Outpatient diuretic intensification as endpoint in HFpEF trials: an analysis from TOPCAT.

BACKGROUND Outpatient treatment for the worsening of signs and symptoms of heart failure (HF) is usually not incorporated in the main outcomes of HF trials. Patients with heart failure with a preserved ejection fraction (HFpEF) may experience frequent episodes of outpatient worsening. OBJECTIVES To study the frequency, prognostic impact, and the effect of spironolactone on outpatient diuretic intensification (ODI), among 1767 patients enrolled in TOPCAT-Americas. METHODS Time-updated Cox models and win ratio analysis. ODI was defined by a post-randomization loop diuretic dose increase or new initiation. The median follow-up was 2.9 years. RESULTS At baseline, 1362 (77%) patients were taking loop diuretics. During the follow-up, 685 (38.8%) patients experienced ODI, which was associated with a higher risk of subsequent cardiovascular events and death: adjusted HR (95%CI) for HF hospitalization or cardiovascular death=1.67 (1.36-2.04), HR (95%CI) for cardiovascular death=2.17 (1.64-2.87), and HR (95%CI) for all-cause mortality=1.75 (1.41-2.16) (p<0.001 for all outcomes). Adding ODI to the composite of HF hospitalization or cardiovascular death increased the event-rate by 3-fold in the placebo group (from 10.4 to 29.9 events per 100 person-years). Spironolactone treatment led to a 26% relative reduction of the extended composite of ODI or HF hospitalization or cardiovascular death: HR (95%CI) 0.74 (0.65-0.85), p-value<0.001 compared with a 16% relative reduction of HF hospitalization or cardiovascular death: HR (95%CI) 0.84 (0.70-0.99), p-value=0.044. Using win ratio provided similar estimates. CONCLUSION In HFpEF, ODI was frequent and independently associated with subsequent cardiovascular events. Spironolactone significantly reduced an extended composite outcome incorporating ODI. This article is protected by copyright. All rights reserved.