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Research Article
Originally Published 8 December 2021
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Determinants of Incident Atherosclerotic Cardiovascular Disease Events Among Those With Absent Coronary Artery Calcium: Multi-Ethnic Study of Atherosclerosis

Mahmoud Al Rifai, MD, MPH https://orcid.org/0000-0002-6933-790X, Michael J. Blaha, MD, MPH https://orcid.org/0000-0001-5138-9683, Vijay Nambi, MD, PhD https://orcid.org/0000-0002-4237-0267, Steven J.C. Shea, MD https://orcid.org/0000-0002-7382-0603, Erin D. Michos, MD, MHS https://orcid.org/0000-0002-5547-5084, Roger S. Blumenthal, MD https://orcid.org/0000-0003-1910-3168, Christie M. Ballantyne, MD https://orcid.org/0000-0002-6432-1730, … Show All … , Moyses Szklo, MD, DrPH, Philip Greenland, MD https://orcid.org/0000-0002-6327-2439, Michael D. Miedema, MD, MPH, Khurram Nasir, MD, MPH https://orcid.org/0000-0001-5376-2269, Jerome I. Rotter, MD https://orcid.org/0000-0001-7191-1723, Xiuqing Guo, PhD https://orcid.org/0000-0002-5264-5068, Jie Yao, MS https://orcid.org/0000-0002-8822-0651, Wendy S. Post, MD, MS https://orcid.org/0000-0002-8655-5204, and Salim S. Virani, MD, PhD https://orcid.org/0000-0001-9541-6954 [email protected]Author Info & Affiliations
Circulation
Volume 145, Number 4
https://doi.org/10.1161/CIRCULATIONAHA.121.056705
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Abstract

Background:

The 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline states that statin therapy may be withheld or delayed among intermediate-risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up.

Methods:

We included participants with CAC=0 at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors (cigarette smoking, diabetes, hypertension, preventive medication use [aspirin and statin], family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers) and adjudicated incident ASCVD outcomes.

Results:

We studied 3416 individuals (mean [SD] age 58 [9] years; 63% were female, 33% White, 31% Black, 12% Chinese American, and 24% Hispanic). Over a median follow-up of 16 years, there were 189 ASCVD events (composite of coronary heart disease and stroke) of which 91 were coronary heart disease, 88 were stroke, and 10 were both coronary heart disease and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000 person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable adjustment, risk factors that were significantly associated with ASCVD included current cigarette smoking: hazard ratio, 2.12 (95% CI, 1.32–3.42); diabetes: hazard ratio, 1.68 (95% CI, 1.01–2.80); and hypertension: hazard ratio, 1.57 (95% CI, 1.06–2.33).

Conclusions:

Current cigarette smoking, diabetes, and hypertension are independently associated with incident ASCVD over a 16-year follow-up among those with CAC=0.

Clinical Perspective

What Is New?

•
Among individuals without coronary artery calcium, cigarette smoking, diabetes, and hypertension are independently associated with incident atherosclerotic cardiovascular disease events over long-term follow-up.

What Are the Clinical Implications?

•
Among individuals without coronary artery calcium who are current smokers, have diabetes, or hypertension, initiation and the long-term use of statin therapy along with a heart-healthy lifestyle and risk factor modification may be warranted as part of the clinician-patient risk discussion.
Clinical prevention of atherosclerotic cardiovascular disease (ASCVD) hinges on the appropriate selection of individuals who may benefit from pharmacotherapy.1 The pooled cohort equations (PCEs) are considered the first step for estimation of absolute ASCVD risk and are endorsed by recent guidelines.2,3 If the decision to treat with statin therapy remains unclear, the 2018 American Heart Association/American College of Cardiology/Multisociety (AHA/ACC/MS) cholesterol guideline recommends screening for ASCVD risk–enhancing factors among intermediate- or borderline-risk individuals.3 If uncertainty still exists, measurement of the coronary artery calcium (CAC) score is reasonable to guide treatment allocation in selected individuals (IIa recommendation).
The absence of CAC (CAC=0) is associated with low risk of ASCVD4 and may therefore be used to justify withholding or postponing statin therapy if there is clinical uncertainty about potential benefit or concerns about statin disutility.5 Although a CAC score of 0, in general, portends a favorable prognosis, a small proportion of individuals will experience ASCVD events, in particular, during long-term follow-up. The 2018 AHA/ACC/MS guideline6 continues to endorse statin therapy among those with diabetes, current cigarette smoking, or a strong family history of premature ASCVD, presumably because these individuals remain at higher risk of ASCVD events despite CAC=0.7–10 However, follow-up in these previous studies was up to 10 years. Because primary ASCVD prevention focuses on a long-term time horizon, in general, it is important to understand which traditional or novel risk factors may be associated with long-term ASCVD events despite CAC=0.
In the present analysis, we evaluate whether traditional cardiovascular risk factors and advanced lipid and inflammatory markers are independently associated with incident ASCVD events among those with baseline CAC=0 over long-term follow-up.

Methods

Study Design and Population

Details of the MESA (Multi-Ethnic Study of Atherosclerosis) design have been reported elsewhere.11 In brief, MESA is a prospective cohort study of 6814 US adults ages 45 to 84 years and of White, Black, Hispanic, or Chinese American race and ethnicity. Participants were enrolled from 6 US field centers (Baltimore, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles, California; New York, New York; and St. Paul, Minnesota) between 2000 and 2002. Five subsequent visits occurred between 2002 and 2004 (visit 2), 2004 and 2005 (visit 3), 2005 and 2007 (visit 4), 2010 and 2011 (visit 5), and 2016 and 2018 (visit 6). All participants were required to be free of clinical ASCVD at the time of enrollment. Institutional review boards at each site approved the study, and all participants provided written informed consent. MESA data are publicly available either from the National Heart, Lung, and Blood Institute’s Biological Specimen and Data Repository Information Coordinating Center repository12 or from the MESA coordinating center13 with an approved study proposal.

Ascertainment of Incident Outcome

The primary outcome for this analysis was a combination of hard ASCVD events, which included myocardial infarction, resuscitated cardiac arrest, coronary heart disease (CHD) death, stroke, or stroke death. Secondary outcomes included (1) CHD events that comprised myocardial infarction, resuscitated cardiac arrest, and fatal CHD; (2) stroke including fatal and nonfatal events; and (3) all-cause mortality.11

Assessment of CAC

CAC was assessed at baseline using either an electron-beam CT scanner (at the Chicago, Los Angeles, and New York centers) or a multidetector CT system (at the Baltimore, Forsyth County, and St. Paul centers). Each participant was scanned twice, and all images were interpreted at the central reading center (the Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance).14 A CAC score was calculated for each scan, and the mean score of the 2 scans was used in all analyses. Intraobserver and interobserver agreement were excellent (κ statistics, 0.93 and 0.90, respectively).15

Assessment of Covariates

Information pertaining to demographics, medical history, medication use, and cigarette smoking was collected using validated questionnaires. Anthropometric measurements were performed according to predefined protocols. Increased waist circumference was defined as ≥90 cm for men or ≥80 cm for women. Systolic and diastolic blood pressures were measured 3 times and the average of the last 2 measurements was used in these analyses. Hypertension was defined according to the 2017 ACC/AHA Guideline for High Blood Pressure in Adults as systolic blood pressure ≥130 mm Hg or diastolic blood pressure 80 mm Hg, as a history of physician-diagnosed hypertension, or taking a medication for hypertension.16 MESA participants at visit 2 were asked about family history of premature ASCVD, which was defined as any first-degree relative (mother, father, sibling, or child) with CHD or heart attack or stroke occurring before the age of 55 years in men and 65 years in women, respectively. With the exception of family history of premature ASCVD, all other risk factors were assessed at MESA visit 1.
A central laboratory (University of Vermont, Burlington) measured concentrations of fasting lipids (total and high-density lipoprotein cholesterol, triglycerides) and glucose from visit 1 samples. Low-density lipoprotein cholesterol was calculated using the Friedewald equation. Lipoprotein(a) mass concentration was evaluated using a latex-enhanced turbidimetric immunoassay (Denka Seiken) that controls for the size heterogeneity of apolipoprotein(a).17 Diabetes was defined as a fasting glucose of ≥126 mg/dL or use of hypoglycemic medication (oral agents and insulin). Chronic kidney disease was defined according to the Kidney Disease: Improving Global Outcomes guideline as glomerular filtration rate <60 mL·min–1·1.73 m–2 or the presence of microalbuminuria (albumin-to-creatinine ratio >30 mg/g). High-sensitivity C-reactive protein was measured using the BN II nephelometer. Intra-assay and interassay coefficients of variation ranged from 2.3% to 4.4% and 2.1% to 5.7%, respectively.18 ASCVD risk was estimated using the pooled cohort equations (PCEs) at the baseline study visit.19

Statistical Analysis

Baseline characteristics were tabulated for those with CAC=0 at baseline and stratified by development of incident ASCVD events at follow-up. Continuous variables were reported using mean (standard deviation) or median (interquartile range), whereas categorical variables were summarized as count (percentage).
Unadjusted incidence rates of events were reported as the number of events per 1000 person-years among those with the presence versus the absence of cardiovascular risk factors. We also calculated event rates by estimated ASCVD risk based on the PCE (<7.5%, 7.5% to <15%, 15% to <20%).6 Given that age is weighted heavily in the PCE, we also stratified event rates by age categories (45−54, 55−64, 65−74, and ≥75 years).
After confirming the proportionality assumption using Schoenfeld residuals, we used multivariable Cox proportional hazards models to examine the association between cardiovascular risk factors and incident outcomes. Models were adjusted for age, sex, race and ethnicity, education, presence of health care insurance, and all risk factors included in this analysis. Results were further stratified by sex, and multiplicative interaction testing was performed in the multivariable-adjusted model.
In sensitivity analyses, we excluded participants on lipid-lowering therapy at the baseline MESA study visit. We further adjusted for pack-years of cigarette smoking given the cumulative effect of smoking burden on ASCVD risk.20 We used 2 higher cutoffs to classify hypertension (≥140/90 mm Hg and ≥150/90 mm Hg). We also assessed incidence rates of the individual components of ASCVD (CHD and stroke) among those diagnosed with hypertension at baseline. We evaluated the association between family history of premature ASCVD and incident ASCVD stratifying by baseline and incident statin use and performed analyses separately for men versus women. We also evaluated the development of incident risk factors between visits 2 and 6 among those with absent risk factors at baseline (visit 1). We modeled the development of incident risk factors as binary (development of a cardiovascular risk factor at any MESA visit after baseline versus absence of risk factors during all visits) or as time varying. Multivariable-adjusted Cox proportional hazards models similar to those discussed earlier were used to study the association between incident risk factors and ASCVD outcomes.
A P value of <0.05 was considered statistically significant. All analyses were conducted using Stata version 16.1 (StataCorp).

Results

The study population consisted of 3416 individuals with CAC=0 with a mean (SD) age 58 (9) years; 63% were female, 33% White, 31% Black, 12% Chinese American, 24% Hispanic, and 27% at intermediate risk of ASCVD (PCE 7.5% to <20%). The prevalence of risk factors was as follows: 13% current smoking, 9% diabetes, 49% hypertension, 18% family history of premature ASCVD, and 8% chronic kidney disease. Compared with participants who did not develop ASCVD, those who did were older (61 versus 58 years), had higher systolic blood pressure (131 versus 122 mm Hg), had higher estimated mean 10-year ASCVD risk (10.7% versus 4.8%), were more likely to currently smoke (23% versus 13%), have diabetes (19% versus 9%), hypertension (66% versus 48%), chronic kidney disease (23% versus 14%), and estimated ASCVD risk ≥7.5% (66% versus 37%); all P<0.05 (Table 1).
Table 1. Baseline Characteristics of the Study Population Among Those With Baseline Coronary Artery Calcium 0, Stratified by Development of Incident Atherosclerotic Cardiovascular Disease
CharacteristicsIncident atherosclerotic cardiovascular diseaseP value
No (n=3212)Yes (n=189)
Age, mean (SD)58 (9)61 (9)<0.001
Sex, n (%)
 Female2047 (64)109 (58)0.09
 Male1165 (36)80 (42) 
Race and ethnicity, n (%)0.06
 White1068 (33)56 (30) 
 Chinese American386 (12)13 (7) 
 Black992 (31)70 (37) 
 Hispanic American766 (24)50 (26) 
Graduate or professional school, n (%)587 (18)28 (15)0.15
Presence of health insurance, n (%)2847 (8)165 (88)0.61
Cigarette smoking status, n (%)<0.001
 Never1811 (57)84 (45) 
 Former983 (31)60 (32) 
 Current406 (13)44 (23) 
Diabetes, n (%)279 (9)35 (19)<0.001
Hypertension, n (%)1545 (48)124 (66)<0.001
Systolic blood pressure, mmHg, mean (SD)122 (20)131 (23)<0.001
Aspirin use, n (%)428 (14)33 (18)0.13
Statin use, n (%)306 (10)21 (11)0.47
Waist circumference, cm96.5 (14.8)99.1 (14.6)0.02
Family history of premature atherosclerotic cardiovascular disease, n (%)468 (18)34 (23)0.13
Chronic kidney disease, n (%)440 (14)43 (23)0.001
High-density lipoprotein cholesterol, mg/dL, mean (SD)53 (15)50 (14)0.01
Triglycerides, mg/dL, mean (SD)116 (31)115 (31)0.54
Low-density lipoprotein cholesterol, mg/dL, mean (SD)126 (81)138 (133)0.07
Lipoprotein (a), mg/dL, median (interquartile range)18.2 (7.6–40.8)18.4 (8.4–47.0)0.70
High-sensitivity C-reactive protein, mg/L, median (interquartile range)1.92 (0.82–4.26)2.55 (0.86–4.99)0.06
10-y atherosclerotic cardiovascular disease risk, %4.84 (2.05–10.68)10.68 (4.61–18.77)<0.001
 <7.5%, n (%)2022 (63)65 (34) 
 7.5% to <15%, n (%)646 (2)60 (32) 
 15% to <20%199 (6)17 (9) 
Over a median follow-up time of 16 years, a total of 189 ASCVD events (composite of CHD and stroke) occurred among those with CAC=0, of which 91 were CHD, 88 were stroke, 10 were both CHD and stroke events, and 443 were all-cause deaths. The unadjusted incidence rates of ASCVD were ≤5 per 1000 person-years for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). ASCVD event rates were 6.2 per 1000 person-years among those with estimated baseline ASCVD risk 7.5% to <15% and 5.87 per 1000 person-years among those with estimated ASCVD risk 15% to <20% (Table 2).
Table 2. Unadjusted Incidence Rates of Atherosclerotic Cardiovascular Disease and All-Cause Mortality Among Those With Coronary Artery Calcium 0 at Baseline
Risk factorAtherosclerotic cardiovascular disease (per 1000 person-years)All-cause mortality (per 1000 person-years)
Cigarette smoking status
 Never3.077.15
 Former4.059.11
 Current7.3013.86
Diabetes
 No3.467.79
 Yes8.9213.49
Hypertension
 No2.555.11
 Yes5.4412.42
Aspirin use
 No3.788.11
 Yes5.1611.14
Statin use
 No3.838.54
 Yes4.569.47
Increased waist circumference
 No2.976.61
 Yes4.149.09
Family history of premature atherosclerotic cardiovascular disease
 No3.497.72
 Yes4.545.98
Chronic kidney disease
 No3.487.29
 Yes6.7517.06
High-density lipoprotein cholesterol ≤50 mg/dL
 No3.508.35
 Yes4.318.85
Triglycerides ≥150 mg/dL
 No3.658.42
 Yes4.629.11
Low-density lipoprotein cholesterol ≥130 mg/dL
 No4.028.96
 Yes3.687.87
Lipoprotein (a) ≥50 mg/dL
 No3.718.68
 Yes4.648.35
High-sensitivity C-reactive protein ≥2 mg/L
 No3.337.58
 Yes4.539.69
Calculated atherosclerotic cardiovascular disease risk
  <7.5%2.093.67
 7.5% to <15%6.1911.51
 15% to <20%5.8716.83
The median follow-up time was 15.9 years. Increased waist circumference is defined as ≥90 cm for men or ≥80 cm for women.
The unadjusted incidence rates of ASCVD and all-cause mortality (per 1000 person-years) for each risk factor stratified by categories of estimated 10-year ASCVD risk and age are shown in Tables S1 and S2, respectively. There was a graded higher risk of ASCVD and mortality for most cardiovascular risk factors with higher estimated ASCVD risk categories (Table S1). Among intermediate-risk participants (estimated ASCVD risk 7.5% to <15%), the incidence rate of ASCVD was highest among current smokers (11.4). Among those with estimated ASCVD risk 15% to <20%, the incidence rate of ASCVD was highest among those with diabetes (16.6) followed by current smokers (14.6). Likewise, there was a graded higher risk of ASCVD and mortality for most cardiovascular risk factors with higher age categories (Table S2). Among those aged 45 to 54 years the highest ASCVD event rates were noted among those with diabetes (7.3) and current smokers (5.2).
After multivariable adjustment, risk factors that remained significantly associated with ASCVD, hazard ratio (95% CI), included current cigarette smoking: 2.12 (1.32–3.42); diabetes: 1.68 (1.01–2.80); and hypertension: 1.57 (1.06–2.33; Table 3). Analyses excluding statin users and additional adjustment for pack-years of smoking yielded similar results (not shown).
Table 3. Association of Cardiovascular Risk Factors and Incident Atherosclerotic Cardiovascular Disease and All-Cause Mortality Among Those With Coronary Artery Calcium 0 at Baseline
Risk factorAtherosclerotic cardiovascular diseaseAll-cause mortality
Cigarette smoking status
 Never1.00 (reference)1.00 (reference)
 Former1.07 (0.71–1.61)1.04 (0.79–1.38)
 Current2.12 (1.32–3.42)*2.66 (1.89–3.74)*
Diabetes1.68 (1.01–2.80)*1.13 (0.78–1.63)
Hypertension1.57 (1.06–2.33)*1.37 (1.03–1.81)*
Aspirin use1.06 (0.66–1.69)0.79 (0.57–1.10)
Time varying statin use0.81 (0.53–1.24)0.79 (0.59–1.05)
Waist circumference, per 10 cm1.05 (0.91–1.20)1.10 (1.00–1.21)*
Family history of premature ASCVD1.30 (0.86–1.96)0.83 (0.59–1.17)
Chronic kidney disease1.23 (0.77–1.95)1.14 (0.84–1.53)
High-density lipoprotein cholesterol, per 10 mg/dL0.92 (0.79–1.06)0.96 (0.87–1.07)
Triglycerides, per 10 mg/dL1.00 (0.97–1.03)0.99 (0.97–1.02)
Low-density lipoprotein cholesterol, per 10 mg/dL0.99 (0.94–1.05)0.97 (0.92–1.01)
Lipoprotein (a), per 5 mg/dL†1.07 (0.46–2.49)1.21 (0.66–2.22)
High-sensitivity C-reactive protein, per mg/L†1.00 (0.84–1.19)1.12 (0.99–1.26)
Values indicate multivariable-adjusted hazard ratios (95% confidence intervals). Model is adjusted for age, sex, race and ethnicity, education, presence of health care insurance, and all listed risk factors. ASCVD indicates atherosclerotic cardiovascular disease.
*
Value is statistically significant (P<0.05).
†
Lipoprotein (a) and high-sensitivity C-reactive protein are log-transformed.
In sex-stratified analyses, current smoking remained significantly associated with ASCVD among men only. Among men, the incidence rate of ASCVD was 10.1 per 1000 person-years for current smokers, whereas the event rate among women was 5.2. Family history of premature ASCVD was significantly associated with incident ASCVD among women only. The corresponding incidence rate among those with premature ASCVD was 4.6 for women and 4.4 for men. There was no significant interaction between sex and any cardiovascular risk factors in the multivariable-adjusted Cox regression model (P for interaction >0.05; Table S3).
Risk factors that were significantly associated with all-cause mortality among those with CAC=0 included current cigarette smoking: 2.66 (1.89–3.74) and a 10 cm higher waist circumference: 1.10 (1.00–1.21; Table 3). In sex-stratified analyses, current cigarette smoking was a significant risk factor for all-cause mortality in both men and women, whereas waist circumference was significant among women only (Table S3). There was no significant interaction between sex and any cardiovascular risk factors in the association with all-cause mortality (P for interaction >0.05).
In analyses of incident CHD, only current cigarette smoking was a significant risk factor: 2.19 (1.14–4.17), whereas hypertension: 1.91 (1.09–3.35) was significantly associated with stroke (Table S4).

Sensitivity Analyses

Among those who developed an ASCVD event over follow-up, 59% developed incident hypertension, 10% incident diabetes, and 3% of never smokers at baseline were current smokers over subsequent MESA follow-up visits. Among those not on statin or aspirin use at baseline, 43% initiated statin therapy and 49% were on aspirin therapy. There was no significant association between incident cardiovascular risk factors and incident ASCVD (results not shown). For example, there was no statistically significant association between incident hypertension (modeled as a time-varying covariate) and risk of ASCVD: 1.44 (0.93–2.24).
The incidence rate of composite ASCVD was 5.4 per 1000 person-years among those with hypertension defined as blood pressure ≥130/80 mm Hg. Examining the individual components of ASCVD, we found that the incidence rate (per 1000 person-years) of CHD was 2.7 and of stroke was 3.1. We further evaluated incidence rates of ASCVD using different blood pressure thresholds to classify hypertension. Using a cutoff ≥140/90 mm Hg the incidence rate of ASCVD (per 1000 person-years) was 5.9 and using ≥150/90 mm Hg it was 5.7.
Among those with a family history of premature ASCVD, 39.5% received statin over follow-up (40.7% among women and 36.9% among men). Among those without a family history of premature ASCVD, 33.9% received statin over follow-up. Among those with family history of premature ASCVD, the incidence rate of ASCVD (per 1000 person-years) was 4.8 among those not on statin at baseline and 2.9 among those who were on a statin. ASCVD incidence rate (per 1000 person-years) among those never started on a statin (neither at baseline nor follow-up) was 3.2 and among those with incident statin use it was 6.9.

Discussion

Several observations can be made from the present study. First, we found that the long-term risk of ASCVD events continues to remain low (5 per 1000 person-years) in most people with baseline CAC=0 (mean age 58, follow-up to mean age 74). Second, 16-year event rates among those with CAC=0 but with diabetes or cigarette smoking are close to the threshold of 7.5% over 10 years, in general, considered to be appropriate for the initiation of statin therapy in primary prevention. Third, current cigarette smoking, diabetes, and hypertension are associated with incident ASCVD events among those with CAC=0 at baseline. Fourth, among those with CAC=0 who develop ASCVD events, CHD- and stroke-related event rates are numerically comparable.
The present analyses support recommendations made by the 2018 AHA/ACC/MS cholesterol guideline that continues to favor statin therapy among individuals with CAC=0 if diabetes or current cigarette smoking are present. ASCVD event rates were highest among individuals with CAC=0 and diabetes in our study. A previous study by Malik et al21 also showed that ASCVD event rates were especially high with concomitant diabetes and insulin use or hemoglobin A1c ≥7%. We also found that ASCVD event rates were high among current smokers, in particular, among those who were at intermediate risk of ASCVD.
We found no significant association between family history of premature ASCVD and incident ASCVD in multivariable-adjusted models. Among those with a family history of premature ASCVD, the incidence rate of ASCVD was lower among those on a statin at baseline presumably because statin therapy lowers ASCVD risk among those with cardiovascular risk factors. ASCVD event rates were lower among those never started on a statin compared with those with incident statin use over follow-up, likely because those who were started on statin therapy represented patients with other cardiovascular comorbidities leading to the initiation of statin therapy by their treating clinician.
Incidence rates of ASCVD were slightly higher among women than men with a family history of premature ASCVD, although incident statin use was also higher in women. Likewise, the higher incident statin use among women may reflect a worse cardiovascular risk profile among women at follow-up prompting statin use. This could explain why a family history of premature ASCVD was associated with incident ASCVD among women only. Because incidence rates of ASCVD were <5 per 1000 person-years in both men and women with a family history of premature ASCVD and CAC=0, it may be reasonable to defer statin therapy in this group. The 2018 AHA/ACC/MS cholesterol guideline listed family history of premature CHD as an exception to statin deferral even in the presence of CAC=0. Close surveillance is still recommended with updated screening of cardiovascular risk factors and possibly repeating CAC measurement given the higher likelihood of developing subclinical atherosclerosis over time in persons with a family history of premature CHD.22
We found that the hazard ratio of ASCVD was significantly higher among those with hypertension, which may be driven by the excess risk of stroke among individuals with CAC=0. Incidence rates of ASCVD were not appreciably different using more stringent blood pressure thresholds in comparison with the 2017 ACC/AHA guidelines. There was no statistically significant association between incident hypertension and incident ASCVD events. In age-stratified analyses (Table S2), we found that ASCVD event rates were relatively high among those aged <65 years. Therefore, it is important to control blood pressure in individuals with hypertension and CAC=0 through lifestyle modification and antihypertensive treatment. Statin therapy can be added in this group to further lower ASCVD risk.
Our results confirm that the warranty period of CAC=0 may extend up to 15 years among most individuals.23 These results are reassuring for most patient groups if clinicians and patients opt to measure CAC when there is clinical uncertainty after risk assessment. A recent study from MESA found that, among those with CAC=0, the estimated warranty period of CAC>0 varied from 3 to 7 years.24 The presence of diabetes was associated with significantly shorter warranty period and, therefore, a shorter time when retesting CAC would be indicated, whereas family history of CHD and cigarette smoking had a smaller impact on the warranty period.
The presence of diabetes, cigarette smoking, or family history of premature ASCVD is associated with a higher likelihood of the presence of CAC and conversion from CAC=0 to CAC>0.7–9 Follow-up ranged from 2.5 to 10 years in these previous studies. A study by Joshi et al10 found that over a median of 10.4 years, hypertension and cigarette smoking significantly predicted ASCVD events among those with CAC=0 at baseline.
Identifying risk factors that are associated with incident ASCVD outcomes among those with CAC=0 can inform treatment decisions with statins. Our results are reassuring that, for most risk factors, absolute event rates remain low in the presence of CAC=0. A previous study from the SCAPIS (Swedish Cardiopulmonary Bioimage Study) cohort showed that, among participants with CAC=0, 5% had coronary computed tomographic angiography–detected atherosclerosis and 0.4% had significant stenosis.25 Therefore, withholding statin therapy for the long term or postponing it is reasonable if there is any disutility regarding the potential benefit of statins on the patient’s part. A previous study demonstrated that CAC testing was cost-effective if there was patient disutility, which was defined as the willingness to trade 2 weeks of perfect health to avoid 10 years of taking statins.5 On the other hand, although a CAC score of 0 does indicate relatively low risk in those with smoking or diabetes, the absolute ASCVD event rates are close to or exceed the threshold for consideration of statin therapy. Therefore, clinicians should consider statin therapy using a shared decision-making approach that includes informing patients on options for risk reduction and the perceived benefits of treatment, and allowing patients to be engaged in informed decision making based on their preferences and values.26,27 Should statin therapy be deferred because of disutility on the part of the patient, it may be reasonable to repeat a CAC scan and reinitiate a preventive pharmacotherapy discussion within 5 years given the shorter warranty period in these individuals.24 In all cases, clinicians should stress the importance of tight control of risk factors including smoking cessation, hemoglobin A1c, and blood pressure control using medications and lifestyle modification.
Our results also highlight the importance of 10-year ASCVD risk assessment in primary ASCVD prevention. We noted that the observed ASCVD event rates in people with calculated 10-year ASCVD risk of ≥7.5% remain very close to the statin net benefit threshold28,29 when these people are followed for long-term 16-year follow-up (Table 2). Likewise, the presence of risk factors in those with calculated 10-year ASCVD risk ≥7.5% portends a worse prognosis over the long term (Table S1). A higher 10-year ASCVD risk in such cases is likely a marker of a longer duration for the presence of a risk factor (by capturing age in the calculation of the 10-year ASCVD risk), and the interaction between various risk factors, as well. These results reaffirm that an initial treatment strategy with statin therapy is reasonable in those with intermediate ASCVD risk as long as the patient and the clinician are comfortable with a strategy of long-term statin use. On the other hand, if there is any disutility associated with long-term statin use, CAC remains an excellent tool available to the clinicians and patients to further guide the risk discussion surrounding long-term statin use.5
Our study has limitations. We presented rates per person-years, which are equivalent to yearly averages, although we acknowledge that event rates are likely not homogeneously distributed throughout the entire follow-up period. The projected benefit of preventive therapies may differ by duration of follow-up and aging of the cohort, although this was not considered in the present study. However, because ASCVD prevention involves risk reduction strategies over a long-term horizon, we believe that average event rates are still helpful information for both the patient and clinician to gauge the risk of ASCVD. Furthermore, AHA/ACC prevention and cholesterol guidelines also use average ASCVD event rates as percentages for risk stratification and guiding statin therapy. Although we performed sex-stratified analyses, we were underpowered to perform analyses by racial and ethnic groups. The association between low-density lipoprotein cholesterol and incident events can be difficult to interpret because of confounding by indication for statin use especially given the high proportion of incident statin therapy over follow-up. Likewise, the effect of intervening antihypertensive therapy may not be adequately assessed. Some risk factors for common mortality causes, such as breast cancer, are missing. Last, CHD deaths may have been underestimated as a result of difficulties in adjudication, although we believe this measurement error would likely be random and similar to what may be found in any epidemiological study.
In summary, the overall risk for ASCVD among a majority of individuals with CAC=0 continues to remain low at long-term follow-up. Current cigarette smoking, diabetes, or hypertension are associated with incident ASCVD events and mortality at long-term follow-up among those with CAC=0. Family history of premature ASCVD may be associated with ASCVD risk among women only. In such individuals, initiation and the long-term use of statin therapy along with a heart-healthy lifestyle and risk factor control may be warranted as part of the clinician-patient risk discussion.

Article Information

Supplemental Material

Tables S1–S4

Footnote

Nonstandard Abbreviations and Acronyms

ACC/AHA/MS
American Heart Association/ American College of Cardiology/Multisociety
ASCVD
atherosclerotic cardiovascular disease
CAC
coronary artery calcium
CHD
coronary heart disease
PCE
pooled cohort equation

Supplemental Material

File (circ_circulationaha-2021-056705_supp1.pdf)

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Circulation
Volume 145 • Number 4 • 25 January 2022
Pages: 259 - 267
PubMed: 34879218

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© 2021 American Heart Association, Inc.

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History

Received: 22 July 2021
Accepted: 29 October 2021
Published online: 8 December 2021
Published in print: 25 January 2022

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Keywords

  1. carotid artery diseases
  2. coronary artery disease
  3. heart disease risk factors

Subjects

  1. Cardiovascular Disease
  2. Computerized Tomography (CT)
  3. Epidemiology
  4. Imaging
  5. Primary Prevention

Authors

Affiliations

Mahmoud Al Rifai, MD, MPH https://orcid.org/0000-0002-6933-790X
Section of Cardiology, Baylor College of Medicine, Houston, TX (M.A.R., V.N., C.M.B., S.S.V.).
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Michael J. Blaha, MD, MPH https://orcid.org/0000-0001-5138-9683
The Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, MD (M.J.B., E.D.M., R.S.B., W.S.P.).
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Vijay Nambi, MD, PhD https://orcid.org/0000-0002-4237-0267
Section of Cardiology, Baylor College of Medicine, Houston, TX (M.A.R., V.N., C.M.B., S.S.V.).
Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (V.N., S.S.V.).
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Steven J.C. Shea, MD https://orcid.org/0000-0002-7382-0603
Departments of Medicine and Epidemiology, Columbia University, New York, NY (S.J.C.S.).
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Erin D. Michos, MD, MHS https://orcid.org/0000-0002-5547-5084
The Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, MD (M.J.B., E.D.M., R.S.B., W.S.P.).
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Roger S. Blumenthal, MD https://orcid.org/0000-0003-1910-3168
The Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, MD (M.J.B., E.D.M., R.S.B., W.S.P.).
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Christie M. Ballantyne, MD https://orcid.org/0000-0002-6432-1730
Section of Cardiology, Baylor College of Medicine, Houston, TX (M.A.R., V.N., C.M.B., S.S.V.).
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Moyses Szklo, MD, DrPH
Department of Epidemiology, Bloomberg School of Public Health, Baltimore, MD (M.S.).
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Philip Greenland, MD https://orcid.org/0000-0002-6327-2439
Departments of Preventive Medicine and Medicine, Northwestern University Feinberg School of Medicine, Chicago IL (P.G.).
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Michael D. Miedema, MD, MPH
Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.).
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Khurram Nasir, MD, MPH https://orcid.org/0000-0001-5376-2269
Division of Cardiovascular Prevention and Wellness, Houston Methodist DeBakey Heart and Vascular Center, TX (K.N.).
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Jerome I. Rotter, MD https://orcid.org/0000-0001-7191-1723
Section of Cardiology, Baylor College of Medicine, Houston, TX (M.A.R., V.N., C.M.B., S.S.V.).
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Xiuqing Guo, PhD https://orcid.org/0000-0002-5264-5068
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., J.Y.).
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Jie Yao, MS https://orcid.org/0000-0002-8822-0651
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., J.Y.).
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Wendy S. Post, MD, MS https://orcid.org/0000-0002-8655-5204
The Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, MD (M.J.B., E.D.M., R.S.B., W.S.P.).
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Salim S. Virani, MD, PhD https://orcid.org/0000-0001-9541-6954 [email protected]
Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (V.N., S.S.V.).
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Notes

This manuscript was sent to Todd Brown, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at Supplemental Material.
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
For Sources of Funding and Disclosures, see page 266.
Correspondence to: Salim S. Virani, MD, PhD, Baylor College of Medicine, 2002 Holcombe Blvd, Houston, TX 77030. Email [email protected]

Disclosures

Disclosures Dr Virani has received research support from Department of Veterans Affairs, World Heart Federation, and Tahir and Jooma Family; honorarium: American College of Cardiology (Associate Editor for Innovations, acc.org). Dr Shea has received funding from the National Heart, Lung, and Blood Institute. Dr Greenland has received grants from National Institutes of Health (NIH) and American Heart Association (AHA). Dr Nambi was supported by a VA Merit grant. He is co-investigator on a provisional patent along with Roche, Baylor College of Medicine on the use of biomarkers in prediction of heart failure, and he is site principal investigator for study sponsored by Amgen. Dr Ballantyne has received grant/research support: All significant (all paid to institution, not individual): Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, Roche Diagnostic, NIH, AHA, and the American Diabetes Association. He is a consultant for Abbott Diagnostics, Althera, Amarin,* Amgen, Arrowhead, Astra Zeneca, Corvidia, Denka Seiken,* Esperion, Genentech, Gilead, Matinas BioPharma Inc, New Amsterdam,* Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo* (*significant where noted [>$10 000]; remainder modest [<$10 000]). The remaining coauthors report no relevant conflicts of interest.

Sources of Funding

The MESA projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Also supported in part by the National Center for Advancing Translational Sciences, Clinical & Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

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