Spironolactone for heart failure with preserved ejection fraction

Nearly half of all patients presenting with heart failure have normal or near normal left ventricular systolic function.  Optimal treatment strategies for this large patient group remain unclear.  Small mechanistic studies have suggested diastolic function may be improved by mineralocorticoid-receptor antagonists.  Whether this mechanistic benefit translates into better patient outcomes is not known.  In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, 3445 patients with heart failure and an ejection fraction of 45% or more were randomised in a double-blind fashion to either spironolactone (15 to 45 mg daily) or placebo.  The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure with patients.  Over a mean follow-up period of 3.3 years, the primary outcome occurred in 18.6% of the spironolactone group and 20.4% of the placebo group (HR, 0.89; 95% CI, 0.77 to 1.04; P=0.14).  Compared with placebo, spironolactone resulted in a statistically significant reduction in hospitalizations for heart failure (206 patients vs. 245 patients, HR, 0.83; 95% CI, 0.69 to 0.99, P=0.04).  Use of spironolactone came at a cost of increased rates of hyperkaliemia (18.7%, vs. 9.1%), but no differences in serious adverse events.

Conclusions

In this large randomised controlled trial of patients with heart failure and preserved systolic function, the mineralocorticoid receptor antagonist spironolactone failed to result in patient benefit aside from a reduction in heart failure hospitalizations.  Whether the reduction in hospitalizations with spironolactone represents a mechanistic benefit, or just better volume control achieved through diuresis, is unclear.  Therapies that clearly improve outcomes in patients with heart failure and preserved ejection fraction remain elusive.

  • Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O’Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S and McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92.

Summarized by Steven M. Bradley and Hussain Contractor