Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction

Abstract

Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction (HFpEF), the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women, compared with men. Methods: In a pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial which compared sacubitril-valsartan and valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older, had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP levels than men. For the primary outcome, the rate ratio for sacubitrilvalsartan versus valsartan was 0.73 (95% CI 0.59-0.90) in women and 1.03 (0.84-1.25) in men; P interaction=0.017. The benefit from sacubitril-valsartan was due to reduction in heart failure hospitalization. The improvement in NYHA class and renal function with sacubitrilvalsartan was similar in women and men, whereas the improvement in KCCQ-CSS was less in women than in men. The difference in adverse events, between sacubitril-valsartan and valsartan, was similar in women and men. Conclusion: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. While the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.

A Putative Placebo Analysis of the Effects of Sacubitril/Valsartan in Heart Failure Across the Full Range of Ejection Fraction

“…Defining single LVEF thresholds for use is challenging given the inherent imprecision and variability in LVEF assessment and since certain subgroups (such as women) may derive benefits to a higher LVEF. 16 Costs, access, and ease of implementation will further modify the ultimate application of this therapy in HF at higher ranges of LVEF.…”

Interactions between left ventricular ejection fraction, sex and effect of neurohumoral modulators in heart failure

“…Recently, the Prospective Comparison of ARNI (angiotensin receptor-neprilysin inhibitor) with ARB (angiotensin receptor blocker) Global Outcomes in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) trial suggested that women might obtain more benefit than men from sacubitril/valsartan, compared with valsartan, in heart failure with preserved ejection fraction (HFpEF). [1][2][3] However, the picture is more complicated as there was also an interaction between left ventricular ejection fraction (LVEF) and the effect of sacubitril/valsartan. 2 Patients with a LVEF at or below the median (57%) seemed to gain more benefit from sacubitril/valsartan than those with a LVEF above the median.…”

“…As detailed elsewhere, the possibilities include sex-related differences in cardiac remodelling in response to blood pressure, age and other stimuli, and differences in age-related arterial stiffening, which is more pronounced in women than men. 3 Women may also have other evidence of contractile dysfunction, compared with men, for a given ejection fraction. 3 Natriuretic peptide levels are lower in women with HFpEF than in men, and women may have reduced cyclic guanosine monophosphateprotein kinase G signalling compared with men, especially after the menopause.…”

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

“…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 cardiovascular mortality/total HF hospitalizations in women but not men. 9,10 Mineralocorticoid receptor antagonists (MRAs) have IA recommendation for the treatment of HFrEF patients remaining symptomatic despite treatment with an ACEi and a beta-blocker and, among the currently used HF medications, are those which have also shown potential efficacy in HFpEF. 11 Although with the several limitations linked with the use of subgroup analyses (e.g.…”

“…In the PARAGON-HF trial, for instance, a significant reduction in the occurrence of the primary outcome was observed in women but not in men, whereas no significant interaction between sacubitril/valsartan and sex in terms of outcomes emerged in the PARADIGM-HF trial. 9,10 Notably, the meta-analysis by Rossello et al reassures on the lack of sex-related differences in the occurrence of spironolactone-associated side effects. Perceived/actual risk of hyperkalaemia is one of the major explanations for MRA underuse in clinical practice, especially in women who are more likely to suffer from chronic kidney disease.…”