Sacubitril/Valsartan, Valsartan Show No Difference in Reduction of NT-proBNP Levels


In patients with advanced heart failure, the median NT-proBNP AUC for valsartan was 1.19 compared to an AUC of 1.08 for sacubitril/valsartan.

Douglas L. Mann, MD

Douglas L. Mann, MD

A recent study aimed to test the hypothesis that sacubitril/valsartan is superior to valastratn alone, in lowering N-terminal pro brain natriuretic peptide (NT-proBNP) levels in patients with advanced heart failure and a reduced ejection fraction.

Led by Douglas L. Mann, MD, Department of Medicine, Washington University in St Louis, investigators observed no statistically significant difference between the combination sacubitril/valsartan and valsartan in the reduction of NT-proBNP levels in this patient population.


The LCZ696 in Advanced Heart Failure (LIFE) trial was a double-blind, randomized clinical trial that assessed tolerability, safety, and efficacy of sacubitril/valsartan compared with valsartan. Enrollment for the trial began in March 2017 and was suspended in March 2020, due to the high risk for adverse outcomes associated with COVID-19 infection.

As a result, the primary analysis was limited to patients randomized before December 2019, whose week 12 study visit occurred before March 2020, leading to a total of 335 patients.

Investigators defined advanced heart failure as follows: NYHA class IV symptoms, defined as chronic dyspnea or fatigue at rest within the previous 3 months, ≥3 months of guideline-directed medical therapy for heart failure, ejection fraction ≤35%, BNP level ≥250 pg/mL or NT-proBNP level ≥800 pg/mL.

Participants were randomized to receive sacubitril/valsartan with a target dose of 200 mg twice daily or valsartan with a target dose of 160 mg twice daily. They were then evaluated at 2, 4, 8, 12, and 24 weeks.

The primary efficacy outcome was identified as the area under the curve (AUC) for the ratio of NT-proBNP compared to the baseline, measured through 24 weeks of therapy. The secondary outcome included the number of days the patient was alive, out of the hospital, and free from cardiac events.


Out of the 335 patients included in the analysis, data show 245 were men (73%) with a mean age of 59.3 years. A total of 167 patients were randomized to sacubitril/valsartan and 168 patients were randomized to receive valsartan.

Investigators noted the study drug was discontinued in 49 patients (29%) receiving sacubitril/valsartan and 36 patients (21%) receiving valsartan (P = .10). The median total daily dose was 178.4 mg in the sacubitril/valsartan group and 138.6 mg in the valsartan group, with both at 48% of the target dosage.

By week 24 of treatment, the mean NT-proBNP level compared to baseline remained elevated over 8 weeks of therapy and decreased below baseline levels in both treatments arms. The median NT-proBNP AUC for the valsartan treatment arm was 1.19 (IQR, 0.91 - 1.64), compared to an AUC of 1.08 (IQR, 0.75 - 1.60) in the sacubitril/valsartan treatment arm.

For the primary endpoint, the estimated ratio of change in NT-proBNP AUC was 0.95 (95% CI, 0.84 - 1.08, P = .45). In terms of the secondary efficacy endpoint, the number of patient-days alive, out of the hospital, and without heart failure was numerically higher in the valsartan arm (median, 157.0), compared to the sacubitril/valsartan arm (median, 147.0).

The study noted no observed safety concerns, aside from a statistically significant increase in non-life threatening hyperkalemia in the sacubitril/valsartan arm (28 versus 15; P = .04).


“The interpretation of these results should take into consideration that LIFE is a phase 4 clinical trial and was underpowered to detect differences in clinical outcomes, as well as the understanding that the premature discontinuation of the trial because of the COVID-19 pandemic nominally reduced the statistical power of the trial,” investigators wrote.

The study, “Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction,” was published in JAMA Cardiology.

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