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Sacubitril/valsartan (Entresto) didn't appear to help patients with advanced heart failure in the LIFE trial when compared with an angiotensin receptor blocker alone.

The combination agent failed to improve N-terminal pro-B-type natriuretic peptides (NT-proBNP) as a marker of decongestion and reverse remodeling, with no difference in the area under the curve of levels over 24 weeks versus valsartan alone (P=0.45).

The researchers were "not only disappointed but surprised" to also find that sacubitril/valsartan tended to worsen heart failure hospitalization risk, Douglas Mann, MD, of Washington University School of Medicine in St. Louis, said at the virtual American College of Cardiology (ACC) meeting.

Days alive and out of the hospital without heart failure events came in at 103 versus 111 with valsartan alone (P=0.45). And there was a relative 32% increased risk of the combined endpoint of cardiovascular death or heart failure hospitalization (P=0.20), driven by a 24% increased risk of heart failure hospitalizations, albeit with wide confidence intervals.

"We stared at the data for a long time partly in disbelief," Mann told attendees at the late-breaking clinical trial session. While not powered for those clinical outcome endpoints, they consistently favored valsartan alone, he noted.

The landmark PARADIGM-HF trial that established sacubitril/valsartan's superiority for outcomes in chronic heart failure with reduced ejection fraction included very few New York Heart Association class IV patients.

"We've all been excited about using sacubitril/valsartan in daily use, but we had questions about how to use it in advanced heart failure, so we appreciate receiving some answers," noted ACC session study discussant Nancy Albert, PhD, CCNS, of the Cleveland Clinic.

Mann suggested clinicians look at the data and figure out for themselves how they will translate it to their prescribing patterns.

One possible explanation, he said, was that the need to maintain blood pressure and the renin-angiotensin system are so powerful that in the end "anything you try to do to paralyze it or override it ends up worsening outcomes."

Potentiation of counter-regulatory peptides that are substrates for neprilysin could have played a role, suggested session panelist Biykem Bozkurt, MD, PhD, of Baylor College of Medicine in Houston.

The included patients with class IV symptoms in the prior 3 months and on guideline-directed medical therapy for at least the same period who had elevated natriuretic peptides, a left ventricular ejection fraction of 35% or less, systolic blood pressure of 90 mg Hg or greater, and at least one additional objective finding of advanced heart failure, like recent heart failure hospitalization or inotrope use.

After a run-in period on low-dose sacubitril/valsartan, they were randomized to a low or moderate dose of sacubitril/valsartan or of valsartan, then titrated up for 24 weeks of double-blind treatment. Before the trial could reach the planned 400 participants, the pandemic interrupted enrollment. The researchers decided to halt enrollment at 335 patients and lower the statistical power modestly so that none of the clinical endpoints collected would be impacted by COVID-19 and patients would be safer.

Those decisions might have affected the results, but it's clear that sacubitril/valsartan wasn't better than valsartan alone, which ACC past president Mary Norine Walsh, MD, of St. Vincent Heart Center in Indianapolis, called disappointing.

"I think it means we have to be really very patient-centric in deciding for whom we prescribe sacubitril/valsartan and when," she told 番茄社区. "These patients had class IV, they were not necessarily hospitalized. But the strategy of starting sacubitril/valsartan in hospital has really become a strategy a lot of us are using. So I think we have to be exceedingly careful, especially for patients with a lot of comorbid disease and renal failure, in how we use this."

"We know from previous data that it's safe in those with more mild symptoms," she added. "So I think the message is really the timing of when we should start the therapy -- wait until the patient is decongested and has not had recent class IV symptoms."

However, Sanjeev Gulati, MD, of Sanger Heart & Vascular Institute in Charlotte, North Carolina, and an investigator on the trial, saw things a bit differently.

"Based on the LIFE study, I would not prescribe sacubitril/valsartan to patients with advanced heart failure," he told 番茄社区. It "reinforces the thought that the advanced heart failure patient is fundamentally and physiologically different than the less advanced heart failure patient. We still have a lot of work to do in terms of research of the advanced heart failure patient and finding therapeutic options for this critically ill patient population."

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