PIONEER-HF: In Acute HF, Early Start to Sacubitril/Valsartan Seems Key to Best Clinical Gains

March 29, 2019

NEW ORLEANS — Patients with acute decompensated heart failure (ADHF) who start on sacubitril/valsartan (Entresto, Novartis) in the hospital and maintain it after discharge will show a continuous drop in natriuretic peptides over at least 3 months.

But the drug will likely cut the risk for heart-failure (HF) rehospitalization primarily in the first few weeks after its in-hospital initiation. Still, it will do it better than a standard ACE inhibitor like enalapril.

So concluded researchers from the PIONEER-HF trial based on its 4-week open-label extension study in combination with its preceding, and previously reported, primary 8-week double-blind comparison of the newer drug to enalapril.

The findings suggest that delays to starting treatment with sacubitril/valsartan, an angiotensin-receptor-neprilysin inhibitor (ARNI), will prevent the treatment from having its full potential clinical effect.

The PIONEER-HF trial as a whole demonstrates that it is safe to initiate sacubitril/valsartan in patients with ADHF in the hospital, Adam D. DeVore, MD, MHS, Duke Clinical Research Institute, Durham, North Carolina, told theheart.org | Medscape Cardiology.

"I don't think that the general sense was that it was a safe strategy before this trial to start vasodilators in the throes of decongestion."

Also, in the PIONEER-HF analyses combined, in-hospital initiation of sacubitril/valsartan, compared with enalapril, was associated with a 33% drop (P = .02) in 12-week risk for a composite clinical end point that was driven mostly by fewer HF hospitalizations in the first few weeks of the trial.

"The really vulnerable period for rehospitalization is early on," DeVore said during a panel discussion after his presentation of the PIONEER-HF open-label extension study here at the American College of Cardiology 68th Annual Scientific Session (ACC.19).

"My suspicion, although I can't prove it, is that's the important time. That's when we need to have them on the best therapy," he said, referring to the earliest days after admission with ADHF.

Because it's standard to initiate such therapy after hospital discharge, but nearly all the clinical risk seems to be in the first few weeks after discharge, "there's a lost opportunity to start it in the hospital to prevent readmissions and other outcomes," DeVore said in an interview.

He cautioned that PARADIGM-HF was statistically powered for safety and biomarker end points, but not clinical outcomes.

But the observed clinical end-point advantage seen for patients who started in-hospital sacubitril/valsartan, compared with enalapril, tracked closely with their steeper continuous decline in N-terminal pro-brain-natriuretic peptide (NT-proBNP) levels throughout the trial, Biykem Bozkurt, MD, PhD, said in an interview.

"We are seeing a reduction in NT-proBNP in acute heart failure patients early on, one that also appears to be accompanied by end-point benefits," said Bozkurt, a PIONEER-HF site investigator but not a coauthor on the primary study.

"I think seeing the concordance is quite promising," in that it suggests the natriuretic peptide decreases are "a potentially reliable surrogate" for improved clinical outcomes, said Bozkurt, from DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston.

In the primary PIONEER-HF trial, nearly 900 patients stabilized from ADHF and with a left-ventricular ejection fraction of 40% or less were randomly assigned double-blind to in-hospital initiation of sacubitril/valsartan or enalapril and followed out to week 8.

In the subsequent 4-week open-label phase with 94% of the original patients, the 417 patients who had been receiving sacubitril/valsartan continued on the drug and the 415 who had been on enalapril were switched to the ARNI.

As previously reported, NT-proBNP levels fell sharply in both groups within a week of starting treatment and continued to fall through week 8, although significantly further in the sacubitril/valsartan group.

From the start of the open-label phase at week 8, those switched from enalapril to sacubitril/valsartan showed a further 35.8% drop in NT-proBNP, whereas those who had continued on the drug showed an additional decrease of 18.5% from weeks 8 to 12 (P < .001 for the difference between groups).

Also as previously reported, the hazard ratio (HR) for the prespecified exploratory end point of death, HF hospitalization, use of a left-ventricular assist device (LVAD), or transplantation was 0.54 (95% CI, 0.37 - 0.79) at 8 weeks for those randomized to early sacubitril/valsartan vs enalapril.

The corresponding HR was 0.67 (95% CI, 0.48 - 0.94) at week 12 for those who started and maintained on sacubitril/valsartan vs those who had been switched from enalapril to sacubitril/valsartan at week 8.

In efforts to reduce heart-failure readmissions, a major focus has been on "trying to improve transitional care as people who are hospitalized then go home," DeVore said in an interview.

"We try very hard to prevent readmissions; it's one of the few things that everybody gets behind. Patients, families, clinicians, hospitals, payers — we're all on the same page. But there's very little evidence base for a lot of the things we do," he said.

"Well here's something that actually works," said DeVore, referring to early in-hospital initiation of therapies like those tested in PIONEER-HF. "And we just have to figure out how to get people to do it."

PIONEER-HF was supported by Novartis, from which DeVores discloses receiving consultant fees or honoraria and receiving research grants; he also discloses receiving research grants from Akros Medical, Amgen, Bayer Healthcare Pharmaceuticals, Intra-Cellular Therapies, and Luitpold Pharmaceuticals. Bozkurt discloses receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, Respicardia, and scPharmaceuticals; serving on a data safety monitoring board for LivaNova USA ; and having other unspecified relationships with Abbott Laboratories.

American College of Cardiology (ACC) 68th Annual Scientific Session: Abstract 402-10. Presented March 16, 2019.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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