Sex‐related differences in therapeutic response to mineralocorticoid receptor antagonists in heart failure: summarizing trial evidence

Abstract

This article refers to 'Sex differences in mineralocorticoid receptor antagonist trials: a pooled analysis of three large clinical trials' by X. Rossello et al., published in this issue on pages 834-844.Sex-related differences in cardiovascular diseases have been overlooked for long time, but it is now becoming more and more evident that improving their understanding is key to precision medicine's success. Heart failure (HF) represents the paradigm of a medical condition with profound differences between sexes covering the whole syndrome, from aetiology to treatment. The overall lifetime risk of HF appears comparable in men vs. women but HF prevalence seems to be higher in women. 1 Phenotypic presentation typically differs between the two sexes, with higher prevalence of HF with preserved ejection fraction (HFpEF) in women and of HF with reduced ejection fraction (HFrEF) in men. Also, the comorbidity burden shows sex-related disparities, with women more likely to be older, with higher New York Heart Association (NYHA) class and natriuretic peptide levels, affected by hypertension and chronic kidney disease, whereas males more likely to suffer from diabetes and ischaemic heart disease. 2,3 Despite the lower quality of life and the more severe symptoms, which have been repeatedly reported in women vs. men with HF, women appear to 'benefit' from a prognostic advantage which is consistent across the ejection fraction spectrum. 3 Sex-related disparities in HF treatment need also to be acknowledged. With few exceptions, the recruitment of females in the largest HF randomized controlled trials (RCT) has been limited, raising concerns about generalizability of RCT evidence to the overall HF population. Several real-world data analyses have shown lower use of HF guideline-recommended therapies in women vs. men, with women more likely to receive diuretics. 3-6 Sex-related differences in pharmacokinetics and pharmacodynamics mightThe 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.influence the net benefit of HF medications and the occurrence of side effects in women vs. men, explaining, at least partially, the under-treatment often observed in women. 2 Based on these considerations, the need for solid data supporting an appropriate use of HF evidence-based therapies in women has become a burning issue. A previous meta-analysis of RCTs showed angiotensin-converting enzyme inhibitors (ACEi) and beta-blockers being effective regardless of sex. 7 Sex-related differences in therapeutic response have been reported in a post-hoc analyses of the DIG trial, with digoxin being associated with higher risk of any death in women. 8 In the HFrEF trial PARADIGM-HF the benefit of sacubitril/valsartan in terms of mortality/morbidity improvement was consistent regardless of sex, whereas in the more 'nebulous' world of HFpEF, a pre-specified subgroup analysis of the PARAGON-HF trial suggested sacubitril/valsartan to reduce cardiovasc...