Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure - PARADIGM-HF

Contribution To Literature:

The PARADIGM-HF trial showed that sacubitril/valsartan was superior to enalapril in patients with heart failure due to reduced EF.


The goal of the trial was to evaluate treatment with the combined neprilysin inhibitor (sacubitril)/angiotensin-receptor blocker (valsartan) (LCZ696) compared with enalapril among participants with heart failure due to reduced ejection fraction (EF).

Inhibition of neprilysin increases levels of natriuretic peptides, bradykinin, and adrenomedullin, thus resulting in natriuresis and vasodilatation.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Participants at least 18 years of age with heart failure due to reduced LVEF and B-type natriuretic peptide (BNP) ≥150 pg/ml or NT-proBNP ≥600 pg/ml

    Number of screened applicants: 10,513
    Number of enrollees: 8,442
    Duration of follow-up: median 27 months
    Mean patient age: 64 years
    Percentage female: 21%
    EF: 30%


  • Symptomatic hypotension
  • Estimated glomerular filtration rate <30 ml/min/1.73 m2
  • Serum potassium >5.2 mmol/L
  • Angioedema

Primary Endpoints:

  • Cardiovascular death or hospitalization for heart failure

Drug/Procedures Used:

Participants with heart failure (New York Heart Association class II-IV) due to reduced EF (≤40%) were randomized to LCZ696 200 mg twice daily (n = 4,187) versus enalapril 10 mg twice daily (n = 4,212) in addition to standard therapy.

Concomitant Medications:

  • Digitalis: 29%
  • Beta-blocker: 93%
  • Mineralocorticoid antagonist: 54%

Principal Findings:

Overall, 8,442 participants were randomized. The mean age was 64 years, 21% were women, mean body mass index was 28 kg/m2, 60% had ischemic etiology for heart failure, 43% had prior myocardial infarction, and 35% had diabetes. The mean left ventricular (LV) EF was 30%. Systolic blood pressure at 8 months was 3.2 mm Hg lower with sacubitril/valsartan compared with enalapril.

The trial was stopped early due to prespecified stopping rules for benefit. At a median of 27 months, the primary outcome of cardiovascular death or hospitalization for heart failure occurred in 21.8% of the sacubitril/valsartan group vs. 26.5% of the enalapril group (p < 0.001). Benefit was consistent among all subgroups. The association for the primary outcome did not vary according to time from heart failure hospitalization to screening.

  • Cardiovascular death: 13.3% vs. 16.5% (p < 0.001), respectively
  • All-cause death: 17.0% vs. 19.8% (p = 0.0009), respectively
  • Hospitalization for heart failure: 12.8% vs. 15.6% (p < 0.001), respectively
  • Symptomatic hypotension: 14.0% vs. 9.2% (p < 0.001), respectively
  • Elevated serum creatinine (≥2.5 mg/dl): 3.3% vs. 4.5% (p = 0.007), respectively
  • Elevated serum potassium (≥5.5 mmol/L): 16.1% vs. 17.3% (p = 0.15), respectively
  • Cough: 11.3% vs. 14.3% (p < 0.001), respectively

There were no episodes of angioedema causing airway compromise in either group.

  • Improved NYHA class: 16.7% vs. 14.9% (p = 0.0015), respectively
  • Treatment failure: (hazard ratio [HR] = 0.84, p = 0.0029), respectively for sacubitril/valsartan vs. enalapril
  • Number of emergency room visits: (HR = 0.70, p = 0.017), respectively for sacubitril/valsartan vs. enalapril
  • Number of HF admissions: (HR = 0.77, p = 0.0004), respectively for sacubitril/valsartan vs. enalapril

Among the 3,778 patients with diabetes:

  • Change in HbA1c during the first year of follow-up: -0.26% with sacubitril/valsartan vs. -0.16% with enalapril (p = 0.023)
  • New use of insulin: 7% with sacubitril/valsartan vs. 10% with enalapril (p = 0.0052)

Renal effects:

  • Change in estimated glomerular filtration rate (eGFR): -1.61 ml/min/1.73 m2/year with sacubitril/valsartan vs. -2.04 ml/min/1.73 m2/year with enalapril (p < 0.001)
  • Change in urinary albumin/creatinine ratio: 1.20 mg/mmol with sacubitril/valsartan vs. 0.90 mg/mmol with enalapril (p < 0.001)
  • The effect of sacubitril/valsartan on cardiovascular death or hospitalization for heart failure was not modified by baseline eGFR (p for interaction = 0.7).

Effects of sacubitril/valsartan across the range of left ventricular ejection fraction (LVEF), from PARADIGM-HF and PARAGON-HF programs combined (n = 13,195):

Sacubitril-valsartan hazard ratios (HR) for the primary outcome according to LVEF:

  • LVEF ≤22.5%; HR 0.77 (95% CI 0.63-0.94)
  • LVEF >22.5%-32.5%; HR 0.81 (95% CI 0.71-0.92)
  • LVEF >32.5%-42.5%; HR 0.81 (95% CI 0.69-0.94)
  • LVEF >42.5%-52.5%; HR 0.89 (95% CI 0.73-1.10)
  • LVEF >52.5%-62.5%; HR 0.89 (95% CI 0.74-1.06)
  • LVEF >62.5; HR 1.03 (95% CI 0.80 to 1.32) (p for trend = 0.037)
  • Women derived benefit to higher LVEF

Effects of sacubitril/valsartan on BNP:

BNP levels increased by a median of 19% during 8-10 weeks of treatment with sacubitril/valsartan, while NT-proBNP levels decreased by a median of 28% during 8-10 weeks of treatment with sacubitril/valsartan. Both peptides retained their diagnostic accuracy for cardiovascular death or hospitalization for heart failure (C-statistic 63-67% for BNP and 64-70% for NT-proBNP).

Effects of sacubitril/valsartan according to implantable cardioverter-defibrillator (ICD) use:

  • Among patients with an ICD, sacubitril/valsartan reduced sudden cardiac risk (HR 0.49, 95% CI 0.25-0.99).
  • Among those who were eligible but did not receive an ICD, sacubitril/valsartan reduced sudden cardiac risk (HR 0.81, 95% CI 0.67-0.98).


Among patients with heart failure due to reduced EF, the use of sacubitril/valsartan was beneficial compared with enalapril. Sacubitril/valsartan was associated with a reduction in cardiovascular death or hospitalization for heart failure. Sacubitril/valsartan was associated with a reduction in sudden cardiac death regardless of ICD use. Benefit for sacubitril/valsartan diminished among those with mild LV systolic dysfunction/normal LVEF; however, women appeared to derive benefit including mild LV systolic dysfunction. Sacubitril/valsartan also slowed progression of heart failure.

This study medication was compared against a comparable dose of enalapril that had previously been shown to reduce mortality in heart failure patients. Sacubitril/valsartan was well tolerated, with a higher frequency of symptomatic hypotension, but a lower frequency of elevated serum creatinine, hyperkalemia, and cough. Sacubitril/valsartan was associated with a slower decline in eGFR vs. enalapril. Although BNP levels tended to rise during treatment with sacubitril/valsartan, the diagnostic accuracy of BNP remained similar to NT-proBNP.

In an earlier study, omapatrilat, which inhibits angiotensin-converting enzyme, neprilysin, and aminopeptidase P, failed to demonstrate improvement over enalapril in the treatment of chronic heart failure. Combined angiotensin-receptor blocker/neprilysin inhibition represents an important change in the treatment of heart failure patients. Sacubitril/valsartan improved glycemic control compared with enalapril.


Rohde LE, Chatterjee NA, Vaduganathan M, et al. Sacubitril/Valsartan and Sudden Cardiac Death According to Implantable Cardioverter-Defibrillator Use and Heart Failure Cause: A PARADIGM-HF Analysis. JACC Heart Fail 2020;8:844-55.

Editorial Comment: Al-Khatib SM, Blumer V, Felker GM. Medications Are Important for Sudden Cardiac Death Prevention But So Is the Implantable Cardioverter-Defibrillator. JACC Heart Fail 2020;8:856-8.

Solomon SD, Vaduganathan M, Claggett BL, et al. Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure. Circulation 2019;Nov 17:[Epub ahead of print].

Presented by Dr. Scott D. Solomon at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.

Myhre PL, Vaduganathan M, Claggett B, et al. B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial. J Am Coll Cardiol 2019;73:1264-72.

Editorial Comment: Anand IS. What Explains the Benefits of ARNI Therapy in Heart Failure? J Am Coll Cardiol 2019;73:1285-7.

Damman K, Gori M, Brian Claggett, et al. Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure. JACC Heart Fail 2018;6:489-98.

Editorial Comment: Mullens W, Martens P. Exploiting the Natriuretic Peptide Pathway to Preserve Glomerular Filtration in Heart Failure. JACC Heart Fail 2018;6:499-504.

Seferovic JP, Claggett B, Seidelmann SB, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2017;Mar 18:[Epub ahead of print].

Presented by Dr. Jelena Seferovic,at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 18, 2017.

Solomon SD, Claggett B, Packer M, et al. Efficacy of Sacubitril/Valsartan Relative to a Prior Decompensation: The PARADIGM-HF Trial. JACC Heart Fail 2016;4:816-22.

Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54-61.

Presented by Dr. John McMurray at the American Heart Association Scientific Sessions, Chicago, IL, November 17, 2014.

McMurray JJ, Packer M, Desai AS, et al., on behalf of the PARADIGM-HF Investigators and Committees. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014;371:993-1004.

Editorial: Jessup M. Neprilysin Inhibition — A Novel Therapy for Heart Failure. N Engl J Med 2014;371:1062-4.

Presented by Dr. Milton Packer at the European Society of Cardiology Congress, Barcelona, Spain, August 30, 2014.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, SCD/Ventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: AHA Annual Scientific Sessions, AHA19, ACC17, ACC Annual Scientific Session, Hypotension, Blood Pressure, Hyperkalemia, Creatinine, Neprilysin, Natriuretic Peptides, Natriuresis, Cough, Bradykinin, Myocardial Infarction, Enalapril, Vasodilation, Pyridines, Valine, Tetrazoles, Adrenomedullin, Natriuretic Peptide, Brain, Peptidyl-Dipeptidase A, Potassium, Body Mass Index, Heart Failure, Thiazepines, Diabetes Mellitus, Glomerular Filtration Rate, Defibrillators, Implantable, ESC Congress

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