Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure.

Velazquez E.J., Morrow D. A., DeVore A.D., et al. for the PIONEER-HF Investigators

N Engl J Med 2019; 380:539-548; [Full Text]

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Summary by Colin Mcguire

Guideline directed medical therapy (GDMT) of heart failure with reduced ejection fraction (HFrEF) involves a combination approach. The earliest medication shown to benefit patients with HFrEF was beta-blockers, particularly bisoprolol, carvedilol, and metoprolol XL, shown in the CIBIS-II [1], COPERNICUS [2], and MERIT-HF [3]. The addition of ACE inhibitors (ACEi) or ARBs followed soon there after, demonstrated in CONSENSUS [4], SOLVD [5], and CHARM-Alternative [6]. A recent development in HFrEF management are ARB-neprilysin inhibitors (ARNI), which in PARADIGM-HF was associated with a reduction in CVD mortality and HF hospitalization compared to ACEi in patients with chronic HFrEF [7].

Neprilysin is an endopeptidase that breaks down BNP, bradykinin, and adrenomedullin. These molecules have a vasodilatory effect on blood vessel walls and are inhibitors of the renin-angiotensin system. Ultimately, inhibition of neprilysin results in decreased BNP, bradykinin, and adrenomedullin resulting in a reduced vascular remodeling, vasoconstriction, and renal sodium retention [7].

A caveat of the PARADIGM-HF study was the exclusion of all patients who had acute decompensated heart failure (ADHF). PIONEER-HF looked at the effect of ARNI initiation in patients with ADHF compared to an ACEi. This distinction is important on multiple fronts: firstly, does the initiation of an ARNI improve a patient’s hospital outcome during an acute exacerbation of ADHF, is initiation safe during ADHF, and finally, should an ARNI be considered superior over an ACEi during ADHF. The study summarizes that the initiation of an ARNI during ADHF results in decreased NT-proBNP and is a well-tolerated medication; however, further research is needed to support the role of ARNI in the reduction of ADHF readmission. Regardless, the 2019 ACC Expert Consensus Decision Pathway does state that PIONEER-HF “provides evidence to support safety of careful initiation of sacubitril-valsartan for hospitalized patients” [8].

Patient Population

Eligible patients had to be 18 years or older, have a LVEF <= 40%, NT-proBNP >1600 pg/mL or BNP >400 pg/mL, have a diagnosis of acute decompensated heart failure and be currently hospitalized. Patients were excluded if there were signs of shock, including hemodynamic instability (systolic BP <100 mmHg) for 6 hours, increased need of IV diuretics for 6 hours and if IV inotropes were used during the hospitalization.

A total of 881 patients were recruited between 2016-2018 from 129 different medical centers in the U.S. Patients were randomly divided into the sacubitril-valsartan (N=440) arm and the enalapril (N=441) arm. The average age was ~62%, the majority were white (~58%) and male (70-74%), with mostly NYHA class III (61-64%) HF symptoms.


Patients were administered either sacubitril-valsartan (24mg or 49mg) or enalapril (2.5mg or 5mg) dose twice daily and either was titrated to a maximum of 97mg sacubitril-valsartan or 10mg enalapril twice daily; concurrently, a placebo was also administered to each. NT-proBNP was obtained daily during the 8-week period. Patients were followed up after the 8-week period at random to determine secondary outcomes. Demographic and clinical baseline characteristics were similar between the two groups.

The primary endpoint was the change of NT-proBNP at the end of the 8 weeks at the maximum tolerated dose for sacubitril-valsartan or enalapril. Secondary outcomes included all-cause mortality, rehospitalization for heart failure, LVAD implantation, heart transplant listing, need for rehospitalization with IV diuretics, and a composite of all previously mentioned secondary outcomes.

Adverse events were also analyzed during the 8-week hospitalization period. The adverse events were worsening renal function defined by elevations of serum creatinine and lowering of eGFR, hyperkalemia, symptomatic hypotension, and angioedema.


Intention-to-treat analysis of the primary outcome found a decrease in NT-proBNP in the patient group treated with sacubitril-valsartan compared to enalapril: decrease of -46.7% vs -25.3% ratio of change 0.7, 95% CI, 0.63 to 0.81; p<0.001, and the difference was evident even at 1 week (RR 0.85).

For secondary ans safety outcomes:

Secondary Outcome (sacubitril-valsartan vs. enalapril) HR
All-cause mortality2.3% vs. 3.4%0.66; CI 0.30-1.48
Rehospitalization for heart failure8.0% vs 13.8%0.56; CI 0.37-0.84
Implantation of an LVAD0.2% vs 0.2%0.99; CI 0.06-15.97
Inclusion on list for heart transplant0% vs 0%
Unplanned outpatient visits leading to IV diuretic use0.5% vs 0.5%1.00; CI 0.14-7.07
Composite of serious clinical events (all-cause mortality, rehospitalization, implantation of an LVAD, heart transplant listing, IV diuretic use)9.3% vs 16.8%0.54; CI 0.37-0.79

Adverse event(sacubitril-valsartan vs. enalapril)HR
Worsening renal function13.6% vs. 14.7%0.93; CI 0.67-1.28
Hyperkalemia11.6% vs. 9.3%1.35; CI 1.04-1.76
Symptomatic hypotension15.0% vs. 12.7%1.18; CI 0.85-1.64
Angioedema0.2% vs. 1.4%0.17; CI 0.02-1.38


This multicenter, double-blind, randomized, active-controlled trial demonstrated that in patients with ADHF, the addition of sacubitril-valsartan compared to enalapril decreased in NT-proBNP more (-46.7% vs -25.3% ) with similar rate of adverse events over the 8-week study period. In PARADIGM-HF, sacubitril-valsartan led to more symptomatic hypotension [7] . This was NOT observed in PIONEER-HF, likely because of patient selection and careful dose titration (see Figure S1, supplementary appendix).

Secondary outcomes were studied in a posthoc analysis of certain heart failure events. Notably, the rehospitalization for patients who are taking sacubitril-valsartan was less than those who are taking enalapril, 8.0% vs. 13.8%, HR 0.56. While statistically significant, as a secondary endpoint, further confirmation would be needed to confirm this observation.

There are limitations to PIONEER-HF, especially with the primary endpoint. NT-proBNP is a surrogate marker for clinical improvement and does not necessarily correlate to patient improvement, especially while hospitalized. Furthermore, as stated in the secondary outcomes data, the confidence interval is likely broader than the statistical analysis the authors initially intended. Overall, PIONEER-HF supports the initiation of an ARNI during ADHF and is supported by consensus ACC recommendations [8]. This is reasonable considering ARNI is already first line GDMT [9] for chronic HFrEF, but in either case (acute or chronic) the cost may be the limiting factor.

F: Follow up4 weeks and 8 weeks during hospitalization
R: RandomizationYes
I: Intention to treatYes
S: Similar at baselineYes
B: BlindingYes
E: Equal treatmentYes
S: Source (funding)Novartis

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