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

Dewan, Pooja; Jackson, Alice; Lam, Carolyn S.P.; Pfeffer, Marc A.; Zannad, Faı̈ez; Pitt, Bertram; Solomon, Scott D.; McMurray, John J.V.

doi:10.1002/ejhf.1776

Cited by 72 publications

(91 citation statements)

References 16 publications

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“…In PARAGON-HF, the benefits of sacubitril/valsartan appeared to be more apparent among patients at the lower range of ejection fraction-based eligibility, 26 one of 12 pre-specified subgroups in the trial, that held up to multivariable adjustment. This finding based on the pre-specified subgroup of LVEF at or below the median (≤57%) was consistent with similar findings in the CHARM-Preserved and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trials [27][28][29] in which renin-angiotensin-aldosterone system inhibitors had shown directionally favourable benefits in reducing HF hospitalization among patients at the lower end of the ejection fraction spectrum in HFpEF trials. 27 In a pre-specified pooled patient-level analysis of data from both PARADIGM-HF and PARAGON-HF encompassing over 13 000 patients with HF, sacubitril/valsartan was superior overall to renin-angiotensin system inhibitors across a broad range of endpoints, including all-cause mortality.…”

Section: Therapeutic Heterogeneity To Angiotensin Receptor-neprilysinsupporting

confidence: 86%

“…This finding based on the pre-specified subgroup of LVEF at or below the median (≤57%) was consistent with similar findings in the CHARM-Preserved and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trials [27][28][29] in which renin-angiotensin-aldosterone system inhibitors had shown directionally favourable benefits in reducing HF hospitalization among patients at the lower end of the ejection fraction spectrum in HFpEF trials. 27 In a pre-specified pooled patient-level analysis of data from both PARADIGM-HF and PARAGON-HF encompassing over 13 000 patients with HF, sacubitril/valsartan was superior overall to renin-angiotensin system inhibitors across a broad range of endpoints, including all-cause mortality. Nevertheless, treatment effects were modified by LVEF such that more prominent effects were observed among participants with ejection fraction below the normal range.…”

Section: Therapeutic Heterogeneity To Angiotensin Receptor-neprilysinsupporting

confidence: 86%

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Angiotensin receptor–neprilysin inhibition in heart failure with preserved ejection fraction: lessons from PARAGON‐HF

Vaduganathan

McMurray

Solomon

2020

European J of Heart Fail

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Identifying effective therapies for patients living with heart failure (HF) with preserved ejection fraction (HFpEF) has remained challenging. The recently completed PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction), 1 the largest HFpEF trial conducted to date, examined a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, compared with valsartan among 4822 patients with signs and symptoms of HF, left ventricular ejection fraction (LVEF) ≥45%, elevated natriuretic peptides, and evidence of structural heart disease. Patients allocated to sacubitril/valsartan experienced modestly lower rates of composite cardiovascular death and total HF hospitalizations compared with patients randomized to valsartan after a median follow-up of 35 months, but this treatment effect did not meet pre-specified statistical significance thresholds (Figure 1). We contextualize these trial findings, including learnings from subsequent secondary analyses, and reflect on key trial elements that may inform the next phase of therapeutic development in HFpEF. Were the intended biological pathways affected and anticipated haemodynamic responses achieved in PARAGON-HF? Irrespective

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Section: Therapeutic Heterogeneity To Angiotensin Receptor-neprilysinsupporting

confidence: 86%

Section: Therapeutic Heterogeneity To Angiotensin Receptor-neprilysinsupporting

confidence: 86%

Angiotensin receptor–neprilysin inhibition in heart failure with preserved ejection fraction: lessons from PARAGON‐HF

Vaduganathan

McMurray

Solomon

2020

European J of Heart Fail

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“…The results presented in the paper by Dewan et al . in this issue of the Journal suggest that the beneficial effect of important neurohumoral modulators is continuous over a wide range of LVEFs.…”

Section: Therapeutic Decisions According To Left Ventricular Ejectionmentioning

confidence: 99%

“…Other important differences according to sex are also generally underappreciated, differences that could in some cases influence the choice of therapeutic interventions. Some of these differences have been outlined in the paper by Dewan et al ., but others exist as well, and could help explain why there is an apparent greater benefit of neurohumoral modulators in women with higher LVEFs as compared with men. They may also help explain why women have more signs and symptoms of HF and a poorer quality of life than men despite higher LVEFs and similar or lower N‐terminal pro‐B‐type natriuretic peptide levels.…”

Section: Considering Sex In Making Therapeutic Decisionsmentioning

confidence: 99%

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Evolving towards a more realistic approach to the importance of left ventricular ejection fraction and sex in heart failure and its therapy

Bouabdallaoui

Rouleau

2020

European J of Heart Fail

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Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction

et al. 2021

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IMPORTANCEWomen may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men.OBJECTIVE To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).DESIGN, SETTING, AND PARTICIPANTS Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021.INTERVENTIONS Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MAIN OUTCOMES AND MEASURESThe primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.RESULTS A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of Ն5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of Ն5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women.CONCLUSIONS AND RELEVANCE Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex.

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

Cited by 72 publications

References 16 publications

Angiotensin receptor–neprilysin inhibition in heart failure with preserved ejection fraction: lessons from PARAGON‐HF

Angiotensin receptor–neprilysin inhibition in heart failure with preserved ejection fraction: lessons from PARAGON‐HF

Evolving towards a more realistic approach to the importance of left ventricular ejection fraction and sex in heart failure and its therapy

Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction

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