Highlight
Quantitative plaque measures derived from coronary computed tomographic angiography (CCTA) significantly enhance the prediction of major adverse cardiovascular events (MACE) in patients without a prior diagnosis of coronary artery disease (CAD).
Total plaque burden (TPB) and noncalcified plaque burden (NCPB) are independent predictors of MACE, even after adjusting for traditional clinical risk factors and qualitative CCTA findings.
Specific volumetric thresholds, such as a total plaque volume of 87 mm3 or greater, identify patients at nearly double the risk for future cardiac events.
Background and Clinical Context
For decades, the clinical assessment of coronary artery disease has been dominated by a stenosis-centric model. Clinicians have primarily focused on the degree of luminal narrowing to guide intervention and assess risk. However, it is well-established in cardiovascular pathology that many acute coronary syndromes arise from non-obstructive plaques that undergo rupture or erosion. This discrepancy highlights a critical need for better prognostic tools that characterize the underlying atherosclerotic burden rather than just the lumen diameter.
Coronary computed tomographic angiography (CCTA) has emerged as a frontline diagnostic tool for symptomatic outpatients. While qualitative assessment (e.g., identifying the presence of obstructive vs. non-obstructive CAD) is standard, the clinical utility of quantitative plaque analysis—measuring the actual volume and composition of the plaque—has remained largely within the realm of research. The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) randomized clinical trial provided a robust platform to investigate whether these quantitative measures could offer incremental prognostic value in a real-world clinical setting.
Study Design and Methodology
This study was a post hoc analysis of the PROMISE trial, involving 4,267 symptomatic outpatients across 193 clinical sites in North America. These participants had no known CAD at baseline and were randomized to receive CCTA as their initial diagnostic strategy. The analysis, conducted between 2021 and 2024, utilized core laboratory-based quantitative plaque measures to ensure high-quality, standardized data.
The investigators examined several volumetric exposures: total plaque volume (TPV), calcified plaque volume (CPV), noncalcified plaque volume (NCPV), and low-attenuation plaque volume (LAPV). They also calculated total plaque burden (TPB) and noncalcified plaque burden (NCPB) by normalizing plaque volumes with the vessel volume. The primary endpoint was MACE, defined as a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina. To determine clinical utility, optimal predictive cut points were identified using Euclidean distance methods and then validated through multivariable Cox regression models.
Key Findings and Results
The study population had a mean age of 60.4 years, with a nearly equal gender distribution (51.5% female). At the time of their first diagnosis, many patients exhibited relatively low plaque volumes, with a median TPV of 39.8 mm3. However, the distribution of plaque was highly correlated with traditional risk factors. Patients with higher-than-median TPV were typically older, more likely to be male, and had significantly higher ASCVD risk scores (median 14.4 vs. 7.9).
Independent Predictors of MACE
The most striking results involved the independent predictive power of plaque burden. After adjusting for clinical risk factors, statin use, and even qualitative CCTA findings (such as the presence of obstructive CAD), both TPB and NCPB remained strongly associated with future events. Specifically, the adjusted hazard ratio (aHR) for TPB was 1.18 (95% CI, 1.05-1.34; P = .006), and for NCPB, it was 1.20 (95% CI, 1.05-1.37; P = .007).
The Power of Thresholds
The identification of optimal cut-off points provided clear clinical targets for risk stratification. The researchers found that:
- Total Plaque Volume (TPV) ≥ 87 mm3: aHR 2.07 (95% CI, 1.24-3.49)
- Total Plaque Burden (TPB) ≥ 35%: aHR 1.96 (95% CI, 1.21-3.17)
- Noncalcified Plaque Burden (NCPB) ≥ 20%: aHR 1.77 (95% CI, 1.12-2.82)
These findings suggest that reaching these volumetric thresholds nearly doubles the risk of MACE, providing a much more granular risk profile than traditional binary (obstructive vs. non-obstructive) classifications.
Expert Commentary and Clinical Implications
The shift toward quantitative plaque analysis represents a significant evolution in preventive cardiology. By focusing on the total volume of noncalcified plaque, clinicians can identify patients who may have ‘vulnerable’ atherosclerotic profiles despite not having significant luminal stenosis. This is particularly relevant for the primary prevention population where early intensification of lipid-lowering therapy or aspirin could change the disease trajectory.
However, several challenges remain for widespread clinical adoption. Currently, quantitative plaque analysis often requires specialized software and can be time-consuming for a busy radiologist or cardiologist. The integration of Artificial Intelligence (AI) and automated segmentation tools will be essential to make these measurements feasible in routine practice. Furthermore, while the PROMISE substudy provides strong evidence for the prognostic value of these measures, prospective trials are needed to determine if treating patients specifically based on plaque volume thresholds leads to better clinical outcomes compared to standard care.
Mechanistically, the importance of NCPB (noncalcified plaque burden) aligns with our understanding of plaque biology. Noncalcified components often contain lipid-rich necrotic cores and are more prone to inflammation and rupture than heavily calcified, stable plaques. This study reinforces that even a small volume of noncalcified plaque in a symptomatic patient warrants aggressive risk factor management.
Conclusion
The PROMISE substudy confirms that in patients with a first diagnosis of coronary artery disease, the volume and burden of coronary plaque are powerful, independent predictors of future cardiovascular events. Moving beyond the simple identification of stenosis to a quantitative assessment of plaque burden allows for more precise risk stratification. As software tools continue to evolve, quantitative CCTA is poised to become an indispensable component of the cardiovascular diagnostic toolkit, enabling a more personalized approach to heart disease prevention.
Funding and Trial Registration
This research was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institutes of Health. The PROMISE trial is registered at ClinicalTrials.gov with the identifier NCT01174550.
References
Karády J, Mayrhofer T, Brendel JM, et al. Prognostic Value of Plaque Volume in Patients With First Diagnosis of Coronary Artery Disease: A Substudy of the PROMISE Randomized Clinical Trial. JAMA Cardiol. Published online February 11, 2026. doi:10.1001/jamacardio.2025.5520.