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PARAGON-HF: Benefits for women and lower ejection fraction

Prof. Scott D. Solomon & Prof. Lynne W. Stevenson
AHA 2019
Two new analyses of the PARAGON-HF trial show that, in patients with heart failure with preserved ejection fraction (HFpEF) receiving sacubitril/valsartan compared with valsartan alone, women in particular had fewer hospitalisations due to HF [1]. In addition, patients with chronic HF and a left ventricular ejection fraction (LVEF) below the normal range also benefited [2].

The main results of PARAGON-HF were reported late last year; sacubitril/valsartan did not reduce the primary outcome of hospitalisation for cardiovascular (CV)-related death and HF in patients with HFpEF (EF >45%). The recent subgroup analyses of the trial examined the same primary outcome by gender and LVEF to detect any benefit for sacubitril/valsartan.

In the analysis based on gender, 2,479 women (mean age 74 years; mean LVEF 59%) and 2,317 men (mean age 72 years; mean LVEF 56%) from the PARAGON-HF cohort were analysed separately. The results indicated that sacubitril/valsartan was associated with a reduction in the primary outcome in women (relative risk [RR] 0.73; 95% CI 0.59-0.90) but not men (RR 1.03; 95% CI 0.84-1.25; Pinteraction=0.017); this was mainly driven by reductions in total HF hospitalisations (RR in women 0.67; 95% CI 0.53-0.85; RR in men 1.07; 95% CI 0.85-1.34; Pinteraction=0.0046). There was no difference in CV mortality in women (HR 1.02; 95% CI 0.76-1.36) or men (HR 0.90; 95% CI 0.7-1.17; Pinteraction=0.5763). No gender-based differences in quality of life, NYHA class, or renal function were observed.

In the second analysis, researchers assessed data in which patients from both the PARAGON-HF and PARADIGM-HF trials were stratified by EF. “We have recently completed the PARAGON-HF trial, and that allows us to take the data from both the PARAGON and the PARADIGM trials, which are the 2 large outcomes trials with sacubitril/valsartan and pool them in a prespecified pooled analysis,” Prof. Scott D. Solomon (Harvard Medical School, USA) explained. “This allows for examination of the effect of sacubitril/valsartan across the full spectrum of ejection fraction.”

PARADIGM-HF’s design was sufficiently similar to PARAGON-HF to allow cross-study data pooling. This pooled analysis included 13,195 patients from both trials whose EFs were then stratified into the following EF groups: <22.5% (n=1,269; mean age 61 years; 19% women); 22.5-32.5% (n=3,987; mean age 63 years; 21% women); 32.5-42.5% (n=3,143; mean age 66 years; 24% women); 42.5-52.5% (n=1,427; mean age 71 years; 40% women); 52.5-62.5% (n=2,166; mean age 73 years; 54% women); and >62.5% (n=1,202; mean age 74 years; 63% women).

The study researchers assessed the primary endpoints for PARADIGM-HF (a composite of CV death or HF hospitalisation) and PARAGON-HF (a composite of total HF hospitalisations or CV death).

Sacubitril/valsartan was superior to renin-angiotensin system inhibition for CV death (HR 0.84; 95% CI 0.76-0.92), all-cause mortality (HR 0.88; 95% CI 0.81-0.96), HF hospitalisation (HR 0.84; 95% CI 0.77-0.91), and first CV death or HF hospitalisation (HR 0.84; 95% CI 0.78-0.9). However, the treatment effect of sacubitril/valsartan was greatest in patients with LVEF below the normal range (Pinteraction=0.02), though the CV death benefit of sacubitril/valsartan was diminished in patients in the lower EF range.

The incidence of non-CV death was similar across all EF categories, although the proportion of patients with non-CV death when considered among total deaths was higher in patients at the highest end of the EF spectrum.

Invited discussant Prof. Lynne W. Stevenson (Vanderbilt University Medical Center, USA) summarised: “It appears that sacubitril/valsartan has impact to decrease hospitalisations for congestion across EF whether it is reduced or preserved, but perhaps disease progression and cardiac mortality present better targets if you have a low EF than if you have a preserved EF. It is particularly important that we understand the patients who benefit and how they benefit for all of the new therapies we are considering both for this and for dapagliflozin.”

1. McMurray J, et al. PARAGON-HF - Effects of sacubitril/valsartan in women compared to men with heart failure and preserved ejection fraction. LBS.05, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.
2. Solomon S, et al. PARAGON-HF -Secondary analysis- Effect of sacubitril/valsartan across the spectrum of ejection fraction in heart failure. LBS.05, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.

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