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

Background and 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 Both PARAGLIDE-HF and PARAGON-HF were multicenter, 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). Results 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=1,088; 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=5,262; 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). Conclusions 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.

Recurrent heart failure hospitalizations in heart failure with preserved ejection fraction: an analysis of TOPCAT trial

“…Therefore, the efficacy of HF therapies needs to be evaluated in the context of the total HFH burden. Late clinical trials, such as the PARAGON‐HF trial, the DELIVER trial, and the EMPEROR‐Preserved trial, which included recurrent HF events as an endpoint in their analyses, have found that angiotensin receptor‐neprilysin inhibitors and sodium‐glucose cotransporter 2 inhibitors reduce the overall HFH burden in patients with HFpEF 18–21 . HF is a complex clinical syndrome, and a single risk factor cannot accurately quantify the prognostic risk of patients.…”

Practical Approaches to the Management of Cardiorenal Disease Beyond Congestion

“…There is less evidence to support the benefit of RAASi in patients with HFpEF. However, in those with an LVEF <60%, the use of an MRA, ARNi, or angiotensin II receptor blockers (when an ARNi is not feasible) may be considered [34,35].…”

The utilization and impact of cardiovascular specialists on guideline‐directed medical scores: An analysis of a diverse, multi‐state, electronic health record‐based registry

“…Furthermore, clinical outcomes including mortality and readmission associated with escalation and de‐escalation of medical therapy could be analysed utilizing an EHR‐embedded GDMT score. Lastly, as evidence grows for the implementation of SGLT2i, MRA, and ARNI in HF with preserved/mildly reduced ejection fraction populations, the development of a composite score for non‐HFrEF patients could be the basis for future implementation work 8–11 . In this initial iteration of the score, medication intolerance was not factored in the tabulation of scores.…”