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).1-3 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.2 To make matters more complex still, it is well known that the distribution of LVEF is different in women and men, with women, on average, having a higher LVEF than men, be it in the general population or in individuals with heart failure (HF).4-6 Despite a higher LVEF, women with HFpEF had worse systolic function, as assessed by tissue Doppler echocardiography, compared to men with HFpEF.7 To further investigate the relationship between sex, LVEF and treatment in HF, we explored the effect of three different neurohumoral modulators in large trials which provide data on clinical outcomes in patients with HF, across the full range of LVEF, incorporating the three commonly described HF phenotypes – HF with reduced ejection fraction (HFrEF, LVEF 50%) and HF with mid-range ejection fraction (HFmrEF, LVEF 40–50%).8 We pooled individual patient-level data from: (i) three trials using an angiotensin receptor blocker – the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) – the CHARM-Alternative and CHARM-Added trials in HFrEF and the CHARM-Preserved trial in HFmrEF/HFpEF;9 (ii) three trials using a mineralocorticoid receptor antagonist (MRA) – two HFrEF trials, the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), and one HFmrEF/HFpEF trial – the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT).10-12 Only TOPCAT patients from the Americas were included; (iii) two trials using sacubitril/valsartan – the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF trial (PARADIGM-HF) in HFrEF and PARAGON-HF in HFmrEF/HFpEF.1, 13 Cox proportional hazards modelling was used to analyse (i) the primary composite outcome (first occurrence of HF hospitalization or cardiovascular death); (ii) first HF hospitalization; and (iii) cardiovascular death. Likelihood ratio tests were used to report (i) two-way interaction between treatment and sex; and (ii) three-way interaction between treatment, sex and LVEF. LVEF, modelled as a fractional polynomial, and its interaction with treatment using the best fit model for each drug category (based on the primary composite outcome) was examined with the mfpi command in Stata. Models were stratified by trial for MRAs and sacubitril/valsartan. All analyses were conducted using Stata version 16 (Stata Corp., College Station, TX, USA). This present analysis included 2400, 1938 and 4311 women and 5199, 4229 and 8884 men in the candesartan, MRA and sacubitril/valsartan trials, respectively (Table 1). Overall mean LVEF (%) was 38.9 ± 14.9%, 35.3 ± 16.0% and 39.7 ± 15.1%, respectively. Women had a higher mean LVEF, with the difference compared to men 6.3%, 9.4% and 10.3%, respectively. Women had a lower incidence of the primary composite outcome (and its components) in each of the treatment and control groups. In keeping with prior reports from the CHARM Programme and TOPCAT, as well as a recent analysis of PARADIGM-HF and PARAGON-HF, we found that treatment with an ARB, MRA or ARNI may be of benefit beyond the upper limit of LVEF eligibility used in contemporary HFrEF clinical trials (40%) and may extend to what has been termed HFmrEF (LVEF 40–49%) and even to the lower part of the LVEF range currently categorized as HFpEF.2, 6, 14, 15 Importantly, the benefit of each treatment seemed to extend to a higher LVEF in women, compared to men (Figure 1). There was no difference in efficacy of therapy between men and women with HFrEF. Because these are post hoc analyses, they are only hypothesis generating. However, the fact that all three neurohumoral modulating therapies demonstrated the same sex-related pattern of response raises the possibility that the differential response between women and men identified in PARAGON-HF may be real rather than due to the play of chance, although interpretation of PARAGON-HF is more complex as it had an active comparator compared with a placebo control in the other trials. Despite this consistent observation in the trials examined, the biological basis for such a finding is uncertain. 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 monophosphate-protein kinase G signalling compared with men, especially after the menopause.3 The possibility that women with HF might benefit from treatment to a higher level of LVEF than previously considered could be of great clinical importance. Women with HF have fewer treatment options than men with HF because HFmrEF and HFpEF are the predominant HF phenotypes in women and no therapy has been approved by regulatory authorities for either of these phenotypes.6 More research on this matter is clearly required. Conflict of interest: P.D. and A.J. report no conflicts. C.S.P.L., M.A.P., F.Z., B.P., S.D.S. and J.J.V.McM. or their institutions were paid for their participation in one or more of these trials. J.J.V.McM reports receiving fees (all fees listed paid to Glasgow University) for serving on a steering committee from AbbVie, Amgen, Bayer, Bristol-Myers Squibb, Cardiorentis, DalCor Pharmaceuticals, GlaxoSmithKline, Novartis, Oxford University–Bayer; Vifor Pharma–Fresenius; fees for serving on an end-point committee from Cardiorentis; fees for serving on an end-point adjudication committee from Vifor Pharma–Fresenius; fees for serving as principal investigator of a trial from Theracos; fees for serving as co-principal investigator of a trial from GlaxoSmithKline, Novartis; fees for serving on a data and safety monitoring committee from Merck, Pfizer; fees for serving on an executive committee from Novartis; advisory board fees from Novartis; and fees for travel support from AbbVie, Amgen, Cardiorentis, GlaxoSmithKline, Novartis, Oxford University–Bayer, Theracos, from Vifor Pharma–Fresenius. C.S.P.L. reports receiving grant support and fees for serving on an advisory board from Abbott Diagnostics, Amgen, Boehringer Ingelheim, Boston Scientific, Roche Diagnostics; grant support, fees for serving on an advisory board, and fees for serving on steering committees from Bayer; grant support from Medtronics; grant support and fees for serving on a steering committee from Vifor Pharma; fees for serving on an advisory board and fees for serving on steering committees from AstraZeneca and Novartis; consulting fees from Merck and Stealth BioTherapeutics, fees for serving on a steering committee from Janssen Research and Development; lecture fees and consulting fees from Menarini, and fees for serving on a scientific committee from Corvia Medical and holding a pending patent (PCT/SG2016/050217) on a method regarding diagnosis and prognosis of chronic heart failure M.A.P. reports receiving consulting fees from AstraZeneca, GlaxoSmithKline, Novo Nordisk, Sanofi, Jazz Pharmaceuticals, MyoKardia, Servier, Takeda Pharmaceutical, and Corvidia and consulting fees and stock options from DalCor Pharmaceuticals. F.Z. recieved personal fees for steering committee membership from Janssen, Bayer, Pfizer, Novartis, Boston Scientific, Resmed, Takeda, General Electric and Boehringer Ingelheim; consultancy fees from Amgen, CVRx, Quantum Genomics, Relypsa, ZS Pharma, AstraZeneca and GSK; he is the founder of Cardiovascular Clinical Trialists and CardioRenal. B.P. is a consultant for Bayer, AstraZeneca, Sanofi, Sarfez, scPharmaceuticals, Relypsa/Vifor, Stealth Peptides, Cytopherx (stock options). S.D.S. reports grant support and consulting fees (all fees listed paid to Brigham and Women's Hospital) from Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, MyoKardia, Novartis, Theracos, Bayer, and Cytokinetics, grant support from Bellerophon Therapeutics, Celladon, Ionis Pharmaceuticals, Lonestar Heart, Mesoblast, Sanofi Pasteur, and Eidos Therapeutics; consulting fees from Akros Pharma, Corvia Medical, Ironwood Pharma, Merck, Roche, Takeda Pharmaceutical, Quantum Genomics, AOBiome, Cardiac Dimensions, Tenaya Therapeutics, and Daiichi Sankyo; fees for serving on a data and safety monitoring board from Janssen.