Sex differences in association between increasing plaque burden and MACE risk

Analysis of PROMISE among patients with stable chest pain showed that women had fewer coronary plaques, but their MACE risk appeared to emerge at a lower plaque burden level and rose more steeply compared with men.

This summary is based on the publication of Brendel JM, Mayrhofer T, Karády J, et al. - Risk in Women Emerges at Lower Coronary Plaque Burden Than in Men: PROMISE Trial. Circ Cardiovasc Imaging. 2026 Feb 23:e019011 [Online ahead of print]. doi: 10.1161/CIRCIMAGING.125.019011

Introduction and methods

Background

The prognostic value of quantitative measures of coronary plaques differ between men and women. For example, the association between quantitative plaque measures and MACE risk may be stronger in women, as shown by analyses of CONFIRM2 and PROMISE (PROspective Multicenter Imaging Study for Evaluation of chest pain) trial data [1,2]. Still, it is unclear whether CVD risk increases proportionally with larger plaque extent in both sexes.

Aim of the study

In an observational analysis of the PROMISE trial, the authors compared CVD risk trajectories across quantitative coronary plaque measures in women and men with stable chest pain.

Methods

The PROMISE trial was a multicenter comparative-effectiveness RCT conducted in the US in which 10,003 stable outpatients with chest pain but no prior history of coronary artery disease who required noninvasive testing were included [3,4]. To assess the effect of the initial diagnostic approach on clinical outcomes, participants were randomized to either a strategy of anatomic testing using coronary CT angiography (CCTA) or functional testing. CCTA analysis quantified total coronary plaque volume and burden including calcified, noncalcified, and low-attenuation components. The present analysis comprised patients assigned to the CCTA arm only (n=4267). Median follow-up time was 26 months (IQR: 18–34).

Outcome

The primary endpoint of the PROMISE trial was adjudicated MACE, defined as a composite outcome of all-cause mortality, nonfatal MI, or hospitalization for unstable angina.

Main results

• At baseline, fewer women had ≥1 plaques than men (1213/2199 (55.2%) vs. 1541/2068 (74.5%); P<0.001).
• Among participants with ≥1 plaques, median total plaque volume was smaller in women than men (77.5 mm³; IQR: 32.8–182 vs. 156 mm³; IQR: 59.3–343; P<0.001), but there was no difference in median total plaque burden (37.8%; IQR: 27.6%–48.8% vs. 38.7%; IQR: 28.9%–47.4%; P=0.791).
• During follow-up, the incidence of MACE was 2.3% in women and 3.4% in men. Sex-stratified Cox proportional hazards analysis adjusted for ASCVD risk score showed progressively greater MACE risk with increasing quartiles of total plaque burden, with an adjusted HR for quartile 4 versus quartile 1 of 6.06 (95%CI: 2.53–14.49; P<0.001) in women and 3.64 (95%CI: 1.56–8.52; P=0.003) in men.
• After additional adjustment for coronary artery calcium score, presence of stenosis ≥50%, and high-risk plaque features, MACE risk was slightly attenuated in women in quartile 4 of total plaque burden versus quartile 1 (adjusted HR: 5.43; 95%CI: 1.94–15.20; P=0.001) but no longer statistically significant in men (adjusted HR: 1.94; 95%CI: 0.59–6.41; P=0.279).
• In sex-stratified Cox-restricted cubic spline regression analysis, both total and noncalcified plaque burden showed nonlinear relationships with incident MACE, and MACE risk rose at lower plaque burden levels in women than men.
• Excess MACE risk (HR>1.0) started at a total plaque burden level of 20% in women compared with 28% in men, whereas HR=1.5 was reached at 32% total plaque burden in women and 42% in men.
• For noncalcified plaque burden, HR=1.0 was crossed at 7% in women compared with 9% in men, whereas HR=1.5 was reached at 13% in women and 20% in men.
• After adjustment for ASCVD risk score, similar results were found for total and noncalcified plaque burden in both sexes.

Conclusion

In this observational analysis of the PROMISE trial among patients with stable chest pain undergoing initial CCTA, women less often presented with ≥1 coronary plaques and had smaller plaque volumes than men. Yet, ~2-year MACE risk appeared to emerge at lower total and noncalcified plaque burden levels in women and rose more steeply. The authors conclude that “modest plaque accumulation seems to carry greater prognostic weight in women.” Furthermore, their “findings support the sex-specific interpretation of CCTA-derived plaque metrics. As [plaque burden] accounts for vessel size, it may better capture sex-specific risk than absolute plaque volume.”

Find this article online at Circ Cardiovasc Imaging.

References

1. Feuchtner GM, Lacaita PG, Bax JJ, Rodriguez F, Nakanishi R, Pontone G, Mushtaq S, Buechel RR, Gräni C, Patel AR, et al. AI-quantitative CT coronary plaque features associate with a higher relative risk in women: CONFIRM2-registry. Circ Cardiovasc Imaging. 2025;18:e018235. doi: 10.1161/CIRCIMAGING.125.018235
2. Brendel JM, Mayrhofer T, Pagidipati N, Karády J, Kolossváry M, Langenbach IL, Langenbach MC, Kerkovits NM, Jung M, Kelsey MD, et al. Sex-specific prognostic value of quantifying coronary plaque in patients with stable chest pain: insights from the PROMISE trial. JACC Cardiovasc Imaging. 2025;18:1279–1281. doi: 10.1016/j.jcmg.2025.06.007
3. Douglas PS, Hoffmann U, Lee KL, Mark DB, Al-Khalidi HR, Anstrom K, Dolor RJ, Kosinski A, Krucoff MW, Mudrick DW, et al; PROMISE investigators. PROspective Multicenter Imaging Study for Evaluation of chest pain: rationale and design of the PROMISE trial. Am Heart J. 2014;167:796–803.e1. doi: 10.1016/j.ahj.2014.03.003
4. Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalidi HR, Cavanaugh B, Cole J, Dolor RJ, Fordyce CB, Huang M, et al; PROMISE Investigators. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med. 2015;372:1291–1300. doi: 10.1056/NEJMoa1415516