Sex based differences in association with plaque burden and ischemia -- a CREDENCE trial substudy

Background Prior studies have identified sex-based differences in coronary computed tomography angiography (CCTA)-derived plaque characteristics and their association with clinical outcomes. Women typically exhibit less severe stenosis and a lower overall plaque burden; however, this does not correspond to a proportionally lower rate of adverse clinical events. The relationship between coronary plaque burden and ischemia, as defined by invasive fractional flow reserve (FFR), across sexes remains unclear. Purpose This study aimed to investigate sex-based differences in quantitative plaque burden assessed by CCTA and their relationship to ischemia, as determined by invasive FFR. Methods A post hoc analysis of the CREDENCE (Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia) trial was conducted, involving 612 symptomatic patients (184 women and 428 men) with suspected stable coronary artery disease. All participants underwent CCTA and invasive coronary angiography with FFR measurements. Quantitative plaque analysis assessed plaque volume and burden of total, calcified, and non-calcified plaque (TP, CP and NCP). Ischemia was defined as invasive FFR ≤ 0.8. Results Women were generally older (66.5±9.1 years vs. 63.5±10.3 years, p=0.001) and had lower prevalence of smoking. Other clinical risk factors, including angina and medication use, were comparable between men and women. CCTA findings revealed that women had a lower prevalence of high-risk plaques, shorter lesion length, and a less severe stenosis. Quantitative plaque analysis showed that women had significantly lower plaque volume and burden across all components (all p<0.05), except for calcified plaque burden, which was similar between sexes (2.60% vs. 3.00%, p=0.166). In the multivariable analysis, a per 5% increase in plaque burden was significantly associated with ischemia in women for TP (OR=1.28, 95% CI [1.12–1.46], p<0.001), CP (OR=1.31, 95% CI [1.10–1.57], p=0.003), and NCP (OR=13, 95% CI [1.05–1.67], p=0.017). In men, only the plaque burden of TP and NCP, but not CP showed significant associations. A significant interaction between sex and plaque burden was observed for TP (p=0.015) and CP (p=0.046). After adjusting for variables shown in the Figure, a significant interaction between sex and plaque volume was noted in the PV of TP, CP, and NCP (all p<0.05), indicating a stronger association between plaque and ischemia in women versus men. Of note, interactions between sex and diameter stenosis were not significant (p=0.928). Conclusion Women exhibit a lower overall plaque burden compared to men, yet the association between plaque burden and ischemia is more pronounced in women. These findings suggest that even modest increase in plaque burden may have greater ischemic implications for women, underscoring the importance of sex-specific diagnostic and therapeutic strategies in managing coronary artery disease.Figure 1