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Results of the LIFE trial suggest sacubitril/valsartan failed to outperform valsartan alone for multiple end points of interest, including reductions of NT-proBNP.
Data from the LIFE trial suggests sacubitril/valsartan provided no statistically significant difference compared with valsartan alone on reducing N-terminal pro–brain natriuretic peptide (NT-proBNP) in patients with advanced heart failure with reduced ejection fraction (HFrEF).
A double-blind randomized clinical trial in patients with NYHA class IV heart failure with a 24-week treatment period, results of the trial also suggest patients receiving sacubitril/valsartan experienced no improvements in the total number of days alive, days out of the hospital, and days that were free from complications of heart failure compared to those receiving valsartan alone.
“The evidence suggests that sacubitril/valsartan helps heart failure patients with mild or moderate heart failure but is no better than valsartan for patients with severe disease,” said Douglas L. Mann, MD, professor of medicine and professor of cell biology and physiology at Washington University School of Medicine in St. Louis, in a statement. “Although we were not able to show a benefit for sacubitril/valsartan in the LIFE trial, we believe that results of the trial will be helpful to the clinicians who provide care for this vulnerable population of advanced heart failure patients.”
Conducted across 38 centers from March 2, 2017, through December 7, 2019, the LIFE trial was designed as a prospective, multicenter, randomized, double-blind, double-dummy, active comparator phase 4 clinical trial with an interest in further describing the safety and efficacy of sacubitril/valsartan in patients with more advanced heart failure than were included in the PARADIGM-HF trial. The trial randomized 167 patients to receive sacubitril/valsartan and 168 patients were randomized to valsartan.
The mean age of patients included in the study was 59.3 (SD, 13.3), 27% were women, 60% were White, and 38% were Black. The study cohort had a median duration of heart failure was 4.3 (IQR, 1.6-10.1) years, the mean ejection fraction was 20.4% (SD, 6.5%), and the median baseline KCCQ overall score was 51.8 (IQR, 33.8-70.8). Investigators pointed out the groups were well-balanced except more patients in the sacubitril/valsartan arm had ischemic heart disease.
As a result of the COVID-19 pandemic and risks associated with COVID-19 infection, the statical analysis plan for the primary analysis was limited to patients randomized on or before December 7, 2019, and whose week 12 study visit occurred prior to March 1, 2020. As a result, the primary analysis included 335 patients.
When assessing the tolerability of sacubitril/valsartan, investigators observed 18% (n=72) of eligible patients were not able to tolerate 100 mg/d of sacubitril/valsartan during the run-in period and 29% (n=49) discontinued use during the 24-week treatment period. Upon analysis, results indicated the median NT-proBNP area under the curve (AUC) among patients in the valsartan arm was 1.19 (IQR, 0.91-1.64) compared to 1.08 (IQR, 0.75-1.60) among patients in the sacubitril/valsartan arm. Results also indicated the estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI, 0.84-1.08; P=.45).
Analysis of secondary outcomes of interest revealed use of sacubitril/valsartan was not associated with improvements in the composite of number of days alive, out of hospital, and free from heart failure events. Additionally, there were no observed safety concerns seen quirk use of sacubitril/valsartan except for a statistically significant increase in non-life-threatening hyperkalemia compared to users of valsartan (17% vs 9%; P=.04).
“For the most severe heart failure patients, sacubitril/valsartan does not appear to provide an advantage over valsartan, which is a generic drug that is far less expensive to use and was not associated with elevated potassium levels and thus is easier to monitor over time,” Mann added.
This study, “Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction,” was published in JAMA Cardiology.