PIONEER-HF: In-Hospital ARNI Shows Biomarker Benefit vs ACE-I

CHICAGO — If sacubitril/valsartan (Entresto, Novartis) remains slow to catch on in chronic heart failure (HF), despite earning support in the guidelines after the PARADIGM-HF trial, a new randomized trial in hospitalized HF patients has given it another chance to win converts.

Levels of a prognostically important biomarker fell quickly after the patients, who had been stabilized after presenting with acute decompensated HF with reduced ejection fraction (HFrEF), were started in hospital on either sacubitril/valsartan or enalapril.

But the drops in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, sustained for the trial's 8 weeks, were significantly deeper in the group getting sacubitril/valsartan.

That newer agent, a conjoined complex of its two eponymous drugs and classified as an angiotensin receptor-neprilysin inhibitor (ARNI), also showed no signs of being less safe than the venerable angiotensin-converting enzyme (ACE) inhibitor in this setting.

In an exploratory analysis, the risk of rehospitalization for HF significantly declined in the sacubitril/valsartan group compared with those getting enalapril during the 8-week study, although it wasn't powered for clinical outcomes.

The trial, called Comparison of Sacubitril-Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF), was published in the New England Journal of Medicine to coincide with presentation here at the American Heart Association (AHA) Scientific Sessions 2018.

The findings bolster support for the strategy of initiating sacubitril/valsartan in stabilized patients who had presented with acute decompensated HF "regardless of prior ACE inhibitor use or prior HF diagnosis," said Eric J. Velazquez, MD, Yale University, New Haven, Connecticut, after unveiling the results.

Of randomized patients, 34% had no prior HF history and 52% were naive to ACE inhibitors and angiotensin-receptor blockers (ARBs), he noted. It was more ethnically diverse than many HF trials; about 36% of the cohort was African American.

Underuse Despite Its Credentials

Four years ago, PARADIGM-HF saw a 20% fall in the primary endpoint of cardiovascular (CV) death or HF hospitalization in its chronic HFrEF patients who took sacubitril-valsartan compared with those on enalapril. There was also a 16% decline in all-cause mortality on the newer agent. Both differences were significant at P < .001.

More recently, the smaller TRANSITION study demonstrated the safety and feasibility of starting sacubitril/valsartan during hospitalization for decompensated HF.

But sacubitril/valsartan is grossly underused in practice despite boasting a class I recommendation in HF guidelines, Larry A. Allen, MD, MHS, University of Colorado School of Medicine, Aurora, told theheart.org | Medscape Cardiology. Registry data, he said, suggest that it is prescribed to less than 15% of eligible patients.

Clinicians have been hesitant to switch their patients on ACE inhibitors or ARBs over to sacubitril/valsartan, perhaps because the new drug is more costly, or possibly because its guideline indication was supported by only one randomized, placebo-controlled trial. Or, said Allen, it could be simply that clinical inertia heavily favors the far more familiar ACE inhibitors and ARBs.

"So PIONEER-HF comes into this setting as a major success," he said, one he believes will change practice now that there is a second major trial giving it the edge over an ACE inhibitor in HFrEF.

Safe To Switch

PIONEER-HF, observed James L. Januzzi Jr, MD, Massachusetts General Hospital, Boston, is in large part "a test of switching from an ACE inhibitor or ARB, after stabilization, to sacubitril/valsartan," and doing it without causing excess hypotension or other complications.

"It opens the door to switching patients to sacubitril/valsartan when they have presented with acute heart failure, which importantly is a time when patients are most receptive to therapy changes," Januzzi, who isn't involved in PIONEER-HF, said when interviewed.

Although exploratory outcomes can't be conclusive, he said, it's worth noting that patients who started on sacubitril/valsartan "had a rapid and substantial reduction in natriuretic peptide concentrations, which translated into a reduction in clinical events, in a very short period of time. That should not go unrecognized."

In PARADIGM-HF, he pointed out, NT-proBNP levels "were a perfect predictor of the benefits of sacubitril/valsartan." Now in PIONEER-HF, those levels dropped further on the newer drug than on enalapril in association with the exploratory clinical-outcomes improvements. "The dots can be connected here."

"I would propose that the PARADIGM-HF study showed that switching is worthwhile. What PIONEER shows is that switching, or starting it de novo, in acute heart failure is safe," he said.

The additional randomized trial might help with acceptance too. Some eyebrows were raised when sacubitril/valsartan became guideline-recommended in HFrEF after a single big trial, but "now we have a very effective, well-performed second randomized controlled trial showing a benefit of the ARNI compounds in the setting of heart failure," agreed Clyde W. Yancy, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

PIONEER-HF, said Yancy, also not connected with the study, has identified another HF "sweet spot" for recommending sacubitril/valsartan. "In PARADIGM-HF it was ambulatory class 2 and 3 with a stable blood pressure. With PIONEER-HF it's going to be the ambulatory patient in the hospital who isn't getting vasoactive drugs and who is anticipating discharge."

Velazquez said when interviewed that a large clinical-outcomes trial using the PIONEER-HF strategy of predischarge initiation of sacubitril/valsartan may never be conducted.

Patients like those entered into PIONEER-HF, once they complete their 8 weeks of sacubitril/valsartan, become like PARADIGM-HF patients, he pointed out. "You could argue the ethics of doing a long-term study, because PARADIGM-HF has already been published and the guidelines changed to support its findings."

Stabilized Acute HF

PIONEER-HF entered 887 adults with LVEF ≤ 40% within the prior 6 months and NT-proBNP levels > 1600 pg/mL or BNP > 400 pg/mL who presented with acute decompensated HF. They had to have been stabilized in hospital without symptomatic hypotension and no increased need for IV diuretics, vasodilators, or inotropes.

They were randomly assigned at 129 US sites to receive sacubitril/valsartan uptitrated up to the equivalent of 97 mg of the first agent and 103 mg of the second drug twice daily, or enalapril uptitrated to 10 mg twice daily, both for 8 weeks. Treatment began a median of 68 hours after presentation.

The ratio of the geometric mean of NT-proBNP concentrations at weeks 4 and 8 to the baseline value, the study's primary endpoint, was 0.53 in the sacubitril/valsartan group and 0.75 in enalapril group, for a ratio of change of 0.71 (95% CI, 0.63 - 0.81; P < .0001).

NT-proBNP levels fell off significantly more in the sacubitril/valsartan group even by the first week of treatment. The ratio of change for the newer drug versus enalapril at 1 week was 0.76 (95% CI, 0.69 - 0.85).

Parameters	Ratio (95% CI)
Efficacy Outcomes	Ratio of Change
Change in hs-Troponin T	0.85 (0.77 - 0.94)
Change BNP – NTproBNP Ratio	1.48 (1.38 - 1.58)
Clinical Outcomes	Hazard Ratio
Death	0.66 (0.30 - 1.48)
HF Rehospitalization	0.56 (0.37 - 0.84)
Composite Outcomes*	0.54 (0.37 - 0.79)

*Death, HF rehospitalization, ventricular-assist pump implantation, or transplantation listing

The newer drug's advantages over enalapril were consistent throughout all predefined subgroups, including those with or without prior HF and with a history or no history of prior ACE inhibitors or ARBs.

Rates of worsening renal function, hyperkalemia, and symptomatic hypotension weren't significantly different between the two groups. There was one confirmed angioedema event in the sacubitril/valsartan group (0.2%) and six (1.4%) in the enalapril group, according to the published report.

"We've never had a positive 'hospitalized heart failure' trial. We have one now," Yancy said. Even if it doesn't change everyday clinical practice, "it certainly is enough to drop some of the inertia against the use of the ARNI compound and explore the potential benefit of providing the ARNI compound during the hospitalization experience."

PIONEER-HF was supported by Novartis. Velazquez has reported receiving research grants from Novartis, Amgen, Pfizer, and Alnylam, and serving as a consultant or on an advisory board for Novartis, Amgen, and Philips. Allen has reported serving as a consultant or on an advisory board for ACI Clinical, Boston Scientific, Janssen/J&J, and Cytokinetics/Amgen. Januzzi has reported receiving research grants and other research support from Roche Diagnostics, Singulex, Abbott, Prevencio, Cleveland Heart Labs, Boehringer Ingelheim, Janssen, AbbVie, and Alere; and serving as a consultant or on an advisory board for Roche Diagnostics, Corvidia, Abbott, Critical Diagnostics, and MyoKardia. Yancy has reported no relevant financial relationships.

American Heart Association (AHA) 2018 Scientific Sessions. Abstract LBS.05. Presented November 11, 2018.

N Engl J Med. Published online November 11, 2018. Full text

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