The Food and Drug Administration has expanded the approval of Entresto® (sacubitril/valsartan) in chronic heart failure to include patients with heart failure with reduced ejection fraction (HFrEF), as well as many with heart failure with preserved ejection fraction (HFpEF).
The approval was based on data from the double-blind, parallel-group, active-controlled phase 3 PARAGON-HF trial (ClinicalTrials.gov: NCT01920711) that compared the long-term efficacy and safety of sacubitril/valsartan to valsartan in 4796 patients with left ventricular ejection fraction (LVEF) greater than or equal to 45%, and structural heart disease (either left atrial enlargement or left ventricular hypertrophy). The primary end point was the composite of cardiovascular death and total (first and recurrent) heart failure (HF) hospitalizations.
The trial missed statistical significance for its composite primary end point (rate ratio [RR] 0.87; 95% CI, 0.75-1.01; P =.06), however a greater benefit was observed in certain predefined subgroups. The treatment effect was primarily driven by the reduction in total HF hospitalizations in patients treated with sacubitril/valsartan (RR 0.85; 95% CI, 0.72-1.00).
Subgroup analyses showed a 22% relative reduction (RR 0.78; 95% CI, 0.64-0.95) in patients with an ejection fraction ≤57% (median) and a 27% relative reduction (RR 0.73; 95% CI, 0.59-0.90) in women. Additionally, pooled data from PARAGON-HF and PARADIGM-HF showed that the therapeutic effects of sacubitril/valsartan varied by LVEF, with an increased benefit seen in patients with LVEF <60%. Findings from the study demonstrated a decrease in the magnitude of effect with increasing LVEF, although therapeutic benefits persisted to a higher level of LVEF in women compared with men.
Based on these findings, the updated labeling for Entresto states that the benefits are most clearly evident in patients with LVEF below normal, and since LVEF is a variable measure, clinical judgement should be used when deciding whom to treat.
“This approval is a significant advancement, providing a treatment to many patients who were not eligible for treatment before because their ejection fraction was above the region we normally considered reduced. Until now, treatment for these patients was largely empiric,” said Scott Solomon, MD, Professor of Medicine at Harvard Medical School and Brigham and Women’s Hospital, and PARAGON-HF Executive Committee Co-Chair. “We can now offer a treatment to a wider range of patients who have an LVEF below normal.”
Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. The treatment is also indicated for symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients 1 year of age and older.
- Novartis Entresto® granted expanded indication in chronic heart failure by FDA. [press release]. Basel, Germany: Novartis; February 16, 2021.
- Entresto [prescribing information]. East Hanover, NJ: Novartis; 2021.