Among 12,748 HFpEF patients followed over 15 years at a single center, persistent outpatient oral loop diuretic use was associated with heart failure hospitalization across all patients — but the association was meaningfully stronger in those with a small left ventricular (LV) volume phenotype (HR 2.52, 95% CI 1.68–3.78) versus normal LV volume (HR 2.10, 95% CI 1.77–2.49), with a statistically significant interaction (P=0.001). Patients with small LV phenotype also initiated diuretics earlier and more frequently, despite comparable maintenance doses.
This finding matters because HFpEF has long resisted a one-size-fits-all treatment model. Loop diuretics remain a cornerstone of congestion management, yet their net benefit in HFpEF — where preload sensitivity varies substantially — has been debated. The small LV phenotype represents a subgroup with heightened preload dependency, where aggressive diuresis could compromise cardiac output more acutely, potentially explaining the stronger hospitalization signal. This aligns with growing literature on phenotype-driven HFpEF management, including work distinguishing obese, hypertensive, and low-flow subtypes.
Critical caveats apply: this is a retrospective, single-center observational study and cannot establish causality — sicker patients may have received more diuretics, inflating risk estimates despite multivariable adjustment. As a preprint posted on medRxiv and not yet peer-reviewed, these results remain preliminary. Prospective phenotype-stratified trials are needed before clinical protocols change. Editorially, this is a confirmatory-but-clinically-useful finding that reinforces the case for echocardiographic phenotyping in HFpEF diuretic decisions.
