Sacubitril/Valsartan in HFmrEF and HFpEF: PARAGLIDE-HF and PARAGON-HF Analyses

Quick Takes

  • In a pooled analysis of the PARAGON-HF and PARAGLIDE-HF studies, sacubitril/valsartan compared to valsartan reduced the composite CV endpoint of worsening HF and CV death (driven by worsening HF).
  • There were also reductions in the secondary composite renal outcome with sacubitril/valsartan compared to valsartan.
  • Early treatment benefit of sacubitril/valsartan was noted.

Study Questions:

In a pooled analysis of PARAGLIDE-HF and PARAGON-HF trials, what is the cardiovascular (CV) and renal impact of sacubitril/valsartan (SV) compared to valsartan in patients with heart failure (HF) with mildly reduced and preserved ejection fraction (EF)?


PARAGLIDE-HF and PARAGON-HF were multicenter, randomized controlled trials of SV vs. valsartan in patients with HF with mildly reduced EF (HFmrEF) and preserved EF (HFpEF). PARAGLIDE-HF included patients with EF >40% and a worsening HF (WHF) event in the last 30 days prior to enrollment. The primary endpoint was change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to weeks 4-8, with SV leading to a significantly larger reduction compared to valsartan. PARAGON-HF was a larger trial that included patients with EF ≥45%, evidence of structural heart disease, and elevated natriuretic peptide levels. The primary endpoint was a composite of total hospitalizations for HF and CV death; no statistically significant difference was seen between groups.

In this analysis, patients from PARAGLIDE-HF were pooled with a subset of patients from PARAGON-HF that also had a recent hospitalization for HF within 30 days prior to enrollment. In a secondary analysis, all patients from both studies were pooled to give a broader look at treatment effects. The primary endpoint was a composite of total WHF events (hospitalizations for HF and urgent HF visits) and CV death. A key secondary endpoint was a renal composite of ≥50% decline in estimated glomerular filtration rate (eGFR) from baseline, end-stage renal disease (ESRD), or renal death.


The primary pooled analysis of patients with a recent WHF event consisted of 1,088 patients (466 from PARAGLIDE-HF, 622 from a subset of PARAGON-HF). The secondary pooled analysis of all patients from the two trials included 5,262 patients (additional 4,174 patients from PARAGON-HF).

In the primary and secondary pooled analyses, SV compared to valsartan was associated with a significant reduction in the primary composite CV endpoint (primary analysis: rate ratio [RR], 0.78; 95% confidence interval [CI], 0.61-0.99; p = 0.042) (secondary analysis: RR, 0.86; 95% CI, 0.75-0.98; p = 0.027). In both analyses, no significant mortality differences were seen between treatment groups. No significant differences in subgroups were noted with the primary analysis. In the secondary analysis including all patients, the SV treatment benefit over valsartan favored patients with EF ≤60% (EF ≤60%: RR, 0.78; 95% CI, 0.66-0.91; EF >60%: RR, 1.09; 95% CI, 0.86-1.40; p for interaction = 0.0210). When assessing time to treatment benefit, the time to first nominal statistical significance in the primary analysis was 267 days (RR, 0.72; 95% CI, 0.52-1.00; p = 0.048) and in the secondary analysis was 9 days (RR, 0.20; 95% CI, 0.06-0.69; p = 0.011).

For the secondary renal composite endpoint, SV compared to valsartan was associated with a trend toward reduction in poor renal outcomes in the primary analysis (hazard ratio [HR], 0.67; 95% CI, 0.43-1.05; p = 0.080) and a significant reduction in the secondary analysis (HR, 0.60; 95% CI, 0.44-0.83; p = 0.002).

Regarding safety outcomes, SV compared to valsartan was associated with a trend toward increased symptomatic hypotension in the primary analysis (odds ratio [OR], 1.31; 95% CI, 0.96-1.77; p = 0.09) and a significant increase in the secondary analysis (OR, 1.50; 95% CI, 1.31-1.72; p < 0.001).


In this pooled analysis of HFmrEF and HFpEF patients in the PARAGLIDE-HF and PARAGON-HF trials, SV compared to valsartan was associated with a reduction in the primary composite CV endpoint of total WHF events and CV death.


Optimal treatment strategies for patients with HFmrEF and HFpEF are rapidly evolving. PARAGON-HF was published back in 2019 and narrowly missed achieving a statistically significant difference in its primary endpoint. However, subsequent analyses suggested benefit in patients with EF less than normal. The Food and Drug Administration did approve an expanded indication for SV based on these works, and the recent 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America HF guidelines reflect this with a Class 2b recommendation for angiotensin receptor-neprilysin inhibitor use (such as SV). PARAGLIDE-HF was recently published and focused on patients with recent WHF and included patients that may have been excluded from PARAGON-HF by allowing for lower blood pressure and eGFR cutoffs and eliminating body mass index restrictions and a medication run-in phase. This study met its biomarker-based primary endpoint, but did not reach CV secondary endpoints (not powered for this though). This provides context in understanding the usefulness of this pooled analysis and helps add to our understanding of SV’s role in HF management.

The study provides additional support for SV use in patients with HFmrEF and HFpEF across care settings, especially when EF is less than normal, for CV and renal benefits. Early benefits with SV initiation were also seen, suggesting early initiation is desired but comes with a risk of symptomatic hypotension. No clear difference in mortality was seen between groups, but this has been a challenging outcome to impact given the heterogeneity of the disease processes. With the emergence of SGLT2 inhibitors as well, it is encouraging to see progress being made to improve outcomes for HFmrEF and HFpEF populations.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Biomarkers, Glomerular Filtration Rate, Heart Failure, Hospitalization, Hypotension, Kidney Failure, Chronic, Natriuretic Peptide, Brain, Renal Insufficiency, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume, Valsartan

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