Response to Letter Regarding Article, “Very high coronary artery calcium (CAC ≥ 1000) and association with CVD events, non-CVD outcomes, and mortality: Results from the Multi-Ethnic Study of Atherosclerosis (MESA)”

We thank Dr. Braillon for his response to our article. Our analysis was a-priori registered with MESA and pre-approved by their Publications and Presentations and Steering Committees, including our statistical analytic plan and proposed tables/figures, which are published on the MESA website (mesa-nhlbi.org) as per MESA protocol. Although we did not prepare a STROBE checklist with this secondary MESA analysis, MESA is a well-established, NHLBI-sponsored prospective cohort that has been reviewed in detail in prior reports.¹ More details about MESA can also be found on their website and in the original design article.² Importantly, MESA is a prospective study; as such, our analysis was by definition not retrospective, but rather a secondary analysis of an established prospective study.

We continue to affirm our conclusion that aggressive prevention and pharmacotherapy may be beneficial for those with very high CAC ≥ 1000. In fact, the new 2021 NLA guidelines state that especially in those with CAC ≥ 1000, and even in CAC ≥ 300, it is reasonable to use high-intensity statins, along with the addition of other guideline-based pharmacotherapy as necessary to achieve LDL-C < 70 mg/dL or ≥ 50% reduction in LDL-C.³

In response to Braillon’s other points:

1. Indeed, we recognize CAC is a continuous variable. However, our CAC categories have been well-studied in the literature, and current guidelines (as discussed above) utilize CAC score cutoffs and categories similar or the same as those used in our paper.^3,4

2. We conducted risk factor adjustment based on clinical definitions, eg. hypertension as defined by blood pressure cutoffs, obesity as defined by BMI ≥ 30, and diabetes as defined by fasting blood glucose level ≥ 126 mg/dL. In short, adjusting our analysis on continuous variables (rather than binary) and changing the smoking definition (smoking in past 30 days or former smoker) as Braillon had mentioned, when compared to our original analysis in our paper, produced no meaningful difference in the results.

3. We certainly agree that variables such as physical activity, alcohol use, nutrition, air pollution, and socio-economic status may all contribute to the development of CAC. However, as upstream risk factors, they are unlikely to be confounders of the relationship between CAC and outcomes. To demonstrate this, we re-ran our analyses adjusting on these variables mentioned by Braillon, and it made no significant difference in our analyses. In fact, adjusting on physical activity, alcohol use, income, and education increased our HR by > 0.1 in hard CHD and all-cause mortality outcomes, while maintaining the same HR in all CVD, hard CVD, and all CHD outcomes.

Lastly, regarding Braillon’s point about screening for CAC, our paper did not comment on screening for CAC or cardiovascular disease. Rather, we discussed the importance of CAC in advanced risk stratification, as well as the beneficial value of aggressive preventive therapy only in those who already have an established CAC score; specifically those with CAC ≥ 1000. Our points are echoed by existing ACC/AHA guidelines along with the new 2021 NLA guidelines.^3,5