ARNI treatment effect across EF spectrum: benefit up to mildly reduced EF

Effect of Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure. A prespecified pooled analysis of the PARADIGM-HF and PARAGON-HF trials

News - Nov. 17, 2019

Presented during the AHA Scientific Sessions 2019 by Scott D Solomon (Brigham and Women's Hosp, Boston, MA) .

Introduction and methods

Although heart failure with reduced ejection fraction (HFrEF) has multiple etiologies, virtually all patients with this disorder respond to several classes of pharmacologic therapies that have, in clinical trials, been shown to contribute to step-wise reductions in morbidity and mortality. Nevertheless, few options have been available for patients with EF above the “reduced” range, generally considered 40% or less.

The angiotensin receptor/neprilysin inhibitor (ARNI) sacubitril/valsartan has now been compared with a renin-angiotensin- system (RAS) inhibitor alone in two similarly designed large outcomes trials of patients with reduced (HFrEF) and preserved LVEF (HFpEF), permitting examination of its effects across the full spectrum of LVEF. PARADIGM-HF compared sacubitril/valsartan 57/103 mg BID with enalapril 10 mg BID and followed HFrEF patients (LVEF <40%) for a median of 27 months. PARAGON-HF compared sacubitril/valsartan 57/103 mg BID with valsartan 160 mg BID and followed HFpEF patients (LVEF >45) for a median of 35 months. All patients had signs and symptoms of HF (NYHA class II-IV) and elevated NT-proBNP. PARAGON-HF also required evidence of structural heart disease.

This pre-specified analysis pooled data from both trials, totalling 13,195 patients. Patients were divided into 10 point EF groups (≤22.5%, >22.5 to 32.5%, >32.5% to 42.5%, >42.5% to 52.5%, >52.5% to 62.5%, >62.5) avoiding cut-offs on multiples of 5 because of substantial digit preference. Treatment effects for those randomized to sacubitril/valsartan were compared with RAS inhibitor (enalapril or valsartan) overall (stratifying by study) and within each EF group, and using continuous analyses. Both time to first composite of CV death or HF hospitalization (PARADIGM primary endpoint) and the composite of total HF hospitalizations and CV death (PARAGON primary endpoint) were assessed across the spectrum of LVEF.

Main results

  • Trends in baseline characteristics were observed across EF categories, for instance of younger age and fewer females in the lower categories. Rates of prior HF hospitalizations and history of MI were higher in lower EF categories, while rates of hypertension and diabetes increased in higher EF categories. SBP, NT-proBNP, eGFR and medication use also showed significant trends across categories.
  • When looking at incidence curves, CV death decreases with increasing EF, while non-CV death is more stable across the EF spectrum. When comparing this with the declining trend for all-cause mortality, it can be concluded that the proportion of those with non-CV death was considerably greater at higher EF.
  • In the pooled data, the primary endpoints of both trials and their components were significantly in favour of treatment with sacubitril/valsartan.
  • When comparing treatment effect on HF hospitalization and CV death in men and women, the benefit of treatment appears to extend to higher EF in women than in men.
  • No significant interactions of EF category with the treatment effect on safety measures (hypotension, creatinine >2.5 mg/dL, potassium >5.5 mmol/L) were seen.


This large patient-level analysis of the PARADIGM-HF and PARAGON-HF data showed overall benefit of sacubitril/valsartan when compared to RAS inhibition alone. These findings were driven by benefit in patients with chronic HF and LVEF below the normal range. Benefit in the EF range above frankly “reduced” but below normal was driven primarily by reduction in HF hospitalization. Women derived benefit to a higher LVEF than men. These data suggest that the therapeutic effects of sacubitril/valsartan, compared with a RAS inhibitor alone, appear to extend to patients with HF and mildly reduced EF.


Lynn Warner Stevenson discussed these results along with the data on gender differences during the press conference. She said that it is tempting to jump on the signal of gender, but she was reluctant to do so. She preferred to look at physiology, to try to understand when therapy is beneficial and she raised the question whether we are truly looking across the spectrum of one disease as described by EF. Alternatively, maybe the one disease-model does not fit the data so well.

She put the data of the two studies and EF ranges next to each other, and suggested that maybe they reflect two different physiologies, and two targets of benefit. Arguments for this viewpoint include that benefit in PARADIGM-HF was not dependent on EF or gender, while in PARAGON-HF benefit was only seen in those with EF<57% and in women. PARAGON-HF showed no mortality benefit in women, and the signal of benefit was limited to class III-IV, while in PARADIGM it was more obvious in class I-II. Lastly, in PARADIGM-HF benefit was irrespective of prior hospitalization, while PARAGON-HF only showed benefit in patients with prior hospitalization in the previous 6 months.

When classifying patients based on EF and hospitalization, those with low EF, sacubitril/valsartan lowers hospitalizations and mortality, regardless of history of hospitalizations. In HFpEF on the other hand, events are decreased only when patients have a history of hospitalization and no impact on mortality is seen. Thus, she concludes that disease progression and cardiac mortality may represent better targets for therapy in those with low, rather than preserved EF.

We need better understanding of which patients will benefit and what kind of benefit they may get, and to what cost. Informing patients and shared decision-making with them is important to effectively use medication.

  • Our reporting is based on the information provided during AHA Scientific Sessions 2019 -

These results were simultaneously published in CIrculation Watch a video by Scott Solomon about this analysis

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