Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction - PARAGON-HF

Contribution To Literature:

The PARAGON-HF trial failed to show that sacubitril-valsartan reduced adverse events among patients with HFpEF.


The goal of the trial was to evaluate the neprilysin-angiotension receptor inhibitor sacubitril-valsartan among patients with heart failure with preserved ejection fraction (HFpEF).

Study Design

  • Randomized
  • Parallel
  • Blinded

Patients with HFpEF were randomized to sacubitril-valsartan 97/103 mg twice daily (n = 2,419) versus valsartan 160 mg twice daily (n = 2,403).

  • Total number of enrollees: 4,822
  • Duration of follow-up: 35 months
  • Mean patient age: 73 years
  • Percentage female: 52%
  • Percentage with diabetes: 44%

Inclusion criteria:

  • Patients ≥50 years of age with HF symptoms (New York Heart Association [NYHA] class II-IV)
  • Left ventricular ejection fraction (LVEF) ≥45%
  • Elevated level of natriuretic peptides
  • Structural heart disease (left atrial enlargement or LV hypertrophy)

Exclusion criteria:

  • Any prior measurement of LVEF <40%
  • Acute coronary syndrome, major cardiovascular surgery, or urgent percutaneous coronary intervention (PCI) within 3 months, or elective PCI within 30 days
  • Any clinical event within the 6 months that could have reduced the LVEF
  • Acute decompensated HF
  • Treatment with ≥2 of: angiotensin-converting enzyme inhibitor, an angiotensin-receptor blocker, or a renin inhibitor
  • Significant pulmonary disease or chronic obstructive pulmonary disease, hemoglobin <10 g/dl, or body mass index >40 kg/m2
  • Systolic blood pressure (SBP) ≥180 mm Hg or SBP <110 mm Hg at entry

Principal Findings:

The primary outcome, rate of cardiovascular deaths or hospitalizations for HF, was 12.8 events per 100 patient-years in the sacubitril-valsartan group vs. 14.6 events per 100 patient-years in the valsartan group (p = not significant).

Secondary outcomes:

  • NYHA class improvement: 15.0% in the sacubitril-valsartan group vs. 12.6% in the valsartan group (p < 0.05)
  • Renal composite outcome: 1.4% in the sacubitril-valsartan group vs. 2.7% in the valsartan group (p < 0.05)


Among patients with HFpEF, sacubitril-valsartan was not effective at reducing the incidence of cardiovascular death or hospitalization for HF compared with valsartan. There was less decline in renal function among the sacubitril-valsartan group. There was possible benefit for sacubitril-valsartan among those with EF in the lower range of eligibility and among women; therefore, these groups deserve further study. This trial contrasts with the PARADIGM-HF trial, which documented benefit from sacubitril-valsartan among patients with HF with reduced EF.


Solomon SD, McMurray JJV, Anand IS, et al., on behalf of the PARAGON-HF Investigators and Committees. Angiotensin–Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction. N Engl J Med 2019;Sept 1:[Epub ahead of print].

Presented by Dr. Scott Solomon at the European Society of Cardiology Congress, Paris, France, September 1, 2019.

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Clinical Topics: Geriatric Cardiology, Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: ESC 19, ESC Congress, Geriatrics, Heart Failure, Hospitalization, Hypertrophy, Left Ventricular, Natriuretic Peptides, Renal Insufficiency, Stroke Volume

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