Solomon SD, Vaduganathan M, L Claggett B, et al. Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure. Circulation. 2020 Feb 4;141(5):352-361. doi: 10.1161/CIRCULATIONAHA.119.044586. Epub 2019 Nov 17. (Original study)

BACKGROUND: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF.

METHODS: We combined data from PARADIGM-HF (LVEF eligibility=40%; n=8399) and PARAGON-HF (LVEF eligibility=45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: =22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF.

RESULTS: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78-0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76-0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77-0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81-0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions.

CONCLUSIONS: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men.

CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Cardiology 6 / 7
Internal Medicine 6 / 7
Comments from MORE raters

General Internal Medicine-Primary Care(US) rater

I don`t think this article helps the average provider to decide on what to use....more studies and more definitive guidance seems to be the way to go from here.

Internal Medicine rater

Sacubitril/valsartan (Entresto) has become standard of care for heart failure patients with reduced EF, adding to a wealth of evidence-based treatments for this condition. Proven options are few for the large group of patients with heart failure with preserved EF. This study indicates that, at least for heart failure patients with "mid-range" EF of 40-50%, sacubitiril/valsartan is of benefit.
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