Highlights
- Quantitative plaque measures, including Total Plaque Burden (TPB) and Noncalcified Plaque Burden (NCPB), are independent predictors of Major Adverse Cardiovascular Events (MACE) in patients with a first diagnosis of coronary artery disease.
- Even in symptomatic outpatients with relatively low total plaque volumes, specific volumetric thresholds (e.g., TPV ≥87 mm³) are associated with a nearly two-fold increase in cardiovascular risk.
- The shift from qualitative ‘stenosis-centric’ assessment to quantitative ‘plaque-centric’ analysis provides incremental prognostic value over standard clinical risk scores and qualitative CCTA findings.
- These findings from the PROMISE trial substudy underscore the potential for automated, AI-driven plaque quantification to refine personalized risk stratification in early-stage CAD.
Background
For decades, the clinical management of coronary artery disease (CAD) has been dominated by a ‘stenosis-centric’ paradigm, where the severity of luminal narrowing dictated therapeutic interventions. However, evidence from large-scale prospective trials has increasingly suggested that the total burden and composition of atherosclerotic plaque may be more accurate predictors of future myocardial infarction and cardiovascular death than the degree of stenosis alone. Coronary computed tomographic angiography (CCTA) has emerged as a frontline diagnostic tool, but its use has traditionally been limited to qualitative assessment (e.g., identifying obstructive vs. non-obstructive disease).
The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial was a landmark randomized controlled trial that compared initial CCTA against functional testing in symptomatic outpatients. While the primary trial provided foundational evidence for CCTA’s utility, the clinical applicability and prognostic weight of detailed volumetric plaque analysis remained an area of active investigation. Understanding the ‘plaque-ome’—the comprehensive profile of calcified, noncalcified, and low-attenuation plaque—is essential for moving toward precision cardiology.
Key Content
The Transition to Quantitative Plaque Analysis
The traditional Agatston score, which quantifies coronary artery calcium (CAC), has long served as a robust predictor of cardiovascular risk. However, it fails to account for noncalcified plaque (NCP), which is often the precursor to acute coronary syndromes. Methodological advances in CCTA software now allow for core laboratory-based quantitative plaque measures. This substudy of the PROMISE trial utilized these advanced techniques to measure Total Plaque Volume (TPV), Calcified Plaque Volume (CPV), Noncalcified Plaque Volume (NCPV), and Low-Attenuation Plaque Volume (LAPV).
A critical metric introduced in this analysis is ‘Plaque Burden,’ which normalizes plaque volume to the total vessel volume. This normalization accounts for variations in coronary anatomy among patients, providing a more standardized assessment of the atherosclerotic process. The study analyzed 4,267 patients, providing one of the most comprehensive datasets on quantitative plaque metrics in a ‘first diagnosis’ population.
Clinical Demographics and Plaque Correlation
The analysis revealed that plaque volumes, while generally low in this early-diagnosis cohort (median TPV of 39.8 mm³), were significantly correlated with traditional risk factors. Patients with higher-than-median plaque volumes were typically older, male, and had higher ASCVD (Atherosclerotic Cardiovascular Disease) risk scores. Specifically, the median ASCVD score for patients with high TPV was 14.4, compared to 7.9 in the lower TPV group.
These correlations reinforce the biological plausibility of plaque volumetrics as a cumulative measure of lifetime risk factor exposure. Interestingly, over 50% of the cohort were female, providing valuable data on sex-specific plaque distribution, which has historically been underrepresented in cardiovascular imaging research.
Prognostic Value and MACE Prediction
The primary finding of the substudy is the independent prognostic value of Total Plaque Burden (TPB) and Noncalcified Plaque Burden (NCPB). In multivariable Cox regression models—after adjusting for clinical risk factors, statin use, and qualitative CCTA findings—both TPB and NCPB remained significant predictors of MACE (composite of death, MI, or unstable angina).
- Total Plaque Burden (TPB): Adjusted Hazard Ratio (aHR) 1.18 (95% CI, 1.05-1.34; P=.006).
- Noncalcified Plaque Burden (NCPB): Adjusted Hazard Ratio (aHR) 1.20 (95% CI, 1.05-1.37; P=.007).
Perhaps most importantly for clinical practice, the researchers identified specific ‘high-risk’ cut-offs using Euclidean distance methods. Patients exceeding these thresholds faced a starkly different prognosis:
| Metric | Threshold | Adjusted HR (95% CI) |
|---|---|---|
| Total Plaque Volume (TPV) | ≥ 87 mm³ | 2.07 (1.24–3.49) |
| Total Plaque Burden (TPB) | ≥ 35% | 1.96 (1.21–3.17) |
| Noncalcified Plaque Burden (NCPB) | ≥ 20% | 1.77 (1.12–2.82) |
Synthesis with Existing Evidence
These results align with and extend findings from the SCOT-HEART trial, which demonstrated that low-attenuation plaque volume (LAPV) was the strongest predictor of myocardial infarction. While the PROMISE substudy emphasizes TPB and NCPB, the converging evidence suggests that noncalcified components of the plaque—representing the ‘vulnerable’ portion of the atherosclerotic burden—are the primary drivers of acute events in the early stages of CAD.
Expert Commentary
The findings from the PROMISE substudy represent a significant leap toward the ‘biopsyless’ characterization of coronary artery disease. From a mechanistic standpoint, the ability of NCPB to predict MACE independently of luminal stenosis highlights a crucial biological truth: plaque progression and rupture are often eccentric processes that do not significantly compromise the lumen until late in the disease course. Therefore, relying solely on stenosis percentage likely misses a substantial portion of the at-risk population.
However, several barriers to clinical implementation remain. First, the quantitative analysis in this study was performed in a core laboratory setting. For these metrics to be useful in a busy clinical environment, we require high-fidelity, AI-automated segmentation tools that can provide these volumes in real-time. Second, the ‘low’ absolute plaque volumes in this cohort suggest that our current primary prevention strategies (statins, BP control) are being applied to a population with a broad range of actual disease burden. Utilizing TPV or NCPB could allow clinicians to ‘intensify’ therapy for those above the 87 mm³ or 35% burden thresholds, while potentially avoiding over-treatment in those with zero or minimal plaque.
One controversy remains: does quantitative analysis change management enough to justify the additional cost or processing time? While the aHRs are statistically significant, the incremental C-statistic improvement over qualitative assessment is often modest. The true value may lie not in predicting the next event for a single patient, but in monitoring plaque regression or stabilization in response to novel therapies like PCSK9 inhibitors or anti-inflammatory agents.
Conclusion
The PROMISE trial substudy establishes that quantitative coronary plaque metrics—specifically total and noncalcified plaque burdens—are potent, independent predictors of cardiovascular risk in symptomatic outpatients with a first diagnosis of CAD. With nearly a two-fold increase in MACE risk for patients above identified volumetric thresholds, these measures offer a more nuanced and accurate risk profile than qualitative CCTA alone. As automated software becomes more accessible, quantitative plaque assessment is poised to become a cornerstone of personalized cardiovascular medicine, shifting the focus from ‘how narrow is the pipe’ to ‘how diseased is the wall.’
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. 2026;11(3):259-267. PMID: 41670958.
- Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease. N Engl J Med. 2015;372(14):1291-1300. PMID: 25773919.
- Williams MC, Moss AJ, Dweck M, et al. Low-Attenuation Plaque and Prediction of Myocardial Infarction in the SCOT-HEART Trial. Circulation. 2020;141(18):1452-1462. PMID: 32174130.
- Ferencik M, Mayrhofer T, Bittner DO, et al. Use of High-Risk Coronary Plaque Features Found on Computed Tomographic Angiography to Predict Heart Failure and Adverse Cardiovascular Events in the PROMISE Trial. JAMA Cardiol. 2018;3(11):1034-1041. PMID: 30264159.
