Characteristics of the patients according to sex
The overall cohort (n = 1619) stratified by sex were described in Table 1. Of the 1619 elderly patients, 898(55.5%) were women, and 721(44.5%) were men. Their age ranged from 70 to 94 years, and the mean age was similar between women and men. Women from the Americas (including the United States, Canada, Brazil, Argentina) or Russia/Georgia were 533(59.4%), 365(40.6%), respectively.
The baseline characteristics of each group were listed in Table 1. Women had fewer comorbidities: AF (41.4% vs. 47.4%; p=0.016), MI (18.7% vs. 30.9%; p<0.001), CABG (7.6% vs 22.3%; p<0.001), PCI (12.5% vs 18.9%; p<0.001), dyslipidemia (57.3% vs. 66.2%; p=0.001), COPD (9.24% vs. 47.4%; p=0.001)) .Moreover, women had a higher prevalence of hypertension (93.0% vs. 89.2%; p=0.007) than men. The prevalence of NYHA functional classes III-IV (38.5% vs. 31.5%, p=0.003) and BMI (30.9±6.2 vs. 30.1±5.8, p=0.011) were higher in women than in men, whereas serum potassium (4.2±0.43 vs. 4.3±0.48, p=0.010), blood urea nitrogen(16.2±14.2 vs. 20.1±14.3, p=0.001), hemoglobin (12.6±1.8 vs. 13.3±2.4, p=0.001), and creatinine levels (1.0±0.3 vs. 1.3±0.31, p<0.001) were lower in women than in men. Moreover, we observed the elderly women with HFpEF had higher LVEF, a higher rate of NYHA functional classes III-IV, and lower Kansas City Cardiomyopathy Questionnaire (KCCQ) scores than men in the present study.
Regarding the use of medications, there were no significant differences between men and women in the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta-blockers, calcium channel blockers (CCB), or diuretics. Men were significantly more likely to take statin, warfarin, any hypoglycemic, other anti-hypertensive, and CV medications. Moreover, no matter in the placebo arm or the spironolactone arm, differences between women and men are the same as the whole cohort.
Differences in outcomes between women and men
Rates of primary and secondary outcomes stratified by sex for the placebo arm and spironolactone arm were summarized in Table 2. In all patients, the rates of all outcomes were significantly lower in women than in men. In the placebo arm, women had lower rate of primary outcome (18.9% vs. 28.1%, p = 0.002), CV mortality (10.6% vs. 15.4%, p = 0.039), HF hospitalization (13.5% vs. 19.0%, p = 0.033), and all-cause mortality (31.5% vs. 50.4%, p < 0.001) than men. The rate of all-cause hospitalization was numerically lower in women than in men, but there were no statistically significant differences. In the spironolactone arm, rates of primary outcome (17.9% vs. 26.8%, p = 0.002), CV mortality (7.3% vs. 14.2%, p = 0.001), all-cause mortality (13.0% vs. 25.7%, p < 0.001), all-cause hospitalization (45.5% vs 53.4%, p = 0.026) in women were significantly lower than in men. HF hospitalization rates were numerically lower in women than men, but there was no statistically significant difference. Kaplan-Meier curves for primary and secondary outcomes stratified by sex summarized in Figure 1 and Figure 2. Sex-specific univariate analysis showed that women had lower rates of all outcomes in all patients and the placebo arm. In the spironolactone arm, there were no significant differences in HF hospitalization (hazard ratios [HR] 0.73, 95% CI: 0.51-1.04, p = 0.083) and all-cause hospitalization (HR 0.71, 95% CI: 0.50-1.01, p = 0.058) between women and men. sex-specific multivariate HR in the placebo arm and spironolactone arms for all outcomes adjusted for region, NYHA class, MI, PCI, CABG, AF, hypertension, dyslipidemia, COPD, SBP, DBP, BR, BMI, baseline eGFR, and baseline potassium levels were summarized detailly in Supplemental Table 1 and Figure 3. In the whole cohort, women had a significantly lower risk of the primary outcome, CV mortality, HF hospitalization, and all-cause mortality after adjusting the covariates. Importantly, both in the placebo arm and the spironolactone arm, there was a reduced likelihood of the primary outcome, CV mortality, and all-cause mortality in women but not in men.
Treatment effect between women and men
Univariate HRs for all outcomes were summarized in Table 3. In women patients, the primary outcome occurred in 84 patients (10.4%) taking placebo and 81 patients (10.0 %) taking spironolactone, with a corresponding HR of 0.95 (95% CI: 0.70 to 1.29). Rates of CV mortality, HF hospitalization, all-cause mortality, and all-cause hospitalization were also numerically lower in patients treated with spironolactone but did not reach statistical significance (p＞0.05 for all outcomes). The spironolactone treatment effect was similar in men patients.
Multivariate HRs and interaction terms between sex and treatment response for outcomes were summarized in Supplemental Figure 1 and Table 3. There was no significant reduction in primary outcome associated with spironolactone in women (HR 0.91, 95% CI: 0.67-1.25, p=0.580) and men (HR 0.88, 95% CI: 0.66-1.17, p=0.377). Rates of CV mortality, HF hospitalization, and all-cause hospitalization all had no significant difference between placebo and spironolactone arm both in women and men (p >0.05). Although there was a decreased rate of all-cause mortality r in women treated with spironolactone (10.0% vs. 7.3%, HR 0.68, 95% CI: 0.48-0.96) but not in men, the sex-treatment interaction was not significant (p interaction=0.190).