Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction

Eur Heart J. 2016 Feb 1;37(5):455-62. doi: 10.1093/eurheartj/ehv464. Epub 2015 Sep 15.


Aims: While mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with reduced left ventricular ejection fraction (LVEF), spironolactone did not reduce the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT trial, which enrolled patients with LVEF of 45% or greater. We utilized data from TOPCAT to assess the relationship between LVEF as well as outcomes and efficacy of spironolactone.

Methods and results: We assessed differences in baseline characteristics and outcomes across LVEF categories in 3444 patients with HFpEF, and determined whether LVEF modified the treatment effect of spironolactone. Ejection fraction ranged from 44 to 85%. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction spectrum. Ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome (P = 0.046) and for heart failure hospitalization (P = 0.039), with stronger estimated benefits of spironolactone at the lower end of the ejection fraction spectrum with respect to the primary endpoint (LVEF <50%: HR 0.72, 95% CI 0.50, 1.05; LVEF ≥60%: HR 0.97, 95% CI 0.76, 1.23) and heart failure hospitalization (LVEF <50%: HR 0.76, 95% CI 0.46, 1.27; LVEF ≥60%: HR 0.98, 95% CI 0.74, 1.30).

Conclusion: In patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by LVEF. The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum.

Clinicaltrialsgov number: NCT00094302.

Keywords: Heart failure with preserved ejection fraction; Spironolactone.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Heart Rate / physiology
  • Hospitalization
  • Humans
  • Male
  • Middle Aged
  • Mineralocorticoid Receptor Antagonists / administration & dosage*
  • Spironolactone / administration & dosage*
  • Stroke Volume / physiology
  • Treatment Outcome


  • Mineralocorticoid Receptor Antagonists
  • Spironolactone

Associated data