Long-Term All-Cause and Cause-Specific Mortality in Asymptomatic Patients With CAC ≥1,000: Results From the CAC Consortium

Abstract

Objectives: This study thoroughly explored the demographic and imaging characteristics, as well as the all-cause and cause-specific mortality risks of patients with a coronary artery calcium (CAC) score ≥1,000 in the largest dataset of this population to date.

Background: CAC is commonly used to quantify cardiovascular risk. Current guidelines classify a CAC score of >300 or 400 as the highest risk group, yet little is known about the potentially unique imaging characteristics and mortality risk in individuals with a CAC score ≥1,000.

Methods: A total of 66,636 asymptomatic adults were included from the CAC consortium, a large retrospective multicenter clinical cohort. Mean patient follow-up was 12.3 ± 3.9 years for patients with cardiovascular disease (CVD), coronary heart disease (CHD), cancer, and all-cause mortality. Multivariate Cox proportional hazards regression models adjusted for age, sex, and conventional risk factors were used to assess the relative mortality hazard of individuals with CAC ≥1,000 compared with, first, a CAC reference of 0, and second, with patients with a CAC score of 400 to 999.

Results: There were 2,869 patients with CAC ≥1,000 (86.3% male, mean 66.3 ± 9.7 years of age). Most patients with CAC ≥1,000 had 4-vessel CAC (mean: 3.5 ± 0.6 vessels) and had greater total CAC area, higher mean CAC density, and more extracoronary calcium (79% with thoracic artery calcium, 46% with aortic valve calcium, and 21% with mitral valve calcium) than those with CAC scores of 400 to 999. After full adjustment, those with CAC ≥1,000 had a 5.04- (95% confidence interval [CI]: 3.92 to 6.48), 6.79- (95% CI: 4.74 to 9.73), 1.55- (95% CI:1.23 to 1.95), and 2.89-fold (95% CI: 2.53 to 3.31) risk of CVD, CHD, cancer, and all-cause mortality, respectively, compared to those with CAC score of 0. The CAC ≥1,000 group had a 1.71- (95% CI: 1.41 to 2.08), 1.84- (95% CI: 1.43 to 2.36), 1.36- (95% CI:1.07 to 1.73), and 1.51-fold (95% CI: 1.33 to 1.70) increased risk of CVD, CHD, cancer, and all-cause mortality compared to those with CAC scores 400 to 999. Graphic analysis of CAC ≥1,000 patients revealed continued logarithmic increase in risk, with no clear evidence of a risk plateau.

Conclusions: Patients with extensive CAC (CAC ≥1,000) represent a unique very high-risk phenotype with mortality outcomes commensurate with high-risk secondary prevention patients. Future guidelines should consider CAC ≥1,000 patients to be a distinct risk group who may benefit from the most aggressive preventive therapy.

Keywords: cardiovascular imaging; coronary artery calcium; high risk; primary prevention; risk scoring.

Figure 1.. Mortality rate per 1000 person-years for CVD, CHD, cancer, and all-cause mortality by CAC score group.

Incidence rates increased for all-cause and cause-specific mortality with increasing CAC score. In particular, those with CAC ≥ 1000 had a 5.1, 8.0, 4.6, and 18.8 mortality rate per 1000 person-years for CHD, CVD, cancer, and all-cause mortality, respectively. In contrast, those with CAC 400–99 had a 2.1, 3.6, 2.7, and 9.8 mortality rate per 1000 person-years for CHD, CVD, cancer, and all-cause mortality, respectively. *A version of this figure including error bars for 95% CI can be found in Supplement Figure S1.

Figure 2.. Causes of mortality for CAC 400–999 and CAC ≥ 1000 groups.

In both CAC groups, the leading cause of death was CVD (CAC 400–999 = 36.5%; CAC ≥ 1000 = 42.6%), followed by cancer (CAC 400–999 = 28.0%; CAC ≥ 1000 = 24.3%). CHD mortality, as a subset of CVD mortality, constituted 21.1% of deaths in the CAC 400–999 group and 27.1% of deaths in the CAC ≥ 1000 group.

Figure 3.. Adjusted hazard ratios and 95% CI for CVD, CHD, cancer, and all-cause mortality by continuous CAC score.

Cubic splines were used to study the relationship between CAC score and mortality outcomes, with hazard ratios adjusted for age, sex, and traditional risk factors. Knots were placed at CAC=100 and CAC=1000. With increasing CAC score, mortality risk continues to increase logarithmically for all-cause and cause-specific mortality, with no apparent plateau in risk.

Central Illustration:. Understanding Extensive CAC (CAC ≥ 1000) in Primary Prevention Patients

Primary prevention patients with extensive CAC (CAC ≥ 1000) are unique in their their burden of coronary and extra-coronary disease and in their long-term outcomes. Those with CAC ≥ 1000 can be found on imaging to have a dispersed pattern of calcification in their coronary artery tree (the majority with 4-vessel disease) and diffuse extra-coronary calcification (TAC, AVC, and MVC). In addition, their annualized CVD mortality rates exceed those of high-risk secondary prevention patients from the FOURIER trial (0.80%/year vs. 0.77%/year).