Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF

Abstract

Aims: The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction.

Methods and results: Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61-0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75-0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43-1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P = 0.002).

Conclusion: In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.

Keywords: Angiotensin receptor–neprilysin inhibitor; Heart failure with mildly reduced ejection fraction; Heart failure with preserved ejection fraction; Sacubitril/valsartan.

Structured Graphical Abstract

A pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF. The primary endpoint for the pooled analysis was total worsening HF events and cardiovascular death. CI, confidence interval; CV, cardiovascular; ED, emergency department; NNT, number needed to treat; RR, rate ratio.

Figure 1

Cumulative incidence of total heart failure hospitalizations, urgent HF visits, and cardiovascular death. The cumulative incidence of the primary endpoint by study arm in both pooled analyses was visualized using the Nelson–Aalen estimator. Treatment effects of sacubitril/valsartan vs. valsartan are summarized as rate ratios with accompanying 95% confidence intervals. HF, heart failure; py, patient-years.

Figure 2

Treatment effects on primary endpoint across key subgroups in the primary pooled analysis of patients with recent worsening heart failure in PARAGLIDE-HF and PARAGON-HF. Treatment effects of sacubitril/valsartan vs. valsartan for the primary endpoint (total worsening heart failure events and cardiovascular death) are summarized as rate ratios with accompanying 95% confidence intervals. ACEi, angiotensin converting enzyme inhibitor; AFF, atrial fibrillation or flutter; ARB, angiotensin receptor blocker; BB, beta-blocker; BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist.

Figure 3

Treatment effect of sacubitril/valsartan vs. valsartan on the primary endpoint by left ventricular ejection fraction. CI, confidence interval; LVEF, left ventricular ejection fraction.

Figure 4

Cumulative incidence of the composite renal endpoint. The cumulative incidence of the composite renal endpoint (time to first occurrence of ≥50% decline in estimated glomerular filtration rate, end-stage renal disease, or renal death) was visualized using the Kaplan–Meier estimator. Treatment effects of sacubitril/valsartan vs. valsartan are summarized as hazard ratios with accompanying 95% confidence intervals. HR, hazard ratios; HF, heart failure.