Sacubitril/valsartan not superior to valsartan alone in advanced HFrEF: LIFE
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In patients with advanced HF, sacubitril/valsartan was not superior to valsartan for reducing N-terminal pro-B natriuretic peptide levels at 24 weeks, according to the results of the LIFE trial.
Results showed no differences in other efficacy, tolerability and clinical outcomes, except for a higher rate of hyperkalemia in the sacubitril/valsartan (Entresto, Novartis) group, Cardiology Today Editorial Board Member Douglas L. Mann, MD, Lewin Distinguished Professor in Cardiovascular Disease and professor of cell biology and physiology at Washington University School of Medicine in St. Louis, said during a presentation at the American College of Cardiology Scientific Session.
“We were surprised and disappointed, and stared at the data for a long time, partly in disbelief,” Mann, who is also past president of the Heart Failure Society of America, said during his presentation. “When we looked at all the endpoints, they consistently favored treatment with valsartan.”
Less than 1% of patients in PARADIGM-HF, the pivotal trial for sacubitril/valsartan in patients with HF with reduced ejection fraction, had NYHA class IV HF, so more information on tolerance and outcomes of sacubitril/valsartan in patients with advanced HF was needed, Mann said.
The LIFE trial included 335 patients with advanced HF (mean age, 59 years; 27% women). Enrollment was reduced from 400 after the trial was suspended in March 2020 due to concerns over the COVID-19 pandemic, Mann said. To be included, patients had to have NYHA class IV HF symptomatology for at least 3 months and left ventricular EF 35% or less, among other criteria.
Patients underwent a 3-to-7-day run-in of low-dose sacubitril/valsartan and those who could tolerate it were randomly assigned sacubitril/valsartan or valsartan for 24 weeks, with dosages varying based on the patient’s past ACE inhibitor or angiotensin receptor blocker dose and escalating after 4 weeks, Mann said.
The primary endpoint of area under the curve for the proportional change in NT-proBNP from baseline to 24 weeks did not differ between the groups (P = .45). Mann said neither sacubitril/valsartan nor valsartan decreased NT-proBNP below baseline levels at 24 weeks.
There was no difference between the groups in the secondary efficacy outcome of days alive out of the hospital free from HF events (sacubitril/valsartan, 103.2 days; valsartan, 111.2 days; P = .45) or the secondary tolerability endpoints of average daily dose of study drug, hypotension (P = .12) and worsening renal function (P = .99).
However, he said, the rate of hyperkalemia was higher in the sacubitril/valsartan group (17% vs. 9%; P = .035).
At 24 weeks, there was no difference between the groups in CV death or HF hospitalization (HR = 1.32; 95% CI, 0.86-2.03; P = .2) or HF hospitalization (HR = 1.24; 95% CI, 0.8-1.93; P = .33), Mann said, noting the study was not powered to detect differences in clinical outcomes.
“The results differ substantially from those of PARADIGM-HF,” Mann said. “The LIFE patients were far sicker, with lower blood pressure, worse renal function, lower ejection fraction, more AF and higher baseline NT-proBNP levels. The run-in period in LIFE was far shorter and used lower doses of sacubitril/valsartan than were required for randomization into PARADIGM. The comparator treatment arm in LIFE was valsartan, whereas enalapril was used in PARADIGM-HF. We believe the results of the LIFE trial are consistent with prior observations that as heart failure advances, chronic excessive activation of the renin-angiotensin system blunts or overrides the effects of natriuretic peptides on the heart, vasculature and kidneys.”
Perspective
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Jerry D. Estep, MD
Patients with advanced HF pose many management challenges, including intolerability to guideline-directed medical therapy, not uncommonly due to low BP. We cannot assume that patients with advanced or end-stage disease will respond similar to patients with less advanced disease.
A key takeaway from the LIFE trial is that about one-third of patients assigned to take sacubitril/valsartan were unable to tolerate the combination drug at the full dose used in previous trials due to side effects including low BP, dizziness and worsening renal function. We know dose matters: The higher dose tolerated, typically the better the outcome. In the LIFE trial, these patients took a reduced dose and neither this treatment nor valsartan decreased the median NT-proBNP levels below baseline, suggesting more work needs to be done to favorably alter the trajectory of patients that suffer from the degree of advanced HF examined in LIFE.
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Mann DL, et al. Late-Breaking Clinical Trials IV. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
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