Spironolactone for Management of Heart Failure with Preserved Ejection Fraction: Whither to After TOPCAT?

Mineralocorticoid receptor antagonists (MRAs) represent an attractive class of drugs for the treatment of heart failure with preserved ejection fraction (HFpEF) because of the deleterious cardiovascular effects of aldosterone and because MRAs combat myocardial fibrosis and improve cardiac structure/function and vascular health. Recently, the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study, a randomized, double-blind clinical trial of spironolactone versus placebo, was conducted in 3445 patients with symptomatic HFpEF. Although considered by some to be a negative trial, TOPCAT demonstrated that spironolactone decreases heart failure hospitalizations in patients with HFpEF. Furthermore, a pre-specified subgroup analysis of TOPCAT by geographic region uncovered concerning findings from Russia/Georgia, questioning (1) whether the correct patients were enrolled in this region and (2) whether enrolled patients actually received the study drug. In the Americas, spironolactone was clearly superior to placebo in reducing cardiovascular events. Given these data from TOPCAT, basic science evidence for the role of aldosterone in HFpEF, and results from other MRA clinical trials in HFpEF, we advocate using spironolactone in HFpEF with close monitoring of potassium and renal function.