Spironolactone: diuretic or disease‐modifying drug in heart failure with preserved ejection fraction?

Abstract

This article refers to 'Diuretic and renal effects of spirono-lactone and heart failure hospitalizations: a TOPCAT Americas analysis' by A.P. Kalogeropoulos et al., published in this issue on pages 1600-1610. With monthly costs of approximately US$12 in the USA and €5 in Europe, spironolactone is by a landslide the most cost-effective drug in the management of heart failure (HF) with reduced ejection fraction (HFrEF). In the Randomized Aldactone Evaluation Study (RALES), the treatment of 10 patients with HFrEF in New York Heart Association functional class III or IV saved one life after 2 years, 1 a number that still looks favourable in comparison with any other HF drug. The story is more nuanced in HF with preserved ejection fraction (HFpEF), but given the high number of treatment strategies that have failed over the past 15 years, the results of spironolactone in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial remain among the best we have to offer our patients. In the TOPCAT trial, spironolactone use was associated with a non-significant 10% lower relative risk for all-cause mortality after 3.3 years, and a borderline significant 17% relative risk reduction for HF readmission was observed. 2 However, the primary endpoint of the trial, which combined both individual endpoints together with aborted cardiac arrest, was not statistically significant. Post hoc analyses of the TOPCAT trial identified significant regional differences in patient profiles, event rates and compliance with the study medication, demonstrating that the trial would have been positive if it had been limited to the subpopulation recruited in America or with objective evidence for HFpEF under the form of elevated natriuretic peptide levels. These somewhat ambiguous results make it even more important to understand how spironolactone exerts its beneficial effects in HF. Spironolactone is a prodrug that is rapidly metabolized in its major active metabolites with a long half-life (t 1/2): 7α-thiomethylspironolactone (t 1/2 = 13.8 h) and canrenone The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology.