Higher doses of loop diuretics limit uptitration of angiotensin-converting enzyme inhibitors in patients with heart failure and reduced ejection fraction

BACKGROUND: Loop diuretics are frequently prescribed to patients with heart failure and reduced ejection fraction (HFrEF) for the treatment of congestion; however, they might hamper uptitration of inhibitors of the renin–angiotensin system. METHODS: Loop diuretic dose at baseline was recorded in 2338 patients with HFrEF enrolled in BIOSTAT-CHF, an international study of HF patients on loop diuretic therapy who were eligible for uptitration of angiotensin-converting enzyme inhibitors (ACEi)/mineralocorticoid receptor antagonists (MRA). The association between loop diuretic dose and uptitration of ACEi/MRA to percentage of target dose was adjusted for a previously published model for likelihood of uptitration and a propensity score. RESULTS: Baseline median loop diuretic dose was 40 [40–100] mg of furosemide or equivalent. Higher doses of loop diuretics were associated with higher NYHA class and higher levels of NT-proBNP, more severe signs and symptoms of congestion, more frequent MRA use, and lower doses of ACEi reached at 3 and 9 months (all P < 0.01). After propensity adjustment, higher doses of loop diuretics remained significantly associated with poorer uptitration of ACEi (Beta per log doubling of loop diuretic dose: − 1.66, P = 0.021), but not with uptitration of MRAs (P = 0.758). Higher doses of loop diuretics were independently associated with an increased risk of all-cause mortality or HF hospitalization [HR per doubling of loop diuretic dose: 1.06 (1.01–1.12), P = 0.021]. CONCLUSIONS: Higher doses of loop diuretics limited uptitration of ACEi in patients with HFrEF and were associated with a higher risk of death and/or HF hospitalization, independent of their lower likelihood of uptitration and higher baseline risk. GRAPHIC ABSTRACT: This figure was created with images adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0 [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00392-020-01598-w) contains supplementary material, which is available to authorized users.