Outpatient diuretic intensification as endpoint in heart failure with preserved ejection fraction trials: an analysis from TOPCAT

Aims 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 HF and a preserved ejection fraction (HFpEF) may experience frequent episodes of outpatient worsening HF. The aim of this study was to evaluate the frequency, prognostic impact, and the effect of spironolactone on outpatient diuretic intensification (ODI), among 1767 patients enrolled in TOPCAT-Americas. Methods and results 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. 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 hazard ratio (HR) for HF hospitalization or cardiovascular death 1.67, 95% confidence interval (CI) 1.36- 2.04; HR for cardiovascular death 2.17, 95% CI 1.64- 2.87); and HR for all-cause mortality 1.75, 95% CI 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 three-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 0.74, 95% CI 0.65- 0.85; p < 0.001) compared with a 16% relative reduction of HF hospitalization or cardiovascular death (HR 0.84, 95% CI 0.70- 0.99; p = 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.