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

Abstract

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.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Figures

Figure 1

Distribution of ejection fractions.

Figure 2

Multivariable adjusted incidence rate (per 100 patient-years) by left ventricular ejection fraction for primary endpoint (upper left, P = 0.02), heart failure hospitalization (upper right, P = 0.79), cardiovascular death (lower left, P = 0.002), and all-cause death (lower right, P = 0.004).

Figure 3

Treatment effect as a function of ejection fraction for primary outcome (upper left panel), heart failure hospitalization (upper right panel), and cardiovascular death (lower panel). Dashed lines represent 95% confidence intervals.

Figure 4

Treatment effect for the primary outcome in men (blue) and women (red). Pinteraction = 0.077.