Women in Heart Failure With Preserved Ejection Fraction Clinical Trials: Bridging the Gap Between Trial Enrollment and Real-World Disease Burden

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and disproportionately affects women, who represent the majority of patients in real-world populations. Despite this, the representation of women in contemporary HFpEF clinical trials remains variable. In this narrative review, we examine sex distribution across major randomized trials, including TOPCAT, PARAGON-HF, EMPEROR-Preserved, and DELIVER, and compare these findings with real-world epidemiology. Women comprised approximately 44–52% of participants across trials, demonstrating modest discordance with real-world cohorts in which women often account for 50–70% of HFpEF patients. Although female enrollment in HFpEF trials has improved substantially compared with historical cardiovascular studies, important questions remain regarding the extent to which enrolled populations adequately reflect female-predominant HFpEF phenotypes, including obesity-associated HFpEF, microvascular dysfunction, and advanced multimorbidity. While some studies, particularly PARAGON-HF, suggested a potential greater treatment benefit among women, sex-specific analyses were frequently underpowered and inconsistently reported. More recent trials of sodium–glucose cotransporter-2 inhibitors demonstrated consistent benefits across sexes without clear evidence of differential effect. Differences in trial eligibility criteria, including natriuretic peptide thresholds, renal function requirements, and left ventricular ejection fraction cutoffs, may further influence the representation of women and the generalizability of trial findings. These findings raise important considerations regarding external validity and generalizability of trial-derived therapies. Greater emphasis on representative enrollment and prospective evaluation of sex-specific outcomes will be essential to advancing equitable and evidence-based care in HFpEF.