Persistent Outpatient Oral Loop Diuretic Use and Clinical Outcomes According to Left Ventricular Volume Phenotype in Heart Failure With Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, and patients with a small left ventricular (LV) volume phenotype exhibit greater preload dependency. Whether the association between persistent outpatient oral loop diuretic use and clinical outcomes differs by LV volume phenotype remains unclear. Methods: We conducted a retrospective single-center cohort study of consecutive patients with heart failure and an LV ejection fraction [≥]50% who underwent transthoracic echocardiography between 2009 and 2024. Patients were stratified by LV volume phenotype using sex-specific LV end-diastolic volume index cutoffs. Associations between outpatient oral loop diuretic use and HF hospitalization, worsening renal function, and all-cause death were evaluated using multivariable time-varying Cox proportional hazards models, including interaction testing by LV phenotype. Results: Among 12,748 eligible patients, 1,437 had a small LV phenotype and 11,311 had a normal LV phenotype. Patients with a small LV phenotype initiated outpatient oral loop diuretics earlier and more frequently than those with a normal LV phenotype, while maintenance doses were comparable between groups. Outpatient oral loop diuretic use was associated with HF hospitalization in both phenotypes, with a significantly stronger association in the small LV group (hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.68-3.78) than in the normal LV group (HR, 2.10; 95% CI, 1.77-2.49; P for interaction = 0.001). No significant interaction by LV phenotype was observed for worsening renal function or all-cause death. Fine-Gray competing-risk analyses showed a consistent interaction pattern. Conclusions: Persistent outpatient oral loop diuretic use was more strongly associated with HF hospitalization in patients with a small LV phenotype than in those with a normal LV phenotype. LV volume phenotype may help identify patients who warrant closer monitoring and more individualized diuretic management.