Sex Based Differences in Association Between Plaque Burden and Ischemia -- a CREDENCE Trial Substudy

Aims: Women with coronary artery disease (CAD) typically have less severe stenosis and lower plaque burden than men but have disproportionately high adverse cardiovascular event rate. This study evaluated sex-based differences in quantitative plaque burden and its association with ischemia. Methods and results: A post-hoc exploratory analysis of the CREDENCE trial included 612 symptomatic patients (184 women, 428 men) with suspected stable CAD who underwent CCTA and invasive coronary angiography with fractional flow reserve (FFR) measurements. Total, calcified, and total non-calcified plaque burden and volume were quantified. Ischemia was defined as FFR ≤0.8. Women were older (66.5 ± 9.1 vs. 63.5 ± 10.3 years, p = 0.001) with lower prevalence of smoking. They exhibited less high-risk plaque, shorter lesion length, and lower stenosis severity. Plaque burden and volume were significantly lower in women across all components (all p < 0.05), except for calcified plaque burden. A 5% increase in plaque burden was significantly associated with ischemia in women for total plaque (OR = 1.28, 95% CI [1.12-1.46], p < 0.001), calcified plaque (OR = 1.31, 95% CI [1.10-1.57], p = 0.003), and total non-calcified plaque (OR = 1.33, 95% CI [1.05-1.67], p = 0.017). In men, only total and total non-calcified plaque burden were significant predictors of ischemia. Significant sex interactions were observed for total (p = 0.015) and calcified plaque burden (p = 0.046), indicating differential effects in women and men, but not for diameter stenosis (p = 0.928). Conclusion: Despite having a lower overall plaque burden, women exhibit a stronger association between plaque burden and ischemia than men. Further investigation in prospective studies is warranted to better understand potential sex-related differences in CAD.