Trials Say Start ARNI in Hospital in HF, Below Normal LVEF

p>Patients with heart failure (HF) who are started on sacubitril-valsartan (Entresto) in the hospital or soon after discharge will see a sharp drop in clinical risk whether their ejection fraction is “reduced” or merely “below normal,” suggests a combined analysis of two major studies.

Short-term risk for cardiovascular (CV) death or HF hospitalization fell 30% for such patients put on the angiotensin-receptor/neprilysin inhibitor (ARNI) at that early stage, compared to those assigned to receive an ACE inhibitor or angiotensin receptor blocker (ARB).

Of note, the risk-reduction benefit reached 41% among the overwhelming majority of patients with a left ventricular ejection fraction (LVEF) of 60% or lower across the two trials, PIONEER-HF and PARAGLIDE-HF. No such significant benefit was seen in patients with higher LVEF.

The prespecified analysis of 1347 patients medically stabilized after a “worsening-HF event” was reported by Robert J. Mentz, MD, Duke Clinical Research Institute, Durham, North Carolina, on October 8 at the Heart Failure Society of America (HFSA) 2023 Annual Scientific Meeting in Cleveland, Ohio.

Across both studies, levels of the prognostically telling biomarker NT-proBNP dropped further in the ARNI group by almost a fourth compared to those getting an ACE inhibitor or ARB. The difference emerged within a week and was “similar and consistent” throughout at least 8 weeks of follow-up, Mentz said.

Sacubitril-valsartan is approved in the US for chronic HF, broadly but with labeling suggesting clearer efficacy at lower LVEF levels, based on the PARADIGM-HF and PARAGON-HF trials.

The PIONEER-HF and PARAGLIDE-HF trials lending patients to the current analysis demonstrated superiority for the drug vs an ACE inhibitor or ARB when started in hospital in stabilized patients with HF.

Cautions About Starting Sacubitril-Valsartan

In the pooled analysis, patients on sacubitril-valsartan were more likely to experience symptomatic hypotension, with a relative risk for drug’s known potential side effect reaching 1.35 (95% CI, 1.05 – 1.72) compared to ACE inhibitor or ARB recipients.

But the hypotension risk when starting the drug is manageable to some extent, observed Mentz. “We can safely start sacubitril-valsartan in the hospital or early post-discharge, but we need to make sure their volume status is okay” and keep track of their blood pressure (BP) trajectory, he told | Medscape Cardiology.

Those with initially low BP, unsurprisingly, seem more susceptible to the problem, Mentz said. In such patients “on antihypertensives or other therapies that aren’t going to give them a clinical outcome benefit,” those meds can be withdrawn or their dosages reduced before sacubitril-valsartan is added.

Such cautions are an “important take-home message” of the analysis, observed invited discussant Carolyn S. P. Lam, MBBS, PhD, National Heart Centre, Singapore, after the Mentz presentation.

Sacubitril-valsartan should be started only in stabilized patients, she emphasized. It should be delayed in those “with ongoing adjustments of antihypertensives, diuretics and so on,” in whom premature initiation of the drug may promote symptomatic hypotension. Should that happen, Lam cautioned, there’s a risk that such patients would be “mislabeled as intolerant” of the ARNI and so wouldn’t be started on it later.

The pooled PIONEER-HF and PARAGLIDE-HF analysis, Lam proposed, might also help overcome the “clinical inertia and fear” that is slowing the uptake of early guideline-directed drug therapy initiation in patients hospitalized with HF.

LVEF Spectrum Across Two Studies

As Mentz reported, the analysis included 881 and 466 patients from PIONEER-HF and PARAGLIDE-HF, respectively. Of the total, 673 were assigned to receive valsartan and 674 to receive either enalapril or valsartan. Overall, 36% of the population were women.

Patients in PIONEER-HF, with an LVEF 40% or lower, were started on their assigned drug during an acute-HF hospitalization and followed a median of 8 weeks. PARAGLIDE-HF patients, with LVEF higher than 40%, started therapy either in hospital (in 70% of cases) or within 30 days of their HF event; they were followed a median of 6 months.

Hazard ratios (HRs) for outcomes in the sacubitril-valsartan group vs those on ACE inhibitors or ARBs were 0.76; 95% CI, 0.69 – 0.83; P < .0001 for change in NT-proBNP levels. For the composite of CV death or HF hospitalization, HRs were as follows:

  • 0.70 (95% CI, 0.54 – 0.91, P = .0077) overall

  • 0.59 (95% CI, 0.44 – 0.79) for LVEF <60%

  • 1.53 (95% CI, 0.80 – 2.91) for LVEF >60%

Current guidelines, Mentz noted, recommend that sacubitril-valsartan “be initiated de novo” predischarge in patients without contraindications who are hospitalized with acute HF with reduced LVEF. The combined analysis of PIONEER-HF and PARAGLIDE-HF, he said, potentially extends the recommendation “across the ejection fraction spectrum.”

Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Lam has reported financial relationships “with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure,” as well as with Medscape/WebMD Global LLC.

Heart Failure Society of America (HFSA) 2023 Annual Scientific Meeting: Presented October 8, 2023.

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