated CT scans, which has the potential to increase availability of the important prognostic data.23

Assessment of plaque density, volume, and area also yields valuable information. While plaque volume and area correlate with mortality,24 Shaw et al. found plaque density to be inversely correlated with mortality among men, but not women.15 Osei et al. similarly found CAC density to be inversely associated with incident CHD mortality among statin naïve patients but found no association between density and these outcomes in statin users, possibly due to statin effects on the natural progression of plaque.25

The Agatston score is calculated by multiplying CAC area by mean density; thus, lower plaque density may mask risk in certain groups. More research is needed to clarify the association between plaque density and risk, how this may differ in men and women, and how best to capture this information.

Conclusions

The CAC Consortium has confirmed prior findings in the real-world setting and studied the value of CAC in the young, elderly, in women, in those with high scores, in those taking a statin, and in those who may be eligible for intensified non-statin therapy. It has yielded a wealth of valuable information. Formal AHA CAC recommendations for non-statin LDL lowering therapies and antihypertensives have yet to be elucidated. Continuing to use CAC as a tool to refine risk prediction in higher risk subgroups, as well as individuals at lower ASCVD risk with a family history of CHD, is of great interest.

References

  1. Blaha MJ, Whelton SP, Al Rifai M, et al. Rationale and design of the coronary artery calcium consortium: a multicenter cohort study. J Cardiovasc Comput Tomogr 2017;11:54–61.
  2. Adelhoefer S, Iftekhar Uddin SM, Osei AD, Obisesan OH, Blaha MJ, Dzqye O. Coronary artery calcium scoring: new insights into clinical interpretation—lessons from the CAC Consortium. Radiol Cardiothorac Imaging 2020;2:e200281.
  3. Grundy SM Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:3168-3209.
  4. Blaha MJ, Whelton SP, Al Rifai M, et al. Comparing risk scores in the prediction of coronary and cardiovascular deaths: Coronary Artery Calcium Consortium. JACC Cardiovasc Imaging 2021;14:411-21.
  5. Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103–16.
  6. Yusuf S, Lonn E, Pais P, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016;374:2032–43.
  7. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. J Am Coll Cardiol 2018;71:e127–e248.
  8. Iftekhar Uddin SM, Mirbolouk M, Kianoush  S, et al. Role of coronary artery calcium for stratifying cardiovascular risk in adults with hypertension. Hypertension 2019;73:983–89.
  9. DeFilippis AP, Young R, Carrubba CJ, et al. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Ann Intern Med 2015;162:266.
  10. Singh GK, Siahpush M, Azuine RE, Williams SD. Widening socioeconomic and racial disparities in cardiovascular disease mortality in the United States, 1969-2013. Int J MCH AIDS 2015;3:106–18.
  11. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:1336–45.
  12. Orimoloye OA,  Budoff MJ, Dardari ZA, et al. Race/ethnicity and the prognostic implications of coronary artery calcium for all-cause and cardiovascular disease mortality: The Coronary Artery Calcium Consortium. J Am Heart Assoc 2018;7:e010471.
  13. Kanaya AM, Vittinghoff E, Lin F, et al. Incidence and progression of coronary artery calcium in South Asians compared with 4 race/ethnic groups. J Am Heart Assoc 2019;8:e011053.
  14. Orimoloye OA, Banga S, Dardari ZA, et al. Coronary artery calcium as a predictor of coronary heart disease, cardiovascular disease, and all-cause mortality in Asian-Americans: The Coronary Artery Calcium Consortium. Coron Artery Dis 2019;30:608–14.
  15. Shaw LJ. Min JK, Nasir K, et al. Sex differences in calcified plaque and long-term cardiovascular mortality: observations from the CAC Consortium. Eur Heart J 2018;39:3727–35.
  16. Miedema MD Dardari ZA, Nasir K, et al. Association of coronary artery calcium with long-term, cause-specific mortality among young adults. JAMA Netw Open 2019;2:e197440.
  17. Osei AD, Iftekhar Uddin SM, Dzaye O, et al. Predictors of coronary artery calcium among 20-30-year-olds: The Coronary Artery Calcium Consortium. Atherosclerosis 2020;301;65–68.
  18. Blaha MJ, Cainzos-Achirica M, Dardari Z, et al. All-cause and cause-specific mortality in individuals with zero and minimal coronary artery calcium: a long-term, competing risk analysis in the Coronary Artery Calcium Consortium. Atherosclerosis 2020;29472–9.
  19. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines  J Am Coll Cardiol 2019;74:e177–e232.
  20. Peng AW, Mirbolouk M, Orimoloye OA, et al. Long-term all-cause and cause-specific mortality in asymptomatic patients with CAC ≥1,000. JACC Cardiovasc Imaging 2020;13:83–93.
  21. Lahti SJ, Feldman DI, Dardari Z, et al. The association between left main coronary artery calcium and cardiovascular-specific and total mortality: The Coronary Artery Calcium Consortium. Atherosclerosis 2019;286;172–78.
  22. Hecht HS, Cronin P, Blaha MJ, et al. 2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: a report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology. J Cardiovasc Comput Tomogr 2017;11:74–84.
  23. Dzaye O, Dudum R, Mirbolouk M, et al. Validation of the Coronary Artery Calcium Data and Reporting System (CAC-DRS): dual importance of CAC score and CAC distribution from the Coronary Artery Calcium (CAC) consortium. J Cardiovasc Comput Tomogr 2020;14:12–17.
  24. Criqui MH, Denenberg JO, Ix JH, et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA 2014;311:271–78.
  25. Osei AD, Mirbolouk M, Berman D, et al. Prognostic value of coronary artery calcium score, area, and density among individuals on statin therapy vs. non-users: The Coronary Artery Calcium Consortium. Atherosclerosis 2021;316:79–83.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Computed Tomography, Nuclear Imaging, Hypertension, Smoking

Keywords: Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Factor XIII, Cholesterol, LDL, Coronary Artery Disease, Cardiovascular Diseases, Blood Pressure, Asian Americans, African Americans, Plaque, Atherosclerotic, Risk Factors, Atherosclerosis, Hypertension, Risk Assessment, Hispanic Americans, Tomography, X-Ray Computed, Diabetes Mellitus, Myocardial Infarction, Primary Prevention, Radiology, Smoking


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