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Solomon SD, et al. "Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction". The New England Journal of Medicine. 2019. 381(17):1609-1620.

Clinical Question

In patients with heart failure with preserved ejection fraction (HFpEF) who have NYHA II-IV symptoms, EF ≥45%, elevated natriuretic peptide levels, and evidence of structural heart disease, does the ARNI sacubitril-valsartan lead to reduced rates of total hospitalisations for heart failure and death from cardiovascular causes, when compared to valsartan alone?

Bottom Line

Among patients with symptomatic HFpEF (LVEF ≥45%), the combination of sacubitril-valsartan did not lead to significantly lower composite outcome of total hospitalisations for heart failure and death from cardiovascular causes, when compared to valsartan alone. There was modest improvement in NYHA class and less decline in renal function in the sacubitril-valsartan group when compared to valsartan alone.

Major Points

While several established treatments have been shown to improve outcomes in heart failure with reduced ejection fraction (HFrEF) such as beta-blockers, ACE-inhibitors and aldosterone antagonists,[1][2][3] there is a lack of evidenced-based treatment shown to be beneficial in heart failure with preserved ejection fraction (HFpEF). More recently, the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril-valsartan, has been found to improve outcomes in patients with HFrEF. The 2014 PARADIGM-HF trial found that HFrEF patients (LVEF ≤40%) treated with sacubitril-valsartan had reduced risk of cardiovascular mortality, heart failure hospitalizations and all-cause mortality compared to those treated with enalapril. The 2018 PIONEER-HF study[4] demonstrated that sacubitril-valsartan reduced NT-proBNP levels in patients hospitalized for acute decompensated heart failure without increased rates of adverse events when compared to enalapril. Taken together, these two trials suggest that HFrEF patients benefit from therapy with an ARNI.

Published in 2019, PARAGON-HF was a randomized controlled trial that enrolled 4,822 patients with NYHA class %ge;II symptoms, preserved EF (defined as ≥45%), elevated natriuretic peptide level, and evidence of structural heart disease. Participants were randomized to sacubitril-valsartan (target dose 97/103mg twice daily) or valsartan (target dose, 160mg twice daily). Of note, randomization followed a run-in period in which patients initially received half target dose valsartan and then sacubitril-valsartan to ensure acceptable side-effect and laboratory values. After a median duration of 35 months follow-up, the primary composite outcome of cardiovascular mortality and hospitalisation for heart failure did not differ significantly between arms. There were numerically fewer composite events in the sacubitril-valsartan group, which was primarily driven by lower numbers of hospitalization for heart failure, though this too was not statistically significant [RR 0.85 (0.72-1.00)]. While there was favourable change in NYHA class from baseline and the renal composite outcome, there was no significant difference in change in KCCQ clinical summary score and death from any cause.

Though PARAGON-HF found no benefit from sacubitril-valsartan in patients with HFpEF, a portion of the population had heart failure with mid-range ejection fraction (HFmrEF).[5] HFmrEF is an emerging HF subtype defined by LVEF 45-49%. Contrary to higher EF phenotypes, HFmrEF appears to benefit from therapies found to be beneficial for HFrEF, like beta blockers.[6] A subgroup analysis identified lower RR for the primary outcome among those with LVEF below the median (median LVEF 57%), but not above the median. The observed reduction in the below-median subgroup (RR 0.78; 95% CI 0.64-0.98) was similar to that in HFrEF trial, PARADIGM-HF (HR 0.80; 95% CI 0.73-0.87). There were other differences by some subgroups, so it is possible that an ARNI might ultimately prove beneficial for some patients meeting PARAGON-HF's enrollment criteria. Further research is needed to further elucidate such a benefit.


No guidelines have been published that reflect the results of this trial.


  • Multinational, double-blind, randomized, parallel group, active-controlled trial
  • N=4,822
    • Sacubitril-valsartan (n=2,407)
    • Valsartan (n=2,389)
  • Setting: 848 centers in 43 countries across the globe
  • Enrolment: 2014-2016
  • Median follow-up: 35 months
  • Analysis: Intention-to-treat
  • Primary outcome: Composite HF hospitalization and CVD mortality


Inclusion Criteria

  • Written informed consent obtained
  • ≥50 years of age, male or female
  • LVEF ≥45%
  • Symptoms of HF requiring treatment with diuretics for at least 30 days prior to screening visit
  • Symptoms of HF (NYHA functional class II to IV)
  • Structural heart disease evidenced by at least 1 of LA enlargement or LVH
  • Patients with at least 1 of:
    • HF hospitalization (defined as HF listed as the major reason for hospitalization) and NT-proBNP >200 for patients not in AF or >600 for patients in AF on screening ECG, or
    • NT-proBNP >300 for patients not in AF or >900 for patients in AF on the screening visit ECG

Exclusion Criteria

  • Any prior echocardiographic measurement of LVEF <40%
  • Acute coronary syndrome (including MI) or cardiac intervention within 3 months or an elective PCI within 30 days
  • Any clinical event within the 6 months that could have reduced the LVEF (e.g., MI, CABG), unless an echocardiographic measurement was performed after the event confirming the LVEF to be ≥45%
  • Current acute decompensated HF
  • Patients who require treatment with 2 or more of the following: an ACEI, an ARB, or a renin inhibitor
  • Hypersensitivity to any of the study drugs or similar drug
  • History of angioedema
  • Probable alternative diagnoses that in the opinion of the investigator could account for the patient’s HF symptoms. Specifically, patients with severe pulmonary disease, hemoglobin <10 g/dl, or BMI >40 kg/m2.
  • Uncontrolled hypertension or hypotension
  • Recent use of other investigational drugs at the time of enrollment
  • History of dilated cardiomyopathy
  • Evidence of right-sided HF in the absence of left-sided structural heart disease
  • Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy
  • Clinically significant congenital heart disease
  • Presence of hemodynamically significant valvular heart disease
  • Recent cerebrovascular disease/event
  • Coronary or carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention during the trial
  • Life-threatening or uncontrolled dysrhythmia
  • Patients with a cardiac resynchronization therapy device
  • Patients with transplanted organ
  • Any surgical or medical condition that in the opinion of the investigator may place the patient at higher risk or prevent compliance
  • Any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of study drugs
  • Evidence of hepatic disease
  • Significant renal dysfunction
  • Presence of known functionally significant bilateral renal artery stenosis
  • Hyperkalemia
  • History or presence of any other disease with a life expectancy of <3 years
  • Pregnant or lactating women and women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 7 days off study drug

Baseline Characteristics

From sacubitril-valsartan group:

  • Demographics: Age 73 years, 52% female, 82% White race
  • Geographic region: North America 12%, Latin America 8%, Western Europe 29%, Central Europe 36%, Asia-Pacific or other 16%
  • Physiological measurements: Systolic BP 130 mm Hg, BMI 30 kg/m2
  • eGFR: 63 (+ 19)
  • Ischemic cause for heart failure: 37%
  • LVEF: 58% (+ 7.8)
  • Median NT-proBNP: 904 (475-1596)
  • NYHA Class I: 3%, Class II: 78%, Class III: 19%, Class IV: 0.3%
  • PMH: Hypertension 96%, DM 44%, AF or flutter 32%, stroke 11%, prior HF hospitalization 47%, prior MI 23%
  • Medications: Diuretic agent at 95%, ACE-inhibitor or ARB 86%, mineralocorticoid antagonist 25%, beta-blocker 80%


  • Renin-angiotensin system inhibitors (other than MRA) were discontinued then all underwent a single-blind screening period with consecutive periods of half target dose valsartan, followed by half target dose sacubitril-valsartan
  • Participants who had no unacceptable side-effects and remained within safety criteria were then randomised 1:1 to double-blind treatment:
    • Sacubitril-valsartan (target dose, 97mg of sacubitril with 103mg valsartan twice daily)
    • Valsartan (target dose, 160mg twice daily)
  • The dose of the trial drugs could be lowered for side effects.


Comparisons are sacubitril-valsartan therapy vs. valsartan therapy alone.

Primary Outcomes

Components of the primary outcome are shown here for simplicity; the composite outcome was the primary outcome.

Composite HF hospitalization and CVD mortality
RR 0.87 (95% CI 0.75-1.01)
# of HF hospitalizations: 690 vs. 797 (RR 0.85; 95% CI 0.72-1.00)
CVD mortality: 8.5 vs. 8.9 (HR 0.95; 95% CI 0.79-1.16)

Secondary Outcomes

Change in NYHA class at 8 months
OR 1.45 (95% CI 1.13-1.86)
Improved 15.0% vs. 12.6%
Unchanged 76.3% vs. 77.8%
Worsened 8.7% vs. 9.6%
Change in KCCQ clinical summary score at 8 months
-1.6 vs. -2.6 (Difference 1.0; 95% CI 0.0-2.1)
Renal composite outcome
Renal failure mortality, ESRD, or decrease in eGFR >50% from baseline
1.4% vs. 2.7% (HR 0.50; 95% CI 0.33-0.77)
All-cause mortality
14.2% vs. 14.6% (HR 0.97; 95% CI 0.84-1.13)

Subgroup Analysis

The primary outcome was similar (except for below) for age stratified at 75, diabetes status, AF status, NTproBNP level, NYHA class, and ability to take an ACE inhibitor.

<65: RR 0.99 (95% CI 0.64−1.53)
≥65: RR 0.85 (95% CI 0.73−0.99)
Male: RR 1.03 (95% CI 0.85−1.25)
Female: RR 0.73 (95% CI 0.59−0.90)
White: RR 0.83 (95% CI 0.71−0.97)
Black: RR 0.69 (95% CI 0.24−1.99)
Asian: RR 1.25 (95% CI 0.87−1.79)
Other: RR 1.03 (95% CI 0.47−2.28)
N America: RR 0.80 (95% CI 0.57−1.14)
Latin America: RR 1.33 (95% CI 0.75−2.36)
Western Europe: RR 0.69 (95% CI 0.53−0.89)
Central Europe: RR 0.97 (95% CI 0.76−1.24)
Asia/Pacific/other: RR 1.10 (95% CI 0.79−1.52)
&le57%: RR 0.78 (95% CI 0.64−0.95)
>57%: RR 1.00 (95% CI 0.81−1.23)
Use of a mineralocorticoid
Yes: RR 0.73 (95% CI 0.56−0.95)
No: RR 0.94 (95% CI 0.79−1.11)
eGFR (mL/min/1.73m2)
<60: RR 0.79 (95% CI 0.66−0.95)
≥60: RR 1.01 (95% CI 0.80−1.27)

Adverse Events

Hypotension with SBP<100mmHg
15.8% vs. 10.8% (p<0.001)
Elevated serum creatinine >2.0 mg/dl
10.8% vs. 13.7% (p=0.002)
Elevated serum potassium
>5.5mmol/liter 13.2% vs. 15.3% (p=0.048)
>6.0mmol/liter 3.1% vs. 4.3% (p=0.04)
0.6% vs 0.2% (p=0.02)


  • This trial included patients with heart failure with mid-range ejection fraction (HFmrEF) with an LVEF of 45% to 49%. This population might benefit from HFrEF-directed therapies.[6]
  • One site was closed for major violations of good clinical practice.
  • The use of valsartan as an active comparator may have reduced the treatment effect, given previously reported potential benefit of ARB in HFpEF (CHARM-Preserved).
  • There were a significant number of patients excluded in the trial run-in period (10,359 screened with 4822 undergoing randomization), for reasons including comprehensive exclusion criteria and side-effects during run-in, which may have impacted on the trial results and may limit generalisability.
  • Inclusion criteria requiring elevation of natriuretic peptides may have excluded some patients with HFpEF.


Funded by Novartis, manufacturer of sacubitril-valsartan. Multiple authors with multiple financial disclosures.

Further Reading

  1. Poole-Wilson PA et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003. 362:7-13.
  2. Yusuf S et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N. Engl. J. Med. 1991. 325:293-302.
  3. Pitt B et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. 1999. 341:709-17.
  4. Velazquez EJ et al. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N. Engl. J. Med. 2018. :.
  5. Andronic AA et al. Heart Failure with Mid-Range Ejection Fraction - a New Category of Heart Failure or Still a Gray Zone. Maedica (Buchar) 2016. 11:320-324.
  6. 6.0 6.1 Cleland JGF et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur. Heart J. 2018. 39:26-35.