Sacubitril/Valsartan Not More Effective Than Valsartan alone in Advanced HF: LIFE trial

Key Points:

• This is the first study to assess the effects of Sacubitril/Valsartan in patients with advanced heart failure with reduced ejection fraction.
• No difference was found between Valsartan and Sacubitril/Valsartan when assessing the change in NT-proBNP levels from baseline in this sicker population.
• The two drugs had similar efficacy and tolerability profiles, with the exception of higher rates of hyperkalemia in the Sacubitril/Valsartan arm.

The adoption of Sacubitril/Valsartan for the treatment of heart failure has grown tremendously since PARADIGM-HF showed favorable effects of the drug on mortality and heart failure readmission. While approved for all patients with systolic heart failure, its effects on those with advanced heart failure remained unknown.  Less than 1% of the participants enrolled in the trial had New York Heart Association Class IV symptoms, likely due to concerns about tolerance and morality. To assess this important population, Dr. Douglas Mann, Professor of Medicine, Washington University in St. Louis, and coinvestigators designed the LIFE trial,( NCT02816736) the results of which were presented May 17 in a Late Breaking Clinical Trial session at the 2021

American College of Cardiology Scientific Sessions.

LIFE attempted to address the gap in knowledge by only enrolling patients with advanced HF. In this 24-week, prospective, double-blinded active comparator trial, 335 participants with advanced heart failure with reduced ejection fraction were randomized in a 1:1 fashion to receive sacubitril/valsartan or valsartan alone. The enrollment criteria differed significantly from PARADIGM-HF. Participants were required to have:

• LVEF ≤ 35%
• Systolic blood pressure > 90 mmHg
• eGFR > 20 mL/min/1.73m²
• NYHA Class IV symptoms
• BNP ≥ 250 pg/mL or NT-proBNP ≥800 pg/mL

To ensure that the above truly captured a sicker population, the investigators required one more objective findings of advanced HF: recent or current inotrope use, one or more recent hospitalizations for heart failure, an LVEF ≤ 25%, or severe functional limitation on exercise testing.

After a run-in period to assess tolerability of sacubitril/valsartan, participants were randomized and received low doses of either drug for 4 weeks, after which their doses were titrated to the maximum tolerated dose.

The primary endpoint was not mortality, but a change in NTpro-BNP levels at 24 weeks. Secondary endpoints included days alive and free from heart failure events, as well as drug tolerability.

While the original protocol called for 400 participants to adequately power the study, enrollment was cut short due to the COVID-19 pandemic, and only 335 participants were randomized. At 24 weeks, there was no difference between groups. 25% of participants were women, and 40% were not white. They reflected a sicker heart failure population, with a mean LVEF of 20% in either group, NT-proBNP close to 2000 pg/mL.

At 24 weeks, neither arm significantly changed NT-proBNP levels from baseline. Sacubitril/Valsartan was associated with higher rates of cardiovascular death and heart failure hospitalizations, but this did not meet statistical significance. The study drug did have a significantly higher adverse event rate with respect to hyperkalemia, but this did not have clinical relevance.

“Sacubitril/Valsartan has been such an exceptional drug for our patient population, especially in those with NYHA Class II and III symptoms, so the heart failure community had been hoping for positive results in anticipation of this trial” says Dr. A. Reshad Garan, Director of Heart Failure and Mechanical Circulatory Support at Beth Israel Deaconess Medical Center. “What these data show more than anything is by the time patients advance to the point of meeting these entry criteria, it is time to consider non-medical options and advanced therapies. Despite some major advancements to heart failure therapies in the past decade, we are not yet at a place where medicine alone can turn back the clock and reverse the course of advanced disease.”  Dr. Garan explained that in his clinical experience many patients with advanced heart failure are unable to

tolerate higher doses of RAAS-inhibitors, which could help explain the trial’s negative results, a sentiment shared by the panelists in the May 17 Late Breaking Clinical Trials session.

The authors recognize that their study was limited by short term-term follow up and low enrollment, as affected by the COVID-19 pandemic. Despite this, they filled the gaps in knowledge left by PARADIGM-HF: namely, how Sacubitril/Valsartan holds up against an angiotensin-receptor blocker used in contemporary heart failure treatment, and whether patients with advanced heart failure would tolerate the medication.