Lower serum chloride was independently associated with increased risk of cardiovascular and all-cause death in HFpEF. Spironolactone was not ( P = 0.33) but loop diuretic use was associated with lower serial serum chloride levels ( P < 0.001). There were no significant interactions between spironolactone use and the serum chloride–risk relationship ( P > 0.1) for each endpoint. After multivariable adjustment, every standard deviation decrease in serum chloride (4.05 mmol/L) was associated with ∼50% increased risk for cardiovascular death and ∼30% increased risk for all-cause death (HR 1.29, 95% CI 1.02-1.62, P = 0.04), but not with the primary composite endpoint or heart failure hospitalization ( P > 0.3 for both). Multivariable Cox proportional hazards models tested the association of serum chloride with clinical outcomes, and mixed effects modelling tested the association of spironolactone or loop diuretic on serial serum chloride levels.
We included participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) who met the following criteria: met inclusion by the natriuretic peptide stratum, had recorded serum chloride levels, and were from the Americas ( n = 942). We aimed to examine the relationship between serum chloride concentration and outcomes in HFpEF. Prior cohorts demonstrating the importance of serum chloride levels in heart failure either excluded or had partial representation of patients with heart failure with preserved ejection fraction (HFpEF).