Certain subgroups may see a greater reduction in heart failure (HF) hospitalizations and cardiovascular death with the combination of sacubitril and valsartan compared with valsartan alone, according to a new subgroup analysis of the global phase 3 PARAGON-HR study of patients with HF with preserved ejection fraction (HFpEF) or diastolic HF.

These new analyses were presented at the American Heart Association’s (AHA) Scientific Sessions 2019 with simultaneous publication of the gender analysis in Circulation and hospitalization analysis in the Journal of the American College of Cardiology.

The benefit with sacubitril/valsartan (Entresto, Novartis) was seen in women with HFpEF and in patients with HFpEF recently hospitalized for HF. In addition, in a pooled analysis of the PARAGON-HF and PARADIGM-HF, researchers observed a greater treatment benefit in patients with left ventricular ejection fraction below approximately 60%.

Sacubitiril/valsartan is an approved and essential treatment for patients with HFrEF, which is typically defined as ejection fraction less than or equal to 40%. The approval is based on its superiority to the angiotensin-converting enzyme inhibitor enalpril in reducing cardiovascular death and HF hospitalizations through the PARADIGM-HF trial.

The PARADIGM-HF trial showed a 13% relative reduction in the primary composite endpoint of cardiovascular death and total (first and recurrent) HF hospitalizations, but narrowly missed statistical significance. The full results of the phase 3 PARAGON-HF study were presented at ESC Congress 2019.

According to the study authors, the new analyses show that the treatment benefit of sacubitril/valsartan may extend to patients with a left ventricular ejection fraction (LVEF) higher than the threshold used to defined HFrEF. The data will help to provide a greater understanding of the heterogeneous nature of HFpEF and the potential benefit of the sacubitril/valsartan combination for those who are still in need of a treatment option.

Data from 4796 patients with HFpEF from the phase 3 PARAGON-HF and PARADIGM-HF trials, which included 8399 patients with HF along with HFrEF studies, were combined in a pooled analysis to assess cardiovascular death and total HF hospitalization. The analysis evaluated the effect of the sacubitril/valsartan combination compared with reninangiotensin-aldosterone system (RAAS) inhibition among different LVEF categories.

In the analysis of the combined groups, total HF hospitalizations and cardiovascular death were reduced in patients receiving the sacubitril and valsartan combination compared with RAAS inhibition. Cardiovascular death reduction was driven by the results of the patients with LVEF of 40% or less from the PARADIGM-HF trial.

The greatest treatment benefits were observed in patients with LVEF below 60%. Magnitude of reduction in HF hospitalizations, cardiovascular death and all-cause mortality decreased with increasing LVEF. The all-cause mortality reduction was driven by the decrease in patients with HFrEF. Additionally, treatment benefits persisted up to a higher level of LVEF in women compared with men.

The new research suggests that the sacubitril and valsartan combination may provide greater benefit in patients with HFpEF who have recently been hospitalized for HF and suggests the potential benefit of initiating treatment during the vulnerable period following hospitalization in order to reduce further events, according to John McMurray, MD, professor of Medical Cardiology at University of Glasgow and PARAGON-HF Executive Committee co-chair.

"Understanding the correlation between time since hospitalization and treatment benefit may help inform optimization of care for patients with heart failure," he said.

Reference
  1. Novartis PARAGON-HF analyses suggest Entresto® benefit beyond HFrEF [press release]. Novartis Pharmaceuticals Corporation website. Published November 17, 2019. https://www.novartis.com/news/media-releases/novartis-paragon-hf-analyses-suggest-entresto-benefit-beyond-hfref. Accessed November 18, 2019.