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

Contribution To Literature:

Highlighted text has been updated as of May 2, 2022.

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)

Benefit of sacubitril/valsartan according to sex:

Sacubitril/valsartan hazard ratios (HRs) for the primary outcome according to sex:

  • Women: HR 0.73 (95% CI 0.59-0.90)
  • Men: HR 1.03 (95% CI 0.84-1.25) (p for interaction = 0.017)

Improvement in NYHA class and renal function was similar in women and men. Symptom improvement was less in women than men.

Association of sacubitril/valsartan initiation from HF hospitalization and benefit: Sacubitril/valsartan vs. placebo was associated with an absolute 6.4% reduction in cardiovascular death or hospitalization for HF when initiated <30 days from index hospitalization, 4.6% when initiated 30-90 days after index hospitalization, 3.4% when initiated 91-180 days after index hospitalization, and no benefit when initiated >180 days after index hospitalization (p for interaction = 0.05).

Association of sacubitril/valsartan and N-terminal pro–B-type natriuretic peptide (NT-proBNP):

  • NT-proBNP was associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR] 1.68 per log increase in NT-proBNP, p < 0.001). This relationship was stronger with atrial fibrillation (p for interaction < 0.001) and weaker with obesity (p for interaction < 0.001).
  • Sacubitril/valsartan compared with valsartan reduced NT-proBNP by 19%.
  • Baseline NT-proBNP did not modify the treatment effect of sacubitril/valsartan compared with valsartan (p for interaction = 0.96).

Association of signs/symptoms of HF and prognosis/response to therapy:

  • ≥3 signs/symptoms of HF vs. ≤2 signs/symptoms were associated with higher risk of total HF hospitalization or cardiovascular death (RR 1.50, 95% CI 1.30-1.74).
  • The individual signs/symptoms of HF most predictive of the primary outcome were orthopnea (RR 1.29, 95% CI 1.04-1.61) and rales (RR 1.52, 95% CI 1.10-2.10).
  • Patients with orthopnea appeared to derive greater benefit from sacubitril/valsartan (RR 0.67, 95% CI 0.49-0.90) compared with those without orthopnea (RR 0.97, 95% CI 0.82-1.14; p for interaction = 0.04).

Echocardiographic features of patients with HFpEF:

  • Prevalence of LV hypertrophy, 21%
  • Prevalence of left atrial enlargement, 83%
  • Prevalence of elevated E/e’ ratio, 53%
  • Prevalence of pulmonary hypertension, 31%

Association of atrial fibrillation on the treatment effect of sacubitril/valsartan:

  • Association of history of atrial fibrillation vs. no atrial fibrillation on the risk of the primary outcome: RR 1.36 (95% CI 1.12-1.65)
  • Association of atrial fibrillation/flutter at baseline vs. no atrial fibrillation on the risk of the primary outcome: RR 1.31 (95% CI 1.11-1.54)
  • There was no treatment interaction for atrial fibrillation/flutter on the association of sacubitril/valsartan vs. valsartan (p for interaction = 0.57).


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. One-half of enrolled subjects were women and there appeared to be treatment interaction according to sex. NT-proBNP did not identify patients with greater benefit from sacubitril/valsartan. Sacubitril/valsartan was associated with a reduction of the primary outcome in women, but not in men. However, women derived less symptom improvement from study medication. A high burden of HF signs/symptoms was associated with a high risk for adverse cardiovascular events.

There was possible enhanced benefit when sacubitril/valsartan was initiated in close proximity to the index hospitalization event; however, this finding deserves prospective validation. HFpEF patients were characterized by a high prevalence of left atrial enlargement, diastolic dysfunction, and pulmonary hypertension. This trial contrasts with the PARADIGM-HF trial, which documented benefit from sacubitril/valsartan among patients with HF with reduced EF.


Cikes M, Planinc I, Claggett B, et al. Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial. JACC Heart Fail 2022;10:336-46.

Editorial Comment: Piccini JP, Arps K. Sacubitril/Valsartan Therapy for AF and HFpEF: Is the Glass Half Empty or Half Full? JACC Heart Fail 2022;10:336-46.

Jering K, Claggett B, Redfield MM, et al. Burden of Heart Failure Signs and Symptoms, Prognosis, and Response to Therapy: The PARAGON-HF Trial. JACC Heart Fail 2021;9:386-97.

Editorial Comment: Drazner MH. Insights From the History and Physical Examination in HFpEF or HFrEF: Similarities and Differences. JACC Heart Fail 2021;9:398-400.

Cunningham JW, Vaduganathan M, Claggett BL, et al. Effects of Sacubitril/Valsartan on N-Terminal Pro-B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail 2020;8:372-81.

Editorial: Januzzi JL, Myhre PL. The Challenges of NT-proBNP Testing in HFpEF: Shooting Arrows in the Wind. JACC: Heart Failure 2020;8:382-5.

Presented by Dr. Jonathan Cunningham at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.

Shah AM, Cikes M, Prasad N, et al., on behalf of the PARAGON-HF Investigators. Echocardiographic Features of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction. J Am Coll Cardiol 2019;74:2858-73.

Editorial Comment: Sharma K, Ying W. Is PARAGON a Paragon Example of an HFpEF Clinical Trial? A Call for Deep Phenotyping. J Am Coll Cardiol 2019;74:2874-7.

McMurray JJ, Jackson AM, Lam CS, et al. Effects of Sacubitril-Valsartan, Versus Valsartan, in Women Compared to Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF. Circulation 2020;141:338-51.

Presented by Dr. John J.V. McMurray at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.

Presented by Dr. Muthiah Vaduganathan at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019.

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;381:1609-20.

Editorial: O’Connor CM, deFilippi C. PARAGON-HF — Why We Do Randomized, Controlled Clinical Trials. N Engl J Med 2019;381:1675-6.

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

Clinical Topics: Arrhythmias and Clinical EP, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Echocardiography/Ultrasound

Keywords: ACC Annual Scientific Session, acc20, AHA19, AHA Annual Scientific Sessions, Atrial Fibrillation, Atrial Flutter, Echocardiography, ESC 19, ESC Congress, Geriatrics, Heart Failure, Hospitalization, Hypertrophy, Left Ventricular, Natriuretic Peptides, Renal Insufficiency, Stroke Volume

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