Efficacy and Safety of Sacubitril/Valsartan by Dose Level Achieved in the PIONEER-HF Trial

Abstract

Objectives: This study sought to evaluate the efficacy and safety of sacubitril/valsartan according to dose level achieved in the PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode) trial.

Background: In patients hospitalized for acute decompensated heart failure (ADHF), in-hospital initiation and continuation of sacubitril/valsartan as compared with enalapril is well tolerated, achieves a greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP), and reduces the risk of cardiovascular death or rehospitalization for HF through 8 weeks. However, not all patients achieve the target dose of sacubitril/valsartan, and its efficacy and safety in such patients are of interest.

Methods: PIONEER-HF was a randomized, double-blind, active-controlled trial of sacubitril/valsartan versus enalapril in 881 patients stabilized during hospitalization for ADHF. Blinded study medication was administered for 8 weeks, with initial dosing selected based on the systolic blood pressure at randomization and titrated toward a target of sacubitril/valsartan 97/103 mg twice daily, or enalapril 10 mg twice daily, with an algorithm based on systolic blood pressure and the investigator's assessment of tolerability.

Results: At 4 weeks, 199 (55%) patients allocated to sacubitril/valsartan and 211 (60%) patients allocated to enalapril were dispensed the target dose. Baseline characteristics were similar in the 2 treatment groups within each dose level. There was no heterogeneity across dose levels in the effect of sacubitril/valsartan on the reduction in NT-proBNP (pinteraction = 0.69), the reduction in cardiovascular death or rehospitalization for heart failure (pinteraction = 0.42), or the pre-specified adverse events of special interest through 8 weeks.

Conclusions: In hemodynamically stabilized patients with ADHF, the efficacy and safety of sacubitril/valsartan are generally consistent across dose levels. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).

Keywords: heart failure; hospitalization; sacubitril/valsartan.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Dosing algorithm of blinded study drug in the PIONEER-HF trial.

Dosing of blinded study drug was selected based on systolic blood pressure at randomization according to a prespecified algorithm. Titration of blinded study drug dose occurred at 1, 2, 4, and 6 weeks following randomization based on SBP and tolerability. SBP, systolic blood pressure.

Figure 2.. Distribution of study drug dose level achieved by study visit.

Shown are the proportions of each dose level dispensed among patients receiving study drug at each study visit. At week 4, 43% of patients remained on submaximal doses of study drug.

Figure 3.. Change in NT-proBNP concentration from baseline through 8 weeks post-randomization by dose of blinded study drug achieved at week 4.

The reduction in the proportional change in NT-proBNP concentration (logarithmic scale) from baseline through week 8 with sacubitril/valsartan was consistent across all dose levels achieved. The model is adjusted for age, systolic blood pressure, and race. NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Figure 4.. Change in NT-proBNP concentration over time among patients who remained at dose level 1 of blinded study drug at 4 weeks post-randomization.

The reduction in NTproBNP concentration with sacubitril/valsartan vs. enalapril was consistent in patients who remained on dose level 1 of blinded study drug at 4 weeks post-randomization. The model is adjusted for age, systolic blood pressure, and race. NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Central Illustration.. Effect of sacubitril/valsartan on clinical outcomes by 8 weeks post-randomization according to the dose of blinded study drug achieved at week 4.

KaplanMeier estimates of the clinical composite of cardiovascular death or rehospitalization for heart failure are shown. Treatment with sacubitril/valsartan, as compared with enalapril, significantly reduced the risk of cardiovascular death or rehospitalization for heart failure in patients who achieved the target dose of study drug and in those who did not.