Sex differences in stable chest pain with zero coronary artery calcium score in the PROMISE trial

Background Sex differences in coronary artery disease (CAD) are well recognized but remain poorly understood among symptomatic patients with a coronary artery calcium score of zero (CAC=0). Non-calcified coronary plaque (NCP), detectable by coronary computed tomography angiography (CCTA), may be present despite CAC=0. Purpose To evaluate sex differences in coronary plaques and determine sex-specific associations with CCTA-derived CAD findings and outcomes in patients with stable chest pain and CAC=0. Methods PROMISE participants without known CAD who underwent CCTA and had CAC=0 (n=1,476) were evaluated for clinical characteristics, CCTA plaque measures, and outcomes stratified by sex. Multivariable regression models assessed baseline associations with NCP presence and CCTA measures. Cox proportional hazards models evaluated associations with major adverse cardiovascular events (MACE: death, non-fatal MI, unstable angina) over 26 months (IQR 18–34). Results In the overall trial, CAC=0 was more common in women (n=935, 63%) compared with men (n=541, 37%). Women with CAC=0 were older than men (60±7 vs 55±6 years) with CAC=0 and had more frequently hypertension (62% vs 56%), dyslipidaemia (65% vs 57%), family history of premature CAD (32% vs 27%), and sedentary lifestyle (52% vs 44%), while men were more often smokers (51% vs 40%). Symptom profiles and statin use were similar between sexes (Table 1). Despite a lower burden of risk factors, NCP was more prevalent in men than in women (16% vs. 10%), and men had more stenosis ≥50% (1.9% vs. 0.6%) and high-risk plaque features (HRP, 4.6% vs. 1.9%). Among those with NCP (n=177), men had higher total plaque volume (51 vs 40 mm3) and low-attenuation NCP burden ≥4% (LAPB, 3.7% vs 1.9%). Male sex was associated with NCP presence (aOR 2.2, 95%CI 1.5-3.2), adjusted for age, statin use, and risk factors (hypertension, dyslipidaemia, diabetes, family history of premature CAD, smoking, sedentary lifestyle, and obesity). Male sex further increased the odds of stenosis ≥50%, HRP and LAPB ≥4% (Figure 1). The likelihood of NCP increased with age, with 2.2x higher odds in men aged ≥50 years (95% CI 1.2-4.2) and 1.8x higher odds in women aged ≥60 years (95% CI 1.1-2.8), independent of statin use and risk factors. Any NCP was associated with a 6.7-fold MACE risk in men (95%CI 1.8-25.0; MACE rate: 5.8%) and a 4.8-fold MACE risk in women (95%CI 1.2-19.0; MACE rate: 3.3%) over a median follow-up of 26 months. Survival analyses were underpowered to detect sex differences (18 events). Conclusions Among stable chest pain patients with CAC=0, women had a lower prevalence of NCP (10% vs 16% in men), with lower plaque volumes and less frequent obstructive stenosis and HRP than men, despite more traditional risk factors. The odds of having NCP were higher in men ≥50 years and women ≥60 years, independent of risk factors. Any NCP conferred a similarly elevated risk of adverse events in both sexes.Table 1Figure 1