PIONEER-HF: Sacubitril/Valsartan Safe and Effective in Acute Decompensated Heart Failure

CHICAGO, IL—Treating acute decompensated heart failure (HF) patients with an angiotensin receptor/neprilysin inhibitor (ARNI), a combination that includes valsartan and sacubitril (Entresto; Novartis), significantly reduces N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and reduces the risk of serious clinical events, according to the results of the PIONEER-HF study.

Presented today at the American Heart Association 2018 Scientific Sessions and published simultaneously in the New England Journal of Medicine, the study showed the clinical benefit was driven by a 44% reduction in HF rehospitalizations. In addition, the sacubitril/valsartan was well tolerated, with comparable rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema when compared with enalapril alone. 

For lead investigator Eric Velazquez, MD (Yale University School of Medicine, New Haven, CT), as long as acute HF patients are medically stable, the PIONEER-HF data may mark a new era for the management of acute decompensated HF. “It’s a new strategy where once you have diagnosed a patient, stabilized them hemodynamically, these data would support earlier initiation of sacubitril/valsartan, starting them in hospital and continuing long-term,” Velazquez told TCTMD.

The long-term continuation of sacubitril/valsartan is not based on their study but rather on the PARADIGM-HF trial, a study that shook up the field when it was published in 2014. In that landmark study, which included stable HF patients with reduced ejection fraction, treatment with sacubitril/valsartan significantly reduced the risk of the combined endpoint of cardiovascular causes and HF hospitalization compared with enalapril. On its own, cardiovascular mortality was reduced 20% in the sacubitril/valsartan-treated patients.

Larry Allen, MD (University of Colorado School of Medicine, Denver), who was not involved in PIONEER-HF, said there is a need for medical therapies in the acute decompensated HF setting.

“If you contrast the medication successes in heart failure with reduced ejection fraction, there are a number of randomized trials in ambulatory patients that support the use of ACE inhibitors, ARBs, beta-blockers, and mineralocorticoid receptor antagonists in this population,” said Allen. “Yet if you go to the hospital setting, there has been very little looking at the initiation and intensification of these drugs in that population.”  

And yet the management of hospitalized HF patients is “where the action happens,” said Allen, noting that these patients are a captive audience for starting treatment and that the transition after discharge can be fragile. “So PARADIGM-HF, while a major success, recapitulated this conundrum we have with inpatient versus outpatient data,” said Allen. He added that even in the outpatient setting, the uptake of sacubitril/valsartan remains low despite the class I indication in HF patients with reduced ejection fraction.

James Januzzi, MD (Massachusetts General Hospital, Boston), who serves on the American College of Cardiology board of trustees, stressed that the PIONEER-HF trial should not be viewed as an acute HF trial, per se, given that patients were medically stabilized. That said, the study answers a critical question about the role of neprilysin inhibitors in patients with decompensated HF.

“Really, there is no better time to initiate and intensify lifesaving chronic therapy for patients than when they are in the hospital,” Januzzi told TCTMD. “They are receptive to changes in their therapy, they’re more willing to learn about the therapies they’re receiving, and compliance is better when therapies are initiated at the time of decompensation. The problem was that sacubitril/valsartan had been studied in PARADIGM-HF, where initiation was done in a very stable population.”

PIONEER Bridges Gap to PARADIGM

The PIONEER-HF study included 881 HF patients with reduced ejection fraction and elevated NT-proBNP concentrations with a primary diagnosis of acute decompensated HF. Study inclusion criteria required all patients to be stabilized before randomization, with stabilization defined as a maintained systolic blood pressure of at least 100 mm Hg and no increase in the use of intravenous diuretics/no use of intravenous vasodilators in the preceding 6 hours, as well as no use of intravenous inotropes during the preceding 24 hours.

There was a 29% reduction in the primary endpoint—defined as the proportional change in NT-proBNP from baseline to the mean of concentrations at weeks 4 and 8—among patients treated with sacubitril/valsartan (n = 440) compared with enalapril (n = 441). Regarding the clinical endpoint, there was a 46% reduction in death, HF rehospitalization, need for a left ventricular assist device, or transplant, a benefit that was driven by reductions in HF hospitalizations.

To TCTMD, Januzzi said that because sacubitril/valsartan is a more potent agent than other drugs used in this setting, particularly its antihypertensive effects, there had been some initial safety concerns about safety, but there were no notable concerns in the trial. “Interestingly, the most-feared complication of sacubitril/valsartan, that being angioedema, occurred in only one patient compared with six patients in the enalapril arm,” said Januzzi. “The study definitively shows that changing patients to this lifesaving therapy, even in the context of acute heart failure, is safe and has a substantial impact on natriuretic peptides.”

The “icing on the cake,” said Januzzi, is the reduction in clinical events, particularly the reduction in HF rehospitalizations. Although the PIONEER-HF is not powered for outcomes, there is consistency with the primary biomarker endpoint, safety outcomes, and clinical outcomes, he said.

Starting Patients on the Drug They’re Going to Take 

To TCTMD, Velazquez said that when designing PIONEER-HF, the researchers were constrained by the positive data from the PARADIGM-HF study. For this reason, they felt it was too challenging, possibly unethical, to continue to treat PIONEER-HF patients long-term with enalapril and deny them access to sacubitril/valsartan. So they kept the duration of the study short and selected a surrogate biomarker as the primary endpoint.

“We thought that [our] information, coupled with the long-term data from PARADIGM-HF that had just come up, might be sufficient,” said Velazquez. “My perspective is that it is. Will there be a large outcome trial in acute heart failure with sacubitril/valsartan? I don’t think it’s going to necessarily be the case. We now have these data which are very consistent and supportive of initiation in acute heart failure. Basically, when the PIONEER patient stops, that patient is essentially a PARADIGM patient now. That was the context of our study design.”

Allen noted that switching from enalapril to sacubitril/valsartan can be tricky, requiring a 36-hour delay, which might partially explain the physician inertia. However, given the positive PIONEER data, Allen believes it offers physicians a simpler treatment algorithm for inpatient care.

“The primary endpoint was a surrogate, but I will say that the NT-proBNP changes correlated impressively with secondary endpoints and these findings are consistent with what we saw in the outpatient setting in PARADIGM,” said Allen, “The post-PIONEER world is exciting. It’s a simple, or at least simpler algorithm, for inpatients and the subsequent outpatient management for HF with reduced ejection fraction. It’s easier for us to start with the therapy we want them to be on and easier for patients to be on the drug they are going to take.”