By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports he is a consultant for Alnylam Pharmaceuticals and Akcea Therapeutics.

SYNOPSIS: In patients hospitalized for acute decompensated heart failure with reduced ejection fraction, administering sacubitril-valsartan led to more improvement in levels of cardiac biomarkers compared to enalapril, with no adverse safety signals.

SOURCE: Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2018; Nov 11. doi: 10.1056/NEJMoa1812851. [Epub ahead of print].

In patients with heart failure with reduced ejection fraction (HFrEF), hospitalization for acute decompensated heart failure (ADHF) is common and associated with high morbidity and mortality. In a large clinical trial of ambulatory patients with HFrEF, initiation of sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was associated with significant improvements in mortality and rehospitalization. However, investigators have not evaluated the safety or efficacy of initiating sacubitril-valsartan among patients hospitalized for ADHF.

The authors of the PIONEER-HF trial enrolled patients with HFrEF during a hospitalization for ADHF. After hemodynamic stabilization, patients were randomized to sacubitril-valsartan (titrated to a target dose of 97/103 mg twice daily) or enalapril (target dose 10 mg twice daily). The primary endpoint was the change in N-terminal pro B-type natriuretic peptide (NT-proBNP) from baseline through eight weeks.

Investigators randomized 881 patients, 34% of whom presented with no prior history of heart failure and 52% of whom were naïve to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). Compared to patients randomized to enalapril, the reduction in NT-proBNP concentration was significantly greater in the sacubitril-valsartan group (46.7% reduction in the sacubitril-valsartan group vs. 25.3% reduction in the enalapril group; P < 0.0001). Sacubitril-valsartan also was associated with a significant reduction in the exploratory outcome of rehospitalization for heart failure. There were no significant differences in rates of worsening angioedema, symptomatic hypotension, hyperkalemia, renal function, or study drug discontinuation between the two groups. The authors concluded that among patients with HFrEF who are hospitalized for ADHF, administering sacubitril-valsartan was associated with a greater reduction in NT-proBNP concentration compared to enalapril, with no significant differences in key safety endpoints.


In the landmark PARADIGM-HF trial, sacubitril-valsartan was associated with a significantly lower risk of death from cardiovascular causes or hospitalization for heart failure compared to enalapril among ambulatory patients with chronic HFrEF who already were treated with ACE inhibitors or ARBs. The PIONEER-HF study adds to the evidence base supporting sacubitril-valsartan for treatment of HFrEF. Velazquez et al demonstrated that sacubitril-valsartan can be initiated safely in patients still hospitalized for ADHF, resulting in greater reductions in key cardiac biomarkers compared to enalapril.

The FDA approved sacubitril-valsartan in 2015. Current practice guidelines give a strong class Ia recommendation for its use in chronic HFrEF. However, use of sacubitril-valsartan remains somewhat limited, with the authors of large registry studies finding that as few as 15% of eligible patients actually receive the drug. Given the magnitude of benefit observed in PARADIGM-HF, this slow uptake is disappointing. There are many potential reasons why providers may choose not to prescribe sacubitril-valsartan, with uncertainty regarding possible side effects likely a significant concern. In this regard, the results of PIONEER-HF should be reassuring and make it difficult to argue that sacubitril-valsartan is riskier than tried-and-true ACE inhibitors.

Another important aspect of PIONEER-HF is the inclusion of patients who were naïve to ACE inhibitors or ARBs; this was the first large trial to evaluate the efficacy of sacubitril-valsartan in such patients. Subgroup analyses showed that patients benefited from sacubitril-valsartan regardless of prior ACE/ARB use. Therefore, the findings support de novo treatment with sacubitril-valsartan in HFrEF. Furthermore, providers can feel empowered to start sacubitril-valsartan in patients while they still are hospitalized. Hospitalization often provides an opportunity to reassess and improve a patient’s medication regimen.

A primary limitation of this study is the use of a surrogate endpoint (change in NT-proBNP) rather than a “hard” outcome such as death or rehospitalization. However, several clinical trials, including PARADIGM-HF, have demonstrated that changes in NT-proBNP levels are a powerful predictor of outcomes among this population. It also is important to remember that sacubitril-valsartan was initiated only when specific criteria were met. During the six hours preceding the initial dose, patients were required to register a systolic blood pressure of at least 100 mmHg, with no escalation of intravenous diuretics or use of intravenous vasodilators. Patients could not receive intravenous inotropes during the 24 hours before starting the study drug.

PIONEER-HF is an important clinical trial for everyone who treats HFrEF and could increase the use of sacubitril-valsartan in HFrEF. The findings should increase comfort with the safety profile of sacubitril-valsartan and encourage clinicians to at least consider initiating it in patients hospitalized for ADHF.