PIONEER-HF

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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 when compared to enalapril?

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

Beta-blockers and ACE inhibitors or ARBs are the backbone of HFrEF management. Earliest evidence for ACE inhibitors includes the CONSENSUS (1987) and SOLVD (1991) trials. ARBs are thought to have a similar effect, as shown in CHARM-Alternative (2003). More recently, ARB-neprilysin inhibitor (ARNI) may provide benefit over ACE-inhibitor as sacubitril/valsartan was associated with a 20% reduction in CVD mortality or HF hospitalization when compared to enalapril in PARADIGM-HF (2014). Patients with ADHF were excluded from PARADIGM-HF. Further, the safety of 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.

Published in 2019, the PIONEER-HF was a biomarker-endpoint trial that randomized 881 adults with ADHF and reduced EF to the ARNI sacubitril/valsartan or enalapril. Sacubitril/valsartan was associated with a greater reduction in NT-proBNP than enalapril (-47% vs. -25%). There were similar rates of adverse reactions in either group. The group also performed several exploratory (presumably post-hoc/hypothesis-generating) analyses of certain HF-relevant events, including rehospitalization. The authors note that the point estimate for rehospitalization suggested a benefit for the sacubitril/valsartan. The 95% confidence intervals did not include 1, which conventionally means that it achieves statistical significance. However, this was one of many endpoints in this exploratory analysis, which would typically invoke the use of wider confidence intervals to adjust for multiple comparisons.[1] The authors note this limitation on the footnote of Table 2 and that "inferences drawn from these intervals may not be reproducible."

Taken as a whole, PIONEER-HF supports the initiation of ARNI therapy during ADHF as it is associated with a reduction in the HF biomarker, NT-proBNP and is generally well-tolerated. Further research is needed to support the role of ARNI therapy to reduce ADHF readmissions.

Guidelines

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

Design

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

Population

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

Interventions

  • Randomized to enalapril or sacubatril-valsartan, with dosing determined by SBP at randomization, receiving placebo formulations resembling the other medication
    • Sacubatril-valsartan - Starting at 26/49 mg PO BID, eventually ramped up to 97/103 mg
    • Enalapril - starting at 2.5 or 5 mg, eventually ramped up to 10 mg po twice daily
  • Drug dosing adjusted to target by algorithm on SBP as well as side effects over 8-week trial period

Outcomes

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)

Additional Outcomes

Note: The WJC editors interpret the following analyses to be hypothesis-generating and recommend against interpreting a confidence interval not including 1 to represent statistical significance. The 95% confidence intervals were not adjusted for multiple comparisons and therefore do not reflect multiple-endpoint analytical best-practices.
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 0.37-0.84)
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)
Hyperkalemia
11.6% vs 9.3% (HR 1.35; 95% CI 1.04-1.76)
Symptomatic hypotension
15.0% vs 12.7% (HR 1.18; 95% CI 0.85-1.64)
Angioedema
0.2% vs 1.4% (HR 0.17; 95% CI 0.02-1.38)

Criticisms

  • Reduction in NT-proBNP is a surrogate endpoint and not a clinical endpoint.
  • Unclear cost-benefit analysis.
  • Given the high cost of the ARNI, real-world therapeutic adherence may be lower than in this trial, which may drive higher readmission rates.

Funding

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

Further Reading

  1. Chen SY et al. A general introduction to adjustment for multiple comparisons. J Thorac Dis 2017. 9:1725-1729.