PARAGLIDE HF: Clinical Impact of ARNI on HFmrEF or HFpEF Patients after Worsening HF

Stable HF patients (age ≥18 years; n=466) were enrolled within 30 days of a WHF event.

The study participants had EF >40% and elevated amino terminal pro–B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide.

Patients needed to be medically stable [systolic blood pressure (SBP) >100 mmHg for the preceding 6 hours, no increase in intravenous diuretic agents or use of intravenous vasodilators within the last 6 hours, and no intravenous inotropes following acute WHF episode], for 24 hours before randomization.

A double-blind, multicenter (conducted across 100 centers in America and Canada), randomized controlled trial.

Patients were randomized 1:1 to receive Sac/Val (titrated to a target dose of 97/103 mg twice daily; n=233) vs. Val (titrated to 160 mg twice daily; n=233)

A time-averaged proportional change in NT-proBNP from baseline through weeks 4 and 8

time to cardiovascular (CV) death 

number and timing of HF hospitalizations during follow-up

number of urgent HF visits during follow-up

time-averaged proportional change in NT-proBNP

Cumulative number of recurrent CV composite events (the total number of HF hospitalizations, urgent HF visits, and CV death)

Incidences of a composite endpoint of worsening renal function (renal death, reaching end stage renal disease or ≥50% decline in estimated glomerular filtration rate (eGFR) relative to baseline. 

Incidence of adverse events (AEs)

Mean age of the study population was 70 years, 52% of them were women, median EF of the study population was 55%, 33% had de novo HF, and median screening NT-proBNP was 2009 pg/ml. 

The mean duration of follow-up was 7.9 and 5.9 months in Sac/Val and Val groups, respectively.

Of the entire study population, 19.1% (n=89) did not contribute to the primary outcomes due to missing data at baseline, week 4 or week 8.

Patients treated with Sac/Val vs. those treated with Val had a 15% reduction in NT-proBNP levels [Ratio of change; 0.85, 95% confidence interval (CI) 0.73-0.999, p=0.049). Greater reduction in NT-proBNP with Sac/Val was evident as early as week 1 of randomization. 

The effect of Sac/Val was generally consistent across prespecified patient subgroups including in patients with worsening chronic HF, with de novo HF, or irrespective of baseline systolic blood pressure [SBP) <110/ ≥110 mmHg]. A pattern of an insignificantly larger treatment effect was observed in the patient subgroup with EF below normal (≤60%) (Pinteraction=0.033). Specifically, the ratio of change was 0.78 (95% CI: 0.65-0.93) in the patients with EF ≤60% and 1.17 (95% CI: 0.86-1.59) in those with EF >60%.

The win ratio for the hierarchical outcome was numerically in favor of patients treated with Sac/Val vs. those treated with Val but was not statistically significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P=0.16).

Patients with EF ≤60% exhibited an unmatched win ratio of 1.46; 95% CI: 1.09-1.95).

The recurrent composite CV events reduced by 17% in Sac/Val-treated vs. Val-treated patients [rate ratio (RR): 0.83, 95% CI: 0.57-1.23]. The recurrent CV events reduced by 39% in Sac/Val-treated vs. Val-treated patients with EF ≤60% (RR: 0.61, 95% CI: 0.37-1.01).

Treatment with Sac/Val reduced worsening renal function [Odds ratio (OR): 0.61; 95% CI: 0.40-0.93)] but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). 

Numerically fewer hypertension-related AEs and more hypotension-related AEs were observed in Sac/Val vs. Val treated patients.

Among HF patients with EF >40% stabilized after WHF, Sac/Val resulted in a greater reduction in NT-proBNP levels.

Sac/Val was clinically beneficial in terms of reduced CV events and renal events, compared with valsartan alone, despite a higher incidence of symptomatic hypotension.

The findings support a potential treatment benefit of Sac/Val in HF patients with EF >40% (particularly in those with EF below normal) and may impact the use of Sac/Val in this population, regardless of treatment setting or HF chronicity.