PIONEER-HF: Efficacy and Safety of Sacubitril/Valsartan in ADHF Patients as per the Dose Level Achieved

27 Dec, 20

Introduction

In-hospital initiation and continuation of sacubitril/valsartan rather than enalapril is not only well tolerated, but also associated with a greater reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP), and reduced risk of cardiovascular (CV) death or rehospitalization for HF through 8 weeks in patients hospitalized for acute decompensated heart failure (ADHF). Nevertheless, all patients do not achieve the target dose of sacubitril/valsartan, and the benefits of sacubitril/valsartan administered below the target dose have not been established as of yet.

Aim

To evaluate the efficacy and safety of sacubitril/valsartan as per the 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.

Patient Profile

Patients (age ≥18 years; n=881) with reduced ejection fraction (EF) (left ventricular EF [LVEF] ≤40% and an NT-proBNP ≥1600 pg/ml or a B-type natriuretic peptide (BNP) ≥ 400 pg/ml
All patients had a primary diagnosis of ADHF, including signs and symptoms of fluid overload.
The enrollment period for patients ranged from no less than 24 hours up to 10 days after initial presentation to the hospital (median; 68 hours), while they were still hospitalized.
Patients were hemodynamically stable (defined as; maintenance of a systolic blood pressure [SBP] of ≥100 mm Hg for the preceding 6 hours, with no increase in the dose of intravenous [IV] diuretics and no use of IV vasodilators during the preceding 6 hours and no use of IV inotropes during the preceding 24 hours) before randomization.

Methods

Study Design

A subgroup analysis of the PIONEER HF trial

PIONEER HF was a multicenter, randomized, double-blind, active-controlled trial conducted across 129 sites in the US

Treatment Strategy

Post-washout period of 36 hours, patients were randomized to sacubitril/valsartan (n=440; initial dose: 24 / 26 mg or 49/ 51 mg twice daily) or enalapril (n=441:2.5 mg or 5 mg twice daily)
The study medications were up-titrated as follows to achieve a target dose of 97/103 mg twice daily for sacubitril/valsartan or 10 mg twice daily for enalapril:

Outcomes

This analysis assessed the following patient outcomes as per the dose level achieved at week 4 post-randomization

Efficacy Outcomes

The time-averaged proportional change in the NT proBNP from baseline through week 8
The composite of rehospitalization for HF or CV death

Safety Outcomes

Incidence of worsening renal function (defined as an increase in the serum creatinine concentration of ≥0.5 mg/dl and a decrease in the estimated glomerular filtration rate of ≥25% from baseline)
Incidence of hyperkalemia (serum potassium concentration of ≥5.5 mmol/l)
Incidence of symptomatic hypotension

Results

At week 4, post-randomization, 57% patients achieved target dose (55% patients on sacubitril/valsartan and 60% patients on enalapril), 24% received dose level 2 and 19% received dose level 1. As per a multivariable analysis, older age, lower baseline SBP, and white race were the significant predictors of not attaining the target dose by week 4 post-randomization.
The baseline characteristics did not differ between the two treatment groups within each dose level.
The proportion of NT-proBNP reduction remained consistent at week 8 regardless of the dose level, with sacubitril/valsartan providing superior reductions as compared to enalapril (overall hazard ratio [HR]; 0.72; p_interaction,0.67; Fig 1).

Fig. 1: Reduction in the proportional change in NT-proBNP levels by week 8 as per the dose achieved

Greater reductions in NT-proBNP concentrations with sacubitril/valsartan vs. enalapril were evident right from the beginning, and throughout the study even in the patients in whom the dose was not escalated beyond dose level 1.
There was a consistent reduction in rehospitalization for HF or CV death with sacubitril/valsartan vs. enalapril regardless of the dose level achieved at week 4 (overall HR; 0.58, 95% CI; 0.39-0.87, p_interaction=0.41; Fig 2)

Fig 2: Clinical outcomes in the study groups by week 8 as per the dose achieved

There was no heterogeneity across dose levels in the effect of sacubitril/valsartan with respect to the pre-specified adverse events (worsening renal function or hyperkalemia) through 8 weeks.
Patients achieving submaximal doses of the study drug had higher overall rates of symptomatic hypotension regardless of treatment group, nevertheless; the risk of symptomatic hypotension did not differ significantly with sacubitril/valsartan vs. enalapril across dose levels. In fact, a non-significant trend toward more frequent symptomatic hypotension with sacubitril/valsartan was evident only in patients achieving dose level 3

Conclusions

Amongst hemodynamically stabilized patients with ADHF, sacubitril/valsartan exhibited generally consistent efficacy and safety across various dose levels.
The findings support the in-hospital initiation and continued post-hospitalization use of sacubitril/valsartan broadly, including in patients who may not tolerate early up-titration to the target dose.

J Am Coll Cardiol HF 2020; 8:834–43.