Pooled analyses show cardiovascular and renal benefits with ARNI in HFpEF and HFmrEF

Sacubitril/Valsartan in HF with Mildly Reduced or Preserved Ejection Fraction: A Pre-Specified Participant-Level Pooled Analysis of PARAGLIDE-HF and PARAGON-HF

News - May 23, 2023

Presented at the ESC Heart Failure 2023 by: Muthiah Vaduganathan, MD- Boston, MA, USA

Introduction and methods

The PARAGLIDE-HF study, which was also presented at the ESC Heart Failure 2023, showed that sacubitril/valsartan reduced NT-proBNP in patients with HFpEF and HFmrEF with a recent worsening HF event. However, this trial was not designed or powered to assess clinical outcomes. The much larger study PARAGON-HF demonstrated a modest reduction with sacubitril/valsartan vs. valsartan in total HF hospitalizations and CV death, but did not meet statistical significance (RR 0.87, 95%CI 0.75-1.01, P=0.059). Post-hoc analyses of PARAGON-HF suggested a more pronounced benefit with sacubitril/valsartan in the subset of patients who were randomized within 30 days after a HF hospitalization (n=622).

To better estimate the efficacy of sacubitril/valsartan on clinical outcomes, two pre-specified participant-level pooled analyses of PARAGLIDE-HF and PARAGON-HF were conducted. The primary pooled analysis included 1088 patients who had a worsening HF event within 30 days of randomization (n=466 from PARAGLIDE-HF and n=622 from PARAGON-HF). The secondary pooled analysis included all participants from both studies (n=5262).

Both studies compared the efficacy and safety of sacubitril/valsartan vs. valsartan. The median follow-up was 0.5 years in PARAGLIDE-HF and 2.9 years in PARAGON-HF.

Main results

  • The primary pooled analysis in patients with recent worsening HF showed a significant reduction in the primary endpoint of total worsening HF events and CV death with sacubitril/valsartan compared to valsartan (rate ratio: 0.78; 95%CI: 0.61-0.99; P=0.042; ARR: 7 per 100 patient years; NNT: 14 patients for 1 year to prevent 1 event).
  • The second pooled analysis of all participants also demonstrated a significant reduction in the primary endpoint with sacubitril/valsartan compared to valsartan (rate ratio: 0.86; 95%CI: 0.75-0.98; P=0.027). Clinical benefits with sacubitril/valsartan appeared rapidly, with first nominal statistical significance on day 9 after randomization.
  • Subgroup analyses by LVEF categories (LVEF ≤60% and LVEF >60%) showed that the benefits of sacubitril/valsartan on the primary endpoint were most prominent in patients with LVEF ≤60% in both pooled analyses.
  • The secondary renal endpoint, which was a composite of time to first ≥50% decline in eGFR from baseline, ESRD, or renal death, was significantly reduced with sacubitril/valsartan compared to valsartan in the secondary pooled analysis (HR 0.60; 95%CI: 0.44-0.83; P=0.002). The HR for the renal composite endpoint in the primary pooled analysis was 0.67 (95%CI: 0.43-1.05; P=0.080).
  • Safety analyses showed that treatment with sacubitril/valsartan led to higher rates of symptomatic hypotension, but lower rates of worsening renal function. There was no difference in hyperkalemia rates between treatment arms.


Pooled analyses of PARAGLIDE-HF and PARAGON-HF show that sacubitril/valsartan, compared to valsartan, reduced cardiovascular and renal outcomes in patients with HFpEF or HFmrEF. The cardiovascular benefits were most prominent in patients with LVEF ≤60%.

“These data strengthen the current evidence base supporting the use of sacubitril/valsartan in patients with heart failure with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting” concluded Muthiah Vaduganathan.

-Our reporting is based on the information provided at the ESC Heart Failure 2023-

The findings of these analyses were simultaneously published in Eur. Heart J.

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