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Velazquez EJ, et al. "Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure". The New England Journal of Medicine. 2018. ePub 2018-11-11:1-10.
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Clinical Question

In patients hospitalized with acute decompensated heart failure with reduced ejection fraction, does initiation of sacubitril-valsartan therapy reduce NT-proBNP levels?

Bottom Line

Sacubitril-valsartan therapy decreased NT-proBNP concentration compared to enalapril therapy at 4 and 8 weeks, without significantly different rates of medication related adverse effects.

Major Points

Several trials have investigated therapies for heart failure with reduced ejection fraction (HFrEF), including ACE inhibitors (ACE-I), beta-blockers, and mineralocorticoid receptor blockers. For example, the CONSENSUS[1] and SOLVD[2] trials found that enalapril led to a reduction in mortality for these patients. More recently, the PARADIGM-HF trial compared an angiotensin receptor-neprilysin inhibitor (ARNI) to enalapril in NYHA class II-IV HFrEF patients on optimal optical medical therapy including a beta-blocker and ACE-I/ARB. This study was stopped at 27 months after crossing a pre-specified boundary for benefit for the ARNI. The patients in the study were excluded if they were acutely decompensated, and it is unknown if ARNIs are safe for initiation during hospitalization for an acute decompensation. Current treatments for acute decompensated heart failure mainly consist of IV diuretics for volume overload.

The PIONEER-HF trial found that therapy with sacubitril-valsartan led to a decrease in concentration of NT-proBNP when compared to enalapril therapy in patients hospitalized for acute heart failure after hemodynamic stabilization. Clinical outcomes also seemed to improve with sacubitril-valsartan therapy, but those analyses were exploratory and not necessarily reproducible. There were no significant differences between the groups in the adverse events studied. Notably 20% of patients in both groups discontinued therapy in this population that was not selected for ability to tolerate high doses of enalapril and sacubitril-valsartan, unlike the PARADIGM-HF trial. Overall, this trial provides important information on the safety of sacubitril-valsartan and its effects on NT-proBNP concentration, but further trials are needed to determine if the reduction in NT-proBNP translates to improved clinical outcomes.


As of December 2018, no guidelines have been published that reflect the results of this trial.


  • Multicenter, double-blind, randomized, active-controlled trial
  • N=881
    • sacubitril-valsartan (n=440)
    • enalapril (n=441)
  • Setting: 129 centers in the United States
  • Enrollment: May 2016 to May 2018
  • Analysis: Intention-to-treat, with data through 8-week trial period
  • Primary outcome: time-averaged proportional change in NT-proBNP concentration from baseline through weeks 4 and 8


Inclusion Criteria

  • Age ≥18 years
  • LVEF ≤40%
  • NT-proBNP concentration of 1600 pg/mL or more, or BNP concentration of 400 pg/mL
  • Received primary diagnosis of acute decompensated heart failure, including signs/symptoms of volume overload
  • 24 hours to 10 days after presentation, while still hospitalized

Exclusion Criteria

  • Hemodynamically unstable: systolic BP < 100 mm Hg for preceding 6 hours
  • Increase in dose of IV diuretics and no use of IV vasodilators in preceding 6 hours
  • Use of IV inotropes during preceding 24 hours

Baseline Characteristics

  • Mean age: 61 (SD 14 years)
  • Sex: 72.1% male
  • Race: 35.9% black
  • 52.1% not receiving treatment with an ACEI/ARB
  • Previous diagnosis of heart failure: 65.4%
    • ≥1 hospitalization for heart failure during previous year of those with previous HF diagnosis: 59.5%
  • Median SBP: 118 mm Hg
  • Median NT-proBNP: 4812 pg/mL
  • Median BNP: 1063 pg/mL
  • Median duration of index hospitalization: 5.20 days


  • Randomized to enalapril or sacubatril-valsartan, with dosing determined by SBP at randomization
  • Patients also received placebo resembling non-assigned drug with each dose to ensure blinding
    • Sacubatril-valsartan targeting 97 mg and 103 mg, respectively, twice daily
      • This group received placebo pills for first two doses for 36 hour washout period
    • Enalapril 10 mg po twice daily
      • Received trial drug and placebo pill with first dose
  • Drug dosing adjusted to target by algorithm on SBP as well as side effects over 8-week trial period


Comparisons are sacubatril-valsartan vs enalapril.

Primary Outcomes

Time-averaged proportional change in NT-proBNP concentration from baseline through weeks 4 and 8
-46.7% vs. -25.3% (Ratio of change 0.71; 95% CI 0.63-0.81; P<0.001)

Secondary Outcomes

Change in high-sensitivity troponin T concentration
-36.6% vs -25.2% (Ratio of change 0.85; 95% CI 0.77-0.94)
NOTE: clinical outcomes analyses were exploratory, as confidence intervals were not adjusted for multiple comparisons and the trial was not powered for these outcomes.
All-cause mortality
2.3% vs 3.4% (HR 0.66; 95% CI 0.30-1.48)
Rehospitalization for heart failure
8.0% vs 13.8% (HR 0.56; 95% CI 0.56 0.37-0.84)
Implantation of left ventricular assist device
0.2% vs 0.2% (HR 0.99; 95% CI 0.06-15.97)
Inclusion on list for heart transplantation
0% vs 0%
Unplanned outpatient visit leading to use of IV diuretics
0.5% vs 0.5% (HR 1.00; 95% CI 0.14-7.07)
Composite of serious clinical events (death, rehospitalization for heart failure, implantation of left ventricular device, or inclusion on the list of patients eligible for heart transplantation)
9.3% vs 16.8% (HR 0.54; 95% CI 0.37-0.79)

Subgroup Analysis

Analyses were consistent across subgroups.

Adverse Events

Worsening renal function
13.6% vs 14.7% (HR 0.93; 95% CI 0.67-1.28)
11.6% vs 9.3% (HR 1.35; 95% CI 1.04-1.76; P=0.02)
Symptomatic hypotension
15.0% vs 12.7% (HR 1.18; 95% CI 0.85-1.64)
0.2% vs 1.4% (HR 0.17; 95% CI 0.02-1.38)


  • Representatives from the sponsor were on the steering committee, which was responsible for oversight and management of the trial.
  • Sacubitril-valsartan is a costly medication; it is not clear if a reduction in NT-proBNP is clinically meaningful in the absence of clinical outcomes data to outweigh financial cost to patients.


Novartis, the maker of Entresto (sacubatril-valsartan), funded the study.

Further Reading

  1. CONSENSUS Trial Study Group Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N. Engl. J. Med. 1987. 316:1429-35.
  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.