Guidance for Sponsors · Volume 5, Issue 7 · 2026 Edition

Coronary Artery Calcium Scoring in Clinical Trials

By Amit Mehta, M.D., Executive Vice President and Chief Medical Officer · Updated for 2026 by Intrinsic Imaging

Introduction

Cardiovascular disease caused 915,973 deaths in the United States in the most recent reporting year, and the majority of these deaths are related to coronary heart disease. Its direct and indirect costs reached an estimated $414.7 billion in 2021–2022.^[1] Biopharmaceutical companies are investing heavily in new therapies, and among the biomarkers available to monitor them, coronary artery calcium (CAC) scoring is one of the best established.

The Agatston Score

Atherosclerosis progresses from lipoprotein retention in the arterial wall to cholesterol deposition, inflammation and, ultimately, calcification. The Agatston score, developed on electron-beam CT and now measured on multidetector CT, quantifies that calcium. Each lesion's area in square millimeters is multiplied by a weighting factor determined by its peak attenuation in Hounsfield units, and the products are summed across the coronary tree.

Because coronary calcium correlates strongly with atherosclerotic plaque burden, the score is a robust predictor of cardiac events. Scores are traditionally stratified as minimal (1–10), mild (11–99), moderate (100–399) and severe (400 and above), and scores above 400 signal markedly increased risk. The Coronary Artery Calcium Data and Reporting System (CAC-DRS), published in 2018, standardized reporting by combining the score category with the number of involved vessels and linking each category to treatment recommendations.^[2]

The Density Paradox

The Multi-Ethnic Study of Atherosclerosis (MESA) complicated this picture. Among more than 3,000 participants with detectable calcium, greater calcium volume predicted more coronary and cardiovascular events, but at any given volume, higher calcium density was associated with fewer events.^[3] Dense, stable calcification appears to be relatively protective. Because the Agatston score rewards density, it may overstate risk in some patients, and the MESA investigators concluded that area or volume scores alone are not optimal measures of risk.^[3] This matters for trials of therapies, such as statins, that may increase calcium density while stabilizing plaque.

Sources of Variability

Calcium scoring remains the mainstay of assessment, and its value in a trial depends on the quality and consistency of the data. Three alternative measures exist: the Agatston score, the volume score and calcium mass. Mass, calibrated against a phantom, is the most physically meaningful and the least dependent on acquisition. A multi-institutional, multimanufacturer international standard defined how calcium mass should be quantified to allow consistent measurement across platforms.^[4]

Scanner and software differences are substantial. In a study of state-of-the-art scanners from four vendors, calcium scores differed significantly, enough to reclassify up to 6.5% of patients into a different risk category.^[5] Different software packages applied to the same images can also produce different results.^[6] For trials that compare scores over time, or pool data across sites, these differences can rival the treatment effect being measured.

Photon-Counting CT

Photon-counting detector CT, first cleared by FDA in 2021, counts individual X-ray photons and measures their energy.^[7] It offers higher spatial resolution, less noise and lower radiation dose, and can reconstruct images at selected energy levels. It also changes calcium scores: in phantom studies, routine photon-counting protocols produced higher Agatston scores than conventional CT, and agreement depended on the reconstruction energy and settings used.^[8] Photon-counting CT promises more precise plaque characterization, but sponsors cannot assume that its scores are interchangeable with those from conventional scanners.

Guidance for Sponsors

Summary

Coronary artery calcium scoring is an inexpensive, widely available and powerful predictor of cardiovascular risk. Its use as a trial biomarker requires an appreciation of what the score measures, how calcium density modifies risk and how scanners, software and the arrival of photon-counting CT alter the numbers. With standardized acquisition and central analysis, calcium scoring remains a precise and dependable tool for evaluating new cardiovascular therapies.

About the Author

Dr. Amit Mehta, Executive Vice President, Chief Medical Officer and Co-founder of Intrinsic Imaging, wrote the original edition of this issue. He completed his diagnostic radiology residency and a fellowship in minimally invasive image-guided surgery at Harvard Medical School’s Massachusetts General Hospital, and he is double board-certified in diagnostic and vascular interventional radiology in Canada and the United States. He has co-authored three medical textbooks and received the Radiological Society of North America’s George Brown Award and the Joseph E. Whitley Award. He is a General Partner at Builders VC and serves as a reviewer of SBIR and STTR grant applications for the National Institutes of Health.

References

1. American Heart Association. Top takeaways from the 2026 Heart Disease and Stroke Statistics update. https://www.heart.org/-/media/PHD-Files-2/Science-News/2/2026-Heart-and-Stroke-Stat-Update/Top-Takeaways-from-the-2026-AHA-Heart-Disease-and-Stroke-Statistics-Update-PDF.pdf?sc_lang=en
2. Hecht HS, Blaha MJ, Kazerooni EA, et al. CAC-DRS: Coronary Artery Calcium Data and Reporting System. An expert consensus document of the Society of Cardiovascular Computed Tomography. J Cardiovasc Comput Tomogr. 2018;12(3):185–191. https://pubmed.ncbi.nlm.nih.gov/29793848/
3. Criqui MH, Denenberg JO, Ix JH, et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA. 2014;311(3):271–278. https://jamanetwork.com/journals/jama/fullarticle/1780017
4. McCollough CH, Ulzheimer S, Halliburton SS, et al. Coronary artery calcium: a multi-institutional, multimanufacturer international standard for quantification at cardiac CT. Radiology. 2007;243(2):527–538. https://pubmed.ncbi.nlm.nih.gov/17456875/
5. Willemink MJ, Vliegenthart R, Takx RA, et al. Coronary artery calcification scoring with state-of-the-art CT scanners from different vendors has substantial effect on risk classification. Radiology. 2014;273(3):695–702. https://pubmed.ncbi.nlm.nih.gov/25153157/
6. Weininger M, Ritz KS, Schoepf UJ, et al. Interplatform reproducibility of CT coronary calcium scoring software. Radiology. 2012;265(1):70–77. https://pubmed.ncbi.nlm.nih.gov/22771886/
7. Siemens Healthineers. FDA 510(k) clearance of Naeotom Alpha, the world's first photon-counting CT. 2021. https://www.siemens-healthineers.com/press/releases/naeotomfda
8. van der Werf NR, Booij R, Greuter MJW, et al. Reproducibility of coronary artery calcium quantification on dual-source CT and dual-source photon-counting CT: a dynamic phantom study. Int J Cardiovasc Imaging. 2022;38:1613–1619. https://link.springer.com/article/10.1007/s10554-022-02540-z
9. U.S. FDA. Clinical trial imaging endpoint process standards: guidance for industry. April 2018. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-imaging-endpoint-process-standards-guidance-industry

Related reading: Computed Tomography Data Acquisition in Clinical Trials · Contrast Echocardiographic Imaging in Clinical Trials