LIFE: ARNI Does Not Best Valsartan in Advanced Heart Failure

Marlene Busko

June 08, 2021

Researchers were astounded to find that in patients with advanced heart failure (HF), the angiotensin-receptor neprilysin inhibitor (ARNI) sacubitril/valsartan was not superior to valsartan for efficacy, tolerability, or safety in the LIFE trial.

Douglas Mann

Compared with patients who received valsartan, those who received sacubitril/valsartan did not have a significantly lower area under the curve (AUC) for change in levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through 24 weeks, a surrogate for reverse cardiac remodeling and the primary study endpoint.

"We were surprised and disappointed and stared at the data for a long time, partly in disbelief," said Douglas L. Mann, MD, during a Late-Breaking Clinical Trial session at the virtual American College of Cardiology 2021 Scientific Session.

Nevertheless, "we know a lot more now about the safety and tolerability and efficacy for this remarkable class of drugs," said Mann, Lewin Distinguished Professor of Cardiovascular Disease, Washington University, St. Louis.

Although sacubitril/valsartan was approved for patients with New York Heart Association (NYHA) class II to IV heart failure on the basis of outcomes in PARADIGM-HF, only 1% of patients in that trial had NYHA class IV heart failure, so LIFE aimed to shed light on the drug's use in patients with advanced heart failure with reduced ejection fraction (HFrEF).

Compared with patients in PARADIGM-HF, "LIFE patients were far sicker, with lower blood pressure, worse renal function, lower LVEF [left ventricular ejection fraction], more atrial fibrillation, and higher baseline NT-proBNP," Mann pointed out. LIFE had a shorter drug run-in time with lower doses of sacubitril/valsartan, and it compared the ARNI with an angiotensin receptor blocker (ARB) as opposed to an angiotensin-converting-enzyme (ACE) inhibitor (enalapril).

"The results of the LIFE trial are consistent with prior observations that as heart failure advances, chronic excessive activation of RAAS [renin-angiotensin-aldosterone system] blunts or overrides the effect of natriuretic peptides on the heart, vasculature and kidneys," Mann concluded.

Results "Absolutely Surprising"

In a press briefing, panelist Gurusher Panjrath, MD, director of the heart failure and mechanical circulatory support program, The George Washington University Hospital, Washington, DC, said that the results were "absolutely surprising," and not what he would have predicted. This was a very good, informative trial that raised more questions that need further investigation, he summarized.

During the Late-Breaking Clinical Trial session, panelist Nancy M. Albert, PhD, said that "since 2014, when PARADIGM-HF was stopped early, and then after FDA approval, we've all been excited about using sacubitril/valsartan in daily use, but we've had questions about how to use it in advanced heart failure, so we appreciate receiving some answers."

"As healthcare professionals, what should we be considering when we interpret these results?" Albert, associate chief nursing officer, Office of Nursing Research and Innovation, Cleveland Clinic Health System, asked Mann.

Although the trial was not powered to say whether sacubitril/valsartan "is inferior, superior, or even the same" as valsartan for clinical outcomes in advanced heart failure, Mann said, "if you look at all the outcomes, they consistently favor treatment with valsartan."

Planned Enrolment Cut Due to COVID

LIFE researchers screened 462 patients at 38 centers and planned to enroll 400 patients. However, because of concerns about patient safety during the COVID-19 pandemic, enrolment was suspended on March 23, 2020, at 335 patients.

Eligible patients had to have NYHA class  IV symptoms, be on or intolerant to guideline-directed medical therapy in the previous 3 months, have an LVEF of 35% or less, a BNP of at least 250 pg/mL or NT-proBNP of at least 800 pg/mL, systolic blood pressure of at least 90 mm Hg, and at least one additional objective finding of advanced heart failure.

The researchers randomized 167 patients to receive sacubitril/valsartan and 168 patients to receive valsartan for 24 weeks.

The patients had a mean age of 59 years, 27% were women, 60% were White, and mean LVEF was 20%.

After a drug run-in phase, the patients entered a 4-week dose-titration phase, followed by a 20-week maximum-tolerated dose phase.

Neither treatment decreased median NT-proBNP levels below baseline through 24 weeks.

The AUC for the proportional change in NT-proBNP levels from baseline through 24 weeks was similar for patients in the two treatment groups (P = .45).

Drug efficacy, tolerability, and safety were similar in the two groups.

Drug efficacy, defined as a composite of days alive out of hospital and free from heart failure events, was 111 days in the valsartan group and 103 days in the ARNI group (= .45).

On average, in each group, patients took 48% of the targeted drug dose, 4% had worsening renal function, and about 15% had hypotension. However, more patients in the sacubitril/valsartan group than in the valsartan group had hyperkalemia (17% vs 9%; P = .035).

A quarter of the patients in each group had premature discontinuation of the study drug, a quarter had syncope or lightheadedness, and 1% of patients in the valsartan group but none in the ARNI group had angioedema.

The risks for cardiovascular (CV) death or heart failure hospitalization, or for heart failure hospitalization alone, were not significantly different in the two groups.

Study limitations include its small size, short duration, and lack of power to detect changes in CV death or HF hospitalizations, HF hospitalizations, CV death, or all-cause death, the researchers note.

Session panelist Biykem Bozkurt, MD, PhD, professor, Medicine-Cardiology, Baylor College of Medicine, Houston, congratulated Mann "on this very important study that raises quite a few questions."

She asked whether, in class IV heart failure, potentiation of peptides that are substrates for neprilysin, such as angiotensin I and endothelin, could play a role in potential adverse outcomes.

Mann replied that this might be a possible mechanism, but it's not currently known.

"Another really interesting question is the use of enalapril versus valsartan," he added. "I realize in overall heart failure trials we consider ARBs and ACE inhibitors to be the same," but "I don't know if we can say that in this particular patient population."

The study was funded by the National Institutes of Health, with additional support from Novartis Pharmaceuticals Corporation through an investigator-initiated trial program. Mann discloses receiving consultant fees/honoraria from MyoKardia, Novartis, and Novo Nordisk. Panjrath discloses receiving consultant fees/honoraria from CVRx and being on a speaker's bureau for Pfizer. Albert discloses receiving consultant fees/honoraria from Amgen, AstraZeneca, Boston Scientific, Merck, and Novartis. Bozkurt discloses receiving consultant fees/honoraria from Amgen, Relypsa/Vifor Pharma, and scPharmaceuticals; being on the data safety monitoring board for LivaNova; and having ties to Abbott Laboratories.

American College of Cardiology (ACC) 2021 Scientific Session: Session 410-12. Presented May 17, 2021.

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